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Archive for the ‘Cancer Genomics’ Category

Real Time Coverage Morning Session on Precision Oncology: Advancing Precision Medicine Annual Conference, Philadelphia PA November 2 2024

Reporter: Stephen J. Williams, Ph.D.

9:20-9:50

How Can We Close the Clinical Practice Gaps in Precision Medicine?

Susanne Munksted, Diaceutics

Studies are showing that genetic tests are being ordered at a sufficient rate however it appears there are problems in interpretation and developing treatment plans based on omics testing results

 

  • 30 % of patients in past and now currently half of all patients are not being given the proper treatment based on genomic testing results (ASCO)
  • E.g. only 1.5% with NTRK fusions received a NTRK based therapy (this was > 4000 patients receiving wrong therapy)
  • A lung oncologist may only see one patient with NTRK fusion in three years

 

Precision Medicine Practice Gaps

48% of oncologist surveyed  agreed pathologist needs to be more informed and relevant in the decision making process with regard to tests needing to be ordered

95% said need to flip cost issues ; what does it cost not to get a test … i.e. what is the cost of the wrong therapy

We need a new commercialization model for therapeutic development for this new era of “n of one” patient

9:50-10:15

Implementation of a CLIA-based Reverse Phase Protein Array Assay for Precision Oncology Applications: Proteomics and Phosphoproteomics at the Bedside (CME Eligible)

Emanuel Petricoin, George Mason University

There are some tumor markers approved by FDA that cant just be measured by NGS and are correlated with a pathologic complete response

 

  • Many point mutations will have no actionable drug
  • Many alterations are post-genomic meaning there is a post translational component to many prognostic biomarkers
  • Prevalence of point mutation with no actionable mutation is a limit of NGS
  • It is important to look at phospho protein spectrum as a potential biomarker

 

Reverse phase protein proteomic analysis

  • Made into CLIA based array
  • They trained centers around the US on the technology and analysis
  • Basing proteomics or protein markers by traditional IHC requires much antibody validation so if the mass spectrometry field can catch up it would be very powerful
  • With multiple MRM.MS there is too low abundance of phosphoproteins to allow for good detection

 

They  conducted the I-SPY2 trial for breast cancer and determining if phosphoproteins could be a good biomarker panel

  • They found they could predict a HER2 response better than NGS
  • There were patients who were predicted HER2 negative that actually had an activated HER2 signaling pathway by proteomics so NGS must have had a series of false negatives
  • HER2 co phosphorylation predicts pathologic complete response and predicts therapy by herceptin
  • They found patients classified as HER2 negative by FISH were HER2 positive by proteomics and had HER2 activation

10:15-11:10

Liquid Biopsy MRD to Escalate or De-escalate Therapy (CME Eligible)

Adrian Lee

Adrian Lee, UPMC

Marija Balic, UPMC

Howard McLeod

Howard McLeod, Utah Tech University

Muhammed, Murtaza, University of Wisconsin-Madison

 

11:15-11:25  PRODUCT PRESENTATION  204A

SpaceIQ™ – Powering Next Generation Precision Therapeutics with AI-Driven Spatial Biomarkers

Dusty Majumdar, PredxBio 

Single Cell and Spatial Omics

 

  • Single cell transcriptomics technology have been scaled up very nicely over the past ten years
  • Spatial informatics field is lacking in innovations
  • Can get a terabyte worth of data from analysis of one slide

11:25-11:35  PRODUCT PRESENTATION  204C

10x Genomics

11:40-12:35

Transcriptomics and AI in Transforming Precision Diagnosis

Maher Albitar, Genomic Testing Cooperative

Transciptomica and AI:Transforming Precision diagnosis

-The Genomics Testing Coopererative at www.genomictestingcooperative.com

 

Advantages of transcriptomics

– mutation frequency and allele variant detection now at 80% (higher sensitivity in mutation detection)

 

– transcriptomics has good detection of chromosomal translocations

– great surrogate for IHC and detect splicing alterations

– can use AI to predict % of PDL1 in tumor cells versus immune cells

– they have developed a software UMAP (uniform manifold approximation and projection) to supervise cluster analysis

– the group has used AI to predict prognosis and survival using transcriptomics data

Marija Balic, UPMC

Andrew Pecora, Hackensack University Medical Center 

12:35-1:00

The Impact of Multi-Omics in the Context of the APOLLO-2 Moonshot Program (CME Eligible)

 

 

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Coverage Afternoon Session on Precision Oncology: Advancing Precision Medicine Annual Conference, Philadelphia PA November 1 2024

Reporter: Stephen J. Williams, Ph.D.

Unlocking the Next Quantum Leap in Precision Medicine – A Town Hall Discussion (CME Eligible)

Co-Chairs

Amanda Paulovich, Professor, Aven Foundation Endowed Chair
Fred Hutchinson Cancer Center

Susan Monarezm Deputy Director ARPA-H

Henry Rodriguez, NCI/NIH

Eric Schadt, Pathos

Ezra Cohen, Tempus

Jennifer Leib, Innovation Policy Solutions

Nick Seddon, Optum Genomics

Giselle Sholler, Penn State Hershey Children’s Hospital

Janet Woodcock, formerly FDA

Amanda Paulovich: Frustrated by the variability in cancer therapy results.  Decided to help improve cancer diagnostics

  •  We have plateaued on relying on single gene single protein companion diagnostics
  • She considers that regulatory, economic, and cultural factors are hindering the innovation and resulting in the science way ahead of the clinical aspect of diagnostics
  • Diagnostic research is not as well funded as drug discovery
  • Biomarkers, the foundation for the new personalized medicine, should be at forefront Read the Tipping Point by Malcolm Gladwell
  • FDA is constrained by statutory mandates 

 

Eric Schadt

Pathos

 

  • Multiple companies trying to chase different components of precision medicine strategy including all the one involved in AI
  • He is helping companies creating those mindmaps, knowledge graphs, and create more predictive systems
  • Population screening into population groups will be using high dimensional genomic data to determine risk in various population groups however 60% of genomic data has no reported ancestry
  • He founded Sema4 but many of these companies are losing $$ on these genomic diagnostics
  • So the market is not monetizing properly
  • Barriers to progress: arbitrary evidence thresholds for payers, big variation across health care system, regulatory framework

 

Beat Childhood Cancer Consortium Giselle

 

  • Consortium of university doctors in pediatrics
  • They had a molecular tumor board to look at the omics data
  • Showed example of choroid plexus tumor success with multi precision meds vs std chemo
  • Challenges: understanding differences in genomics test (WES, NGS, transcriptome etc.
  • Precision medicine needs to be incorporated in med education.. Fellowships.. Residency
  • She spends hours with the insurance companies providing more and more evidence to justify reimbursements
  • She says getting that evidence is a challenged;  biomedical information needs to be better CURATED

 

Dr. Ezra Cohen, Tempest

 

  • HPV head and neck cancer, good prognosis, can use cituximab and radiation
  • $2 billion investment at Templest of AI driven algorithm to integrate all omics; used LLM models too

Dr. Janet Woodcock

 

  • Our theoretical problem with precision and personalized medicine is that we are trained to think of the average patient
  • ISPAT II trial a baysian trial; COVID was a platform trial
  • She said there should there be NIH sponsored trials on adaptive biomarker platform trials

This event will be covered by the LPBI Group on Twitter.  Follow on

@Pharma_BI

@StephenJWillia2

@Aviva1950

@AdvancingPM

using the following meeting hashtags

#AdvancingPM #precisionmedicine

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Real Time Coverage Morning Session on Precision Oncology: Advancing Precision Medicine Annual Conference, Philadelphia PA November 1 2024

Reporter: Stephen J. Williams, Ph.D.

Notes from Precision Medicine for Rare Diseases 9:00AM – 10:50

Precision Medicine and markers Cure models vs disease models  Dr Ekker from UT MD Anderson

 

  • UT MD Anderson zebrafish disease model program now focusing more on figuring the mechanisms by which a disease model is reverted to normal upon CRISPR screens
  • Traditional drug development process long and expensive
  • 2nd in class only takes 4 years while 3rd in class drugs take only 1.5 years
  • Health-in-a-fish: using a CRE system to go from disease to normal
  • The theory is making a CRE or CURE avatar; taking a diseased zebrafish and reverse engineering the disease genome
  • He used transposon based CRE mutational mutants with protein trap and 3’ exon trap (transposon based mutagenesis)
  • He reverted the diseased gene by CRE
  • He feels that can scale up to using organoids to develop more cure based models

 

FDA Christine Nguyen MD regulatory perspective of framework of drug approval for rare diseases

  • 1 in 10 Amercians have rare diseases; 70% genetic and half are children
  • Due to Orphan Drug Act in 2023 half of novel drugs approved for rare diseases
  • CDER and FDA 550 unique drugs for over 1000 rare diseases
  • Clinical and surrogate validated endpoints are important for traditional approvals
  • For accelerated approval need predictive surrogate endpoint of clinical benefit
  • For accelerated approval needs completion of a confirmatory trials so FDA has new authority under FDORA; FDA can dictate trial milestones
  • Candidate surrogate endpoints: known to predict (validated) for traditional approval but reasonably likely to predict for accelerated approval
  • Does surrogate endpoint associated with a causal pathway?  Also important to understand the magnitude of benefit so surrogate should be quantitative not just qualitative
  • RDEA is a series of 3 public workshops at FY2027 to promote innovation and novel endpoints and guidance

 

Frank Sasinowski FDA regulatory flexibility beyond One Positive Adequate and Well Controlled Trial

  •  As we move to rare diseases we may only have one well controlled study so FDA feels we need new regulatory frameworks and guidelines especially for rare disease clinical trails especially with precision medicine
  • Accelerated approval does not mean your evidence is any less stringent that traditional approval (only difference is endpoint but quality of evidence the same)

 

  • Confirmatory evidence is a primary concern
  • In 2021 FDA coordinated with the two divisions CBER and CDER
  • Sometimes a primary endpoint shows positive benefit but secondary endpoints may not; FDA now feels that results from one well designed AWC gives confirmatory evidence
  • FDA can be flexible by taking in consideration the quantity and quality of confirmatory evidence and the totality of evidence
  • So pharmacology studies, natural history etc.  can be enough
  • For a drug like Lamzede for mannosidosis there were no positive endpoint studies or for ADA SCID disease there was other compelling evidence
  • The FDA does have flexibility when it comes to advanced precision medicines and ultr rare diseases

10:50 Do we Really Need Liquid Biopsy? A Panel Discussion on the Issues Hampering the full Adoption of Liquid Biopsy

  • In Mexico leading cancer is colorectal but only have the FIT test and noone except one organization who issupplying health access
  • Access to precision medicine is a concern:  the communication between the patient, who is pushing this more than healthcare, needs to be coordinated better with all stakeholders in care
  • We also need to educate many physicians even oncologists (like in Virginia) a better understanding of genetics and omics
  • FT3 consortium does testing to therapy (multistakeholder group comprised of patient advocacy groups); focus on amplifying global efforts to increase access; they are trying to make a roadmap to help access in other countries; when it comes to precision medicine it is usually the nurses that are aksing for training because they are usually the first responders for the patient’s questions
  • In rural areas just getting access to liquid biopsy is a concern and maybe satellite sites might be useful because the time to schedule is getting worse (like 3 or more months)
  •  A recent paper showed that liquid biopsy may actually perpetuate health disparities and not ameliorate them
  • BloodPAC: there are barriers to LB access and adoption so consortium felt that there were many areas that need to be addressed: financial, access, disparities, education
  • ctDNA to define variants was the past focus; there is growing realization that there are representatives populations in your R&D studies
  • Submission of data to BloodPac is easier to do for tissue not for liquid biopsy;  there is lack of harmonization across many of these databanks
  • Reimbursement: is a barrier to access for liquid biopsy
  • Illumina: challenge finding clinical utility for payers; FDA approval is not as hard; show improved outcomes for patients; Medicare is starting to approve some tests but the criteria bar keeps changing with payers; 
  • How do we leverage the on-market data to support performance of your diagnostic test or genomic panel

 

This event will be covered by the LPBI Group on Twitter.  Follow on

@Pharma_BI

@StephenJWillia2

@Aviva1950

@AdvancingPM

using the following meeting hashtags

#AdvancingPM #precisionmedicine

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Real Time Coverage Advancing Precision Medicine Annual Conference, Philadelphia PA November 1,2 2024

Reporter: Stephen J. Williams, Ph.D.

Source: https://www.advancingprecisionmedicine.com/apm-annual-conference-and-exhibition-in-philadelphia/ 

This event will be covered by the LPBI Group on Twitter.  Follow on

@Pharma_BI

@StephenJWillia2

@Aviva1950

@AdvancingPM

using the following meeting hashtags

#AdvancingPM #precisionmedicine

The Advancing Precision Medicine (APM) Annual Conference 2024 will take place at the Pennsylvania Convention Center in Philadelphia,  November 1-2, 2024. Located in the heart of the biopharma ecosystem and with easy access to some of the most renowned academic and research institutions in the world, the APM Annual Conference 2024 will attract all segments of the precision medicine landscape.

The event will consist of two parallel tracks composed of keynote addresses, panel discussions and fireside chats which will encourage audience participation. Over the course of the two-day event leaders from industry, healthcare, regulatory bodies, academia and other pertinent stakeholders will share an intriguing and broad scope of content.

his event will consist of three immersive tracks, each crafted to explore the multifaceted dimensions of precision medicine. Delve into Precision Oncology, where groundbreaking advancements are reshaping the landscape of cancer diagnosis and treatment. Traverse the boundaries of Precision Medicine Outside of Oncology, as we probe into the intricate interplay of genetics, lifestyle, and environment across a spectrum of diseases and conditions including rare disease, cardiology, ophthalmology, and neurodegenerative disease. Immerse yourself in AI for Precision Medicine, where cutting-edge technologies are revolutionizing diagnostics, therapeutics, and patient care. Additionally, explore the emerging frontiers of Spatial Biology and Mult-Omics, where integrated approaches are unraveling the complexities of biological systems with unprecedented depth and precision.

Whether you are a seasoned researcher, a dedicated clinician, or a visionary industry professional, this conference serves as a vibrant hub of knowledge exchange, collaboration, and innovation. Elevate your expertise, expand your network, and chart the course of your career trajectory amidst a community of like-minded individuals.  Join us as we embark on this transformative journey, where the possibilities are as limitless as the potential of precision medicine itself.

Agenda – What’s on when

7:30 – 8:25

Registration and Check-in          Meeting Room 203          Philadelphia Convention Center

8:25 – 8:30

Welcome and Introduction

8:30 – 9:00

Opening Keynote

Advancing Precision Medicine in the Prevention and Treatment of Cardiometabolic Disease (CME Eligible)

Daniel Rader

Daniel Rader, Penn Medicine and Children’s Hospital of Philadelphia

9:00 – 10:20

9:00-10:20

Diagnosis to Treatment – A Case Study in Non Small Cell Lung Cancer

Jason Crites

Moderator: Jason Crites, Assurance Health Data

Miriam Bredella, NYU Lagone Health

Robert Dumanois

Rob Dumanois, Thermo Fisher Scientific

Joe Lennerz

Joe Lennerz, BostonGene

10:20 – 10:50

Networking, Exhibits and Product Presentations

10:25-10:35  PRODUCT PRESENTATION  204C

The Genexus Integrated Sequencer System:
NGS Results in 24 hours for Oncology Genomic Profiling

Jeff Smith,  Thermo Fisher Scientific

10:35-10:45  PRODUCT PRESENTATION  204A

Shifting the Paradigm in Patient Management with MRD Testing: Why Evidence-Generated Performance and Experience is Key

Karen Lin, Natera

10:50 – 12:50

10:50-11:50

Who Needs Liquid Biopsy? Opportunities to Increase Access and Improve Outcomes

Nicole St. Jean, GSK

Phil Febbo,  Veracyte, Inc.

Andrea Ferreira-Gonzalez, Virginia Commonwealth University

Lauren Leiman, BloodPAC

Nicole Sheahan, Global Colon Cancer Association

11:50-12:50

Advancing Digital Pathology and Precision Medicine – Where Are We Now?

Shruti Mathur, Genentech

Luke Benko, Roche Diagnostics

Kimberly GasuadJK Life Sciences

Eric Walk, PathAI

10:50-11:10

Real World Data vs Multi Modal Omics Data for Therapeutic Discovery (CME Eligible)

Adam Resnick, CHOP

11:10-11:30

An Academic Perspective on Rare Disease Target Discovery to Commercial Treatment Development (CME Eligible)

Hakon Hakonarson

Hakon Hakonarson, CHOP

11:30-11:50

NCATS Perspective on Success and Failures of Drug Repurposing for Rare Disease (CME Eligible)

PJ Brooks, NIH

11:50-12:10

Pharma Perspective and Realities (CME Eligible)

Sundeep Dugar, Rarefy Therapeutics

12:10-12:50

A Panel Discussion: Scaling Precision Therapeutic Development for Rare Disease (CME Eligible)

Marni Falk

Marni Falk, CHOP

Stephen Ekker, University of Texas at Austin

Christine Nguyen, FDA

Frank Sasinowski, Hyman, Phelps & McNamara

Adam Resnick, CHOP

Hakon Hakonarson

Hakon Hakonarson, CHOP

Sundeep Dugar, Rarefy Therapeutics

PJ Brooks, NIH

12:50 – 1:50

Lunch & Product Presentations

1:10-1:25  PRODUCT PRESENTATION  204C

The Power of ctDNA Testing in Therapy Selection and Recurrence Monitoring

Taylor Jensen,  LabCorp

1:50 – 3:50

1:50-3:50

Unlocking the Next Quantum Leap in Precision Medicine – A Town Hall Discussion (CME Eligible)

Co-Chairs

Amanda Paulovich

Amanda Paulovich, Fred Hutchinson Cancer Center

Henry Rodriguez

Henry Rodriguez, NCI/NIH

Eric Schadt

Eric Schadt, Pathos

Participants

Ezra Cohen, Tempus

Jennifer Leib, Innovation Policy Solutions

Susan Monarez, ARPA-H

Nick Seddon, Optum Genomics 

Giselle Sholler, Penn State Hershey Children’s Hospital

Janet Woodcock

Janet Woodcock, Former FDA

1:50-2:50

Advancing Precision Medicine in Non-Oncology Therapeutic Areas

Moderator: Mike Montalto, Amgen

Scott Friedman, Mt. Sinai

Sana Syed, University of Virginia

Lei Zhao, Amgen

2:50-3:20

Towards a Precision Neuroimmunology Platform (CME Eligible)

Amit Bar-Or, Penn Medicine

3:20-3:50

3:50 – 4:20

Networking and Exhibits

4:20 – 6:15

4:20-4:45

Advancing Precision Medicine: Polygenic Risk Scores and Beyond (CME Eligible)

Dokyoon Kim, Penn Medicine

4:45-5:30

The Rocky Road to Clinical Trial Diversity (CME Eligible)

Ysabel Duron, The Latino Cancer Institute

Porscha Johnson, PJW Clinical Pharmacy Consulting

Victor LaGroon, Department of Veterans Affairs

5:30-6:15

In the Rising Age of Women’s Health, How Do We Build Diagnostics to Last?

Oriana Papin Zoghbi, AOADx

Sarah Huah, Johnson & Johnson

6:30 – 7:00

Evening Keynote

Reimagining Health Equity in the Era of Precision Medicine (CME Eligible)

Rick Kittles

Rick Kittles, Morehouse School of Medicine

7:00 – 7:45

Cocktail Networking Reception 

November 02, 2024

8:00-8:55

Registration and Check-in          Meeting Room 203          Philadelphia Convention Center

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10th annual World Medical Innovation Forum (WMIF) Monday, Sept. 23–Wednesday, Sept. 25 at the Encore Boston Harbor in Boston

Dr. Aviva Lev-Ari, PhD, RN, Founder

Leaders in Pharmaceutical Business Intelligence Group, LLC, Doing Business As LPBI Group, Newton, MA

will be in attendance

covering this event in REAL TIME for PharmaceuticalIntelligence.com and WMIF organizers

#WMIF2024

@Pharma_BI

@AVIVA1950

CLAIMER: Live coverage in REAL TIME on X.com for 9/23/2024

my two X.com accounts had exceeded tweeting volume capacity and were inactivated to verify if I am a person or a BOT. Account authentication reported SOmething went wrong, try later.

  • 9/23/2024 contacted Customer Services at X.com for reactivated these two accounts

 

For Speaker’s quotes on 9/23/2024 from 4PM EST to end on the day

  • see below on WordPress.com by Date, Time, Session Name and Speaker Name

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UPDATE on reactivation of handles on X.com will be posted, here.

Usage of X.com will resume after Handle reactivation by X.com

 

UPDATED on 9/26/2024

Unmet Needs Panel

https://www.youtube.com/watch?v=e6hk7yavBzk

100+ Mass General Brigham Leading Experts Identify

Top Unmet Needs in Healthcare

Project from Harvard Medical School-affiliated clinicians and scientists in the Mass General Brigham healthcare system stimulates new consideration, urgency regarding

innovation in life sciences, healthcare

Top 10 List Announced at World Medical Innovation Forum

BOSTON, MA September 25, 2024 – Some of the most vexing challenges and transformational opportunities in healthcare are included in a new list, “Top Unmet Needs in Healthcare” released by leading experts at Mass General Brigham. Identified by more than 100 Harvard Medical School faculty at Mass General Brigham, the findings range from the need to expand and accelerate rare disease treatment, to the coming “gray tsunami” of aging patients and the implications for patient care, delivery, and technology. The project, revealed at the 10th annual World Medical Innovation Forum, is meant to stimulate new consideration and urgency regarding solving and advancing these issues for improved patient care.

Views from Leading Clinicians, Researchers, and Practitioners in Academic Medicine

The Top Unmet Needs emerge from structured one-on-one discussions with more than 100 Harvard faculty who practice medicine and conduct research at Mass General Brigham, the largest hospital system-based research enterprise in the U.S., with an annual research budget exceeding $2 billion, and five of the nation’s top hospitals according to US News & World Report.

Through one-on-one discussions with these key opinion leaders from diverse clinical and research fields, and subsequent analyses by internal teams of experts, Mass General Brigham has identified the following top 10 unmet clinical needs:

#1. Preparing for the ‘Gray Tsunami’

The need for better tools and therapies aimed at caring for geriatric populations and maintaining geriatric independence, with a particular focus on expanded hospital-at-home capabilities, and the need to better understand the pathways that lead to chronic and acute disease in geriatric patients to enable better and more proactive treatment.

#2. Defining and Maintaining Brain Health

The need for a model of brain health and neurological care that clearly defines not only what brain health is but also integrates our current understanding of the mechanisms and phases of neuroinflammatory and neurodegenerative diseases; enables better and earlier diagnoses and treatment; and propels the development of therapies that target these mechanisms and phases.

#3. A Paradigm Shift in Cancer Treatment

The need for a new framework for therapeutic development in cancer that is focused on improving curability as opposed to an exclusive focus on the development of drugs for metastatic disease. This

framework also requires effective tools for early-stage cancer detection across the board in all cancers, but especially in lung, ovarian, pancreatic, and GI cancers (esophagus, stomach and colon).

#4. Targeting Fibrosis, a Shared Culprit in Disease

The need for therapeutics that target fibrosis (tissue scarring), which is responsible for a significant percentage of deaths worldwide, representing diseases of the lung, liver, kidney, heart, and skin.

#5. New Approaches for Infectious Disease in a Changing World

The need for novel strategies for the rapid diagnoses, treatment, and even prevention of antibiotic-resistant infections, and the need for the next generation of globally deployable vaccines to enable pandemic preparedness.

#6. Striving for Equity in Healthcare

The need to radically rethink how, when, and where patients interact with healthcare services to optimize healthcare access and efficiency without diminishing its effectiveness, and to proactively meet the needs of currently underserved populations.

#7. Riding the Wave of Clinical Data

The need to expand the scope of available clinical data to include historically understudied populations (including women) and to model and implement a cohesive, dynamic data “stream,” which flows as patients do between the different phases of health and clinical care, enabling comparisons of patients to their previously healthy selves and the development of AI/ML approaches to harness these data to improve diagnosis, prognosis, and treatment.

#8. A Systems-Level View of Human Disease

The need to rethink how we understand and treat disease — not only from an organ-specific standpoint but from a whole-body, systems-level view — and to fully elucidate the roles that inflammation and immune pathways play in autoimmune and infectious diseases and their effects on chronic and acute diseases in diverse human systems, such as the cardiovascular/circulatory and nervous systems.

#9. A New Approach to Psychiatric Disease

The need for novel treatments for psychiatric disease, improved biomarkers and minimally invasive and ambulatory ways of measuring them, and more productive interactions with industry to advance new therapies to the clinic. This includes hybrid therapies (therapies that combine elements such as talk therapy, novel biomarkers, and pharmacological treatments) as well as new diagnostic and treatment modalities, such as psychedelic therapeutics and precision psychiatry.

#10. Charting a Course in Rare Disease Treatment

The need for viable treatments for the 7,000 identified rare diseases, especially the roughly 70% of such diseases that are genetic and the effects of which are first observed in early childhood.

The Unmet Needs list also include the following honorable mentions which rose to significant rankings in the analysis:

  • Driving Innovation in Chronic Disease: Improved Diagnosis, Treatment, and Prevention
  • A New Era of Obesity Medicine
  • A New Generation of Pain Treatments
  • Unlocking Novel Treatments for the Skin

Overarching Themes

Addressing unmet clinical needs involves solving a number of common challenges, including commercialization hurdles, regulatory considerations, and funding. The Mass General Brigham project identified overarching themes to help address these challenges and support innovation across multiple sectors. These include:

  • Taking a systems view of human disease and the practice of system-medicine
  • Developing a global view of infectious disease, including antimicrobial resistance
  • An expansion in high-quality, real-world data that closes gaps in current data (particularly for women and other underserved populations) and ensures that data sets are sufficiently enabling for AI/ML
  • Improving health and healthcare across key populations, including geriatrics and rare genetic disease
  • Addressing major diseases of the brain, including both neurodegenerative and neuropsychiatric conditions; these include Alzheimer’s disease, Parkinson’s disease, ALS, as well as psychiatric and mental health disorders
  • Opening an era of precision medicine across disease areas that includes early diagnosis, treating staged disease, and biomarker discovery and utilization

Panel co-chairs José Florez, Physician-in-Chief and Co-Chair of the MGB Department of Medicine and the Jackson Professor of Clinical Medicine at Harvard Medical School, and Bruce Levy, Physician-In-Chief and Co-Chair of the MGB Department of Medicine and the Parker B. Francis Professor of Medicine at Harvard Medical School, noted how the observations of a broad and representative set of faculty help illuminate the innovation landscape ahead.

“As a leader in patient care and healthcare innovation, our goal is to build on the legacy of research and discovery that has shaped the hospitals of the Mass General Brigham healthcare system for more than a hundred years, and continue to bring breakthroughs forward that can help solve pressing needs,” said Dr. Florez.

Dr. Levy added that “This is a roadmap for the future that can inform discussions happening throughout the healthcare and investment ecosystem regarding the future of medicine.”

More than 2000 decision-makers from healthcare, industry, finance and government attended the World Medical Innovation Forum this week in Boston. A premier global event, the Forum highlights leading innovations in medicine and transformative advancements in patient care.

###

About Mass General Brigham

Mass General Brigham is an integrated academic health care system, uniting great minds to solve the hardest problems in medicine for our communities and the world. Mass General Brigham connects a full continuum of care across a system of academic medical centers, community and specialty hospitals, a health insurance plan, physician networks, community health centers, home care, and long-term care services. Mass General Brigham is a nonprofit organization committed to patient care, research, teaching, and service to the community. In addition, Mass General Brigham is one of the nation’s leading biomedical research organizations with several Harvard Medical School teaching hospitals. For more information, please visit massgeneralbrigham.org.

Contact: Tracy Doyle Mass General Brigham Innovation

(262) 227-5514

Tdoyle5@mgb.org

SOURCE

From: “Doyle, Tracy” <tdoyle5@mgb.org>
Date: Thursday, September 26, 2024 at 10:19 AM
Cc: “Card, Matthew” <matthew.card@bofa.com>
Subject: Unmet Needs in Healthcare — Press Release and link to panel

 

@@@@@@@

Invitation as MEDIA

From: “Doyle, Tracy” <tdoyle5@mgb.org>
Date: Wednesday, August 14, 2024 at 4:04 PM
Cc: “Doyle, Tracy” <tdoyle5@mgb.org>, “Card, Matthew” <matthew.card@bofa.com>
Subject: Media Invite: World Medical Innovation Forum, Sept. 23-25, Boston — Hundreds of clinical experts, industry, investment leaders

 

Media Invite: World Medical Innovation Forum: Monday, Sept. 23—Wednesday, Sept. 25, Boston

At the intersection of innovation and investment in healthcare

Join Us!

Register Now: WMIF24 Media Registration

Mass General Brigham, one of the nation’s leading academic medical centers, is pleased to invite reporters to the 10th annual World Medical Innovation Forum (WMIF) Monday, Sept. 23–Wednesday, Sept. 25 at the Encore Boston Harbor in Boston. The event features expert discussions of scientific and investment trends for some of the hottest areas in healthcare, including

  • GLP-1s,
  • the cancer care revolution,
  • generative AI-enabled care paths,
  • xenotransplant,
  • community health,
  • hospital at home, and
  • therapeutic psychedelics, among many others.

 

The agenda includes nearly 175 executive speakers from healthcare, pharma, venture, start-ups, and the front lines of care, including many of Mass General Brigham’s Harvard Medical School-affiliated researchers and clinicians who this year will host 20+ focused sessions. Bank of America, presenting sponsor of the Forum, will provide additional expert insights on the investment landscape associated with healthcare innovation.

 

Forum highlights include:

 

1:1 and panel interviews with leading CEOs and government officials including:

  • Stéphane Bancel, CEO, Moderna
  • Albert Bourla, PhD, CEO, Pfizer
  • Marc Casper, CEO, Thermo Fisher
  • Deepak Chopra, MD, Founder, The Chopra Foundation
  • Scott Gottlieb, MD, PhD, Former Commissioner, FDA (2017-2019)
  • Maura Healey, Governor, Commonwealth of Massachusetts
  • David Hyman, MD, CMO, Eli Lilly
  • Haim Israel, Head of Global Thematic Investing Research, BofA Global Research
  • Reshma Kewalramani, MD, CEO, Vertex
  • Anne Klibanski, MD, President and CEO, Mass General Brigham
  • Peter Marks, MD, PhD, Director, Center for Biologics Evaluation and Research, FDA
  • Tadaaki Taniguchi, MD, PhD, Chief Medical Officer, Astellas Pharma
  • Christophe Weber, CEO, Takeda
  • Renee Wegrzyn, PhD, Director, ARPA-H

 

Expert panels including:

  • Oncology’s New Paradigm
  • Gene Therapies for Rare Diseases
  • Future of Metabolic Therapies
  • Digital Transformation
  • Biologic Revolution in Radiotherapies
  • Cell Therapies for Autoimmune Diseases
  • Hospital Venture Funds

 

Leading biotech and venture speakers from companies including:

  • Abata Therapeutics
  • Atlas Venture
  • Be Biopharma
  • Everly Health
  • Flagship Pioneering
  • Fractyl Health
  • MindMed
  • Mirador Therapeutics
  • Regor Therapeutics
  • RH Capital
  • Transcend Therapeutics


Exclusive programming:  

  • First Look – 15 rapid-fire presentations on the latest research from leading Mass General Brigham scientists
  • Un-Met Clinical Needs – 100+ key opinion leaders in healthcare weigh in on the top un-met clinical needs in medicine today
  • Emerging Tech Zone – Hands-on exploration of some of the latest digital and AI-based healthcare technologies

 

Our program keeps growing — explore the current Forum agenda and list of speakers.

FORUM AGENDA

SOURCE

https://2024.worldmedicalinnovation.org/agenda/

Monday, September 23, 2024

    • 7:00 AM – 8:30 AM

      Picasso Foyer

    • 7:00 AM – 5:00 PM

      Rotunda

    • 8:00 AM – 10:00 AM

      Picasso Ballroom

      First Look

      First Look: 14 rapid fire presentations

      Moderators

      Giles Boland, MD

      President, Brigham and Women’s Hospital and Brigham and Women’s Physicians Organization;

      Philip H. Cook Distinguished Professor of Radiology, Harvard Medical School

      Marcela del Carmen, MD

      President, Massachusetts General Hospital and Massachusetts General Physicians Organization (MGPO);

      Executive Vice President, Mass General Brigham;

      Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School

      Presenters

      Natalie Artzi, PhD

      Associate Professor of Medicine, Brigham and Women’s Hospital & Harvard Medical School

      Yolonda Colson, MD, PhD

      Chief, Division of Thoracic Surgery, Massachusetts General Hospital;

      Hermes C. Grillo Professor of Surgery, Harvard Medical School

      Nobuhiko Hata, PhD

      Director, Surgical Navigation and Robotics Laboratory, Brigham and Women’s Hospital;

      Professor of Radiology, Harvard Medical School

      John Hanna, MD, PhD

      Associate Professor, Brigham and Women’s Hospital & Harvard Medical School

      Leigh Hochberg, MD, PhD

      Director of Neurotechnology and Neurorecovery, Massachusetts General Hospital;

      Senior Lecturer on Neurology, Harvard Medical School

      Daphne Holt, MD, PhD

      Director of the Resilience and Prevention Program, Massachusetts General Hospital;

      Associate Professor of Psychiatry, Harvard Medical School

      Ole Isacson, MD-PhD

      Founding Director, Neuroregeneration Research Institute, McLean Hospital;

      Professor of Neurology and Neuroscience, Harvard Medical School

      Farouc Jaffer, MD, PhD

      Director, Coronary Intervention, Massachusetts General Hospital;

      Associate Professor of Medicine, Harvard Medical School

      Albert Kim, MD

      Assistant Physician, Mass General Cancer Center;

      Assistant Professor, Harvard Medical School

      Vesela Kovacheva, MD, PhD

      Director of Translational and Clinical Research, Mass General Brigham;

      Assistant Professor of Anesthesia, Harvard Medical School

      Mark Poznansky, MD, PhD

      Director, Vaccine and Immunotherapy Center, Massachusetts General Hospital;

      Steve and Deborah Gorlin MGH Research Scholar;

      Professor of Medicine, Harvard Medical School

      Daniel Solomon, MD

      Matthew H. Liang Distinguished Chair in Arthritis and Population Health, Brigham and Women’s Hospital;

      Professor of Medicine, Harvard Medical School

      Scott Solomon, MD

      Director, Clinical Trials Outcomes Center;

      Edward D. Frohlich Distinguished Chair in Cardiovascular Pathophysiology, Brigham and Women’s Hospital;

      Professor of Medicine, Harvard Medical School

      Guillermo Tearney, MD, PhD

      Principal Investigator, Wellman Center for Photomedicine, Massachusetts General Hospital;

      Remondi Family Endowed MGH Research Institute Chair;

      Professor of Pathology, Harvard Medical School

      Raul Uppot, MD

      Interventional Radiologist, Massachusetts General Hospital;

      Associate Professor, Harvard Medical School

      David Walt, PhD

      Professor of Pathology, Brigham and Women’s Hospital;

      Hansjörg Wyss Professor of Biologically Inspired Engineering, Harvard Medical School

    • 10:00 AM – 10:20 AM

    • 10:20 AM – 10:30 AM

    • 10:30 AM – 10:55 AM

      Fireside

      Fireside Chat

      Moderator

      Keith Flaherty, MD

      Director of Clinical Research, Mass General Cancer Center;

      Professor of Medicine, Harvard Medical School

      Panelist

      Albert Bourla, PhD

      Chairman & CEO, Pfizer

    • 11:00 AM – 11:45 AM

Concurrent Events

  • 11:00 AM – 11:45 AM

    Oncology’s New Paradigm

    Moderators

    Keith Flaherty, MD

    Director of Clinical Research, Mass General Cancer Center;

    Professor of Medicine, Harvard Medical School

    Jason Zemansky, PhD

    SMid-Cap Biotech Analyst, BofA Global Research

    Panelists

    Jonathan Carlson, MD, PhD

    Director of Chemistry, Center for Systems Biology, Massachusetts General Hospital;

    Assistant Professor of Medicine, Harvard Medical School

    Gad Getz, PhD

    Director of Bioinformatics, Krantz Center for Cancer Research and Department of Pathology;

    Paul C. Zamecnik Chair in Cancer Research, Mass General Cancer Center;

    Professor of Pathology, Harvard Medical School

    Russell Jenkins, MD, PhD

    Krantz Family Center for Cancer Research, Massachusetts General Hospital;

    Mass General Cancer Center, Center for Melanoma;

    Assistant Professor of Medicine, Harvard Medical School

    Gregory Simon

    President, Simonovation

    Shannon Stott, PhD

    Associate Investigator, Krantz Family Center for Cancer Research and Mass General Cancer Center;

    d’Arbeloff Research Scholar, Massachusetts General Hospital;

    Associate Investigator, Krantz Family Center for Cancer Research Harvard Medical School

  • 11:00 AM – 11:45 AM

    GLP-1s: How Far Will They Go?

    Moderators

    Tazeen Ahmad

    SMid-Cap Biotech Analyst, BofA Global Research

    Fatima Cody Stanford, MD

    Obesity Medicine Physician Scientist, Massachusetts General Hospital;

    Associate Professor of Medicine and Pediatrics, Harvard Medical School

    Panelists

    Caroline Apovian, MD

    Co-Director, Center for Weight Management and Wellness, Brigham and Women’s Hospital;

    Professor of Medicine, Harvard Medical School

    Vanita Aroda, MD

    Director, Diabetes Clinical Research, Brigham and Women’s Hospital;

    Associate Professor, Harvard Medical School

    Paul LaViolette

    Managing Partner & COO, SV Health Investors

  • 11:00 AM – 11:45 AM

    Generative AI: Breakthrough Research and Limitations

    Moderators

    Adam Landman, MD

    Chief Information Officer & SVP, Digital, Mass General Brigham;

    Associate Professor of Emergency Medicine, Harvard Medical School

    Alec Stranahan, PhD

    SMid-Cap Biotech Analyst, BofA Global Research

    Panelists

    Katherine Andriole, PhD

    Director of Academic Research and Education, Mass General Brigham Data Science Office;

    Associate Professor, Harvard Medical School

    David Blumenthal, MD

    Professor of Practice of Public Health and Health Policy, Harvard TH Chan School of Public Health;

    Research Fellow, Harvard Kennedy School of Government;

    Samuel O. Thier Professor of Medicine, Emeritus, Harvard Medical School

    Faisal Mahmood, PhD

    Associate Professor, Brigham and Women’s Hospital & Harvard Medical School

    William Morris, MD

    Chief Medical Information Officer, Google Cloud

  • 11:00 AM – 11:45 AM

    Gene and Cell Therapy’s Unlimited Potential

    Moderators

    Roger Hajjar, MD

    Director, Gene & Cell Therapy Institute, Mass General Brigham

    Charlie Yang, PhD

    Large/SMid-Cap Biotech and Major Pharma Analyst, BofA Global Research

    Nathan Yozwiak, PhD

    Head of Research, Gene and Cell Therapy Institute, Mass General Brigham

    Panelists

    Samarth Kulkarni, PhD

    CEO, CRISPR Therapeutics

    Peter Marks, MD, PhD

    Director, Center for Biologics Evaluation and Research, FDA

    Marcela Maus, MD, PhD

    Director of Cellular Therapy and Paula O’Keeffe Chair in Cancer Research, Krantz Family Center for Cancer Research and Mass General Cancer Center;

    Associate Director, Gene and Cell Therapy Institute, Mass General Brigham;

    Associate Professor, Harvard Medical School

    Joanne Smith-Farrell, PhD

    CEO & Director, Be Biopharma

  • 11:00 AM – 11:45 AM

    Xenotransplant: Game Changing Organ Replacement

    Moderators

    Jason Gerberry

    Specialty Pharma and SMid-Cap Biotech Analyst, BofA Global Research

    Joren Madsen, MD, PhD

    Director, MGH Transplant Center;

    Paul S. Russell/Warner-Lambert Professor of Surgery, Harvard Medical School

    Panelists

    Tatsuo Kawai, MD, PhD

    Director of the Legorreta Center for Clinical Transplantation Tolerance,

    A.Benedict Cosimi Chair in Transplant Surgery, Massachusetts General Hospital;

    Professor of Surgery, Harvard Medical School

    Richard Pierson III, MD

    Scientific Director, Center for Transplantation Sciences, Massachusetts General Hospital;

    Professor of Surgery, Harvard Medical School

    Leonardo Riella, MD, PhD

    Medical Director of Kidney Transplantation, Massachusetts General Hospital;

    Harold and Ellen Danser Endowed Chair in Transplantation, Harvard Medical School

Concurrent Events

  • 12:00 PM – 12:45 PM

    Future of Cancer Care

    Moderator

    Alec Stranahan, PhD

    SMid-Cap Biotech Analyst, BofA Global Research

    Panelists

    Gerard Doherty, MD

    Surgeon-in-Chief, Mass General Brigham Cancer;

    Surgeon-in-Chief, Brigham and Women’s Hospital;

    Moseley Professor of Surgery, Harvard Medical School

    Daphne Haas-Kogan, MD

    Chief, Enterprise Radiation Oncology, Mass General Brigham;

    Professor, Harvard Medical School

    Benjamin Kann, MD

    Assistant Professor, Brigham and Women’s Hospital & Harvard Medical School

    David Ryan, MD

    Physician-in-Chief, Mass General Brigham Cancer;

    Professor of Medicine, Harvard Medical School

  • 12:00 PM – 12:45 PM

    Generative AI Enabled Care Paths

    Moderators

    Adam Ron

    Health Care Facilities and Managed Care Analyst, BofA Global Research

    Marc Succi, MD

    Executive Director, Mass General Brigham MESH Incubator;

    Associate Chair of Innovation & Commercialization, Mass General Brigham Radiology;

    Assistant Professor, Harvard Medical School

    Panelists

    Christopher Longhurst, MD

    Chief Medical & Digital Officer, UC San Diego Health

    Rebecca Mishuris, MD

    Chief Medical Information Officer, Mass General Brigham;

    Member of the Faculty, Harvard Medical School

    Shiv Rao, MD

    CEO & Founder, Abridge

    Alkesh Shah

    Head of US Equity Software Research, BofA Global Research

  • 12:00 PM – 12:45 PM

    Transforming Care in a Resource Limited Era

    Moderator

    Niyum Gandhi

    CFO & Treasurer, Mass General Brigham

    Panelists

    Fritz François, MD

    Executive Vice President and Vice Dean, Chief of Hospital Operations, NYU Langone Health

    Susan Huang, MD

    EVP, Chief Executive, Providence Clinical Network, Providence Southern CA

    Ron Walls, MD

    Chief Operating Officer, Mass General Brigham;

    Neskey Family Professor of Emergency Medicine, Harvard Medical School

  • 12:00 PM – 12:45 PM

    Cardiovascular Pipeline Renewal

    Moderators

    Jason Gerberry

    Specialty Pharma and SMid-Cap Biotech Analyst, BofA Global Research

    Calum MacRae, MD, PhD

    Vice Chair for Scientific Innovation, Department of Medicine, Brigham and Women’s Hospital;

    Professor of Medicine, Harvard Medical School

    Panelists

    Lotte Bjerre Knudsen, DMSc

    Chief Scientific Advisor, Novo Nordisk

    David Grayzel, MD

    Partner, Atlas Venture

    Christoph Westphal, MD, PhD

    General Partner, Longwood Fund

    Deborah Wexler, MD

    Chief, Diabetes Unit, Massachusetts General Hospital;

    Associate Professor of Medicine, Harvard Medical School

  • 12:45 PM – 1:00 PM

  • 1:00 PM – 1:20 PM

    Picasso Ballroom

    Opening Remarks

    Introducer

    Miceal Chamberlain

    President of Massachusetts, Bank of America

    Opening Remarks

    Maura Healey

    Governor of the Commonwealth of Massachusetts

  • 1:20 PM – 2:00 PM

    Picasso Ballroom

    Healthcare Innovation and Regional Competitiveness

    Panelists

    John Fish

    Chairman & CEO, Suffolk

    Reshma Kewalramani, MD

    CEO & President, Vertex Pharmaceuticals

    Jonathan Kraft

    President, The Kraft Group;

    Board Chair, Massachusetts General Hospital

  • 2:05 PM – 2:30 PM

    Picasso Ballroom

    Fireside

    Fireside Chat

    Moderators

    Tazeen Ahmad

    SMid-Cap Biotech Analyst, BofA Global Research

    Roger Hajjar, MD

    Director, Gene & Cell Therapy Institute, Mass General Brigham

    Panelist

    Reshma Kewalramani, MD

    CEO & President, Vertex Pharmaceuticals

  • 2:35 PM – 3:10 PM

    Picasso Ballroom

    Delivering Care: New Tools, Evolving Challenges, Bold Aspirations

    Moderator

    Andrew Bressler

    Washington Healthcare Policy Analyst, BofA Global Research

    Panelists

    Rod Hochman, MD

    President & CEO, Providence

    Anne Klibanski, MD

    President & CEO, Mass General Brigham;

    Laurie Carrol Guthart Professor of Medicine, Harvard Medical School

    Kevin Mahoney

    CEO, University of Pennsylvania Health System

  • 3:10 PM – 3:35 PM

    Picasso Ballroom

    Fireside

    Fireside Chat

    Moderators

    Caroline Sokol, MD, PhD

    Assistant Physician, Massachusetts General Hospital;

    Assistant Professor, Harvard Medical School

    Charlie Yang, PhD

    Large/SMid-Cap Biotech and Major Pharma Analyst, BofA Global Research

    Panelist

    Mark McKenna

    Chairman & CEO, Mirador Therapeutics

3:40 PM – 4:05 PM

Picasso Ballroom

RECORDING OF SPEAKERS’ QUOTES ON WordPress.com
 
STARTS HERE

Fireside

Fireside Chat

Moderators

Jason Gerberry

Specialty Pharma and SMid-Cap Biotech Analyst, BofA Global Research

Allan Goldstein, MD

Chief of Pediatric Surgery, Massachusetts General Hospital;

Surgeon-in-Chief, Mass General for Children;

Marshall K. Bartlett Professor of Surgery, Harvard Medical School

Panelist

Christophe Weber, President & CEO, Takeda

  • pipeline is very diverse at the R&D center in Boston

Phase III:

  • TAK-279 Psorisis
  • Neurocrine’s Takeda-Partnered Drug Candidate Aces Phase II Depression Study

The Markets for Takeda

  • US market is 40% of revenue, It is a difficult market but still the most important for Phama in the World
  • Japan is 8%
  • Growth by acquisitions and internal development like above, two Phase III drugs

Price control and policies:

  • negotiation
  • price war create tension

Team:

Public company traded in NYSE

  • Management team has 10 nationalities – Global company
  • AI is adopted as a digital companion

Recruiting Patients for Clinical Trial:

  • Very difficult

M&A

  • After acquisition of Shire – not many other opportunities are left

4:05 PM – 4:40 PM

Picasso Ballroom

The Innovation Gap: A Review of the Future of Viral Vector Manufacturing and the Delivery of Genetic Medicines

Moderators

Elizabeth Henske, MD, Director, Center for LAM Research and Clinical Care, Brigham and Women’s Hospital; Professor of Medicine, Harvard Medical School

Alec Stranahan, PhD, SMid-Cap Biotech Analyst, BofA Global Research

Panelists

Peter Anastasiou, CEO, Capsida Biotherapeutics

  • Capsid technology for Liver disease, Parkinson’s
  • AV and CNS crossing BBB
  • One capsid for one disease
  • manufacture caspids
  • Challenges:  manufacturable after screening
  • IV delivery – brain disorder, blood flow would bring therapeutics to all brain tissue consistently vs localized
  • Partnership with Eli Lilly and with Crisper technologies with Abbvie

Steve Favaloro, Chairman & CEO, Genezen

  • 200 persons Team manufacture
  • Partnerships: synthetic plasma

Alexandria Forbes, PhD, CEO, MeiraGTx

  • Optimize promoters, control transcription expression by injection or by pill, control translation
  • improving potency of gene therapies capsule technology
  • cost hundred of $ not thousand of $
  • ALL manufacturing in house
  • 9 years of data can help to narrow down the parameters
  • time frame is shortened
  • company established 9 years ago
  • apply DNA expression – invented a technology
  • splicing control mRNA
  • control cell lines
  • give an injection or a pill and control antibodies, glucagon
  • control dosing for efficatious therapeutics
  • Potency
  • Ribozon is a delivery system
  • Partnership with J&J –

Fraser Wright, PhD, Chief Gene Therapy Officer, Kriya Therapeutics

  • manufacturing – changing in capsule design
  • manufacture viruses
  • cost of manufacturing – efficiency matters a lot
  • delivery of the gene in the tissue
  • Partnerships: basic vs applied Quality from research to manufacturing

4:45 PM – 5:20 PM

Picasso Ballroom

A Deep Dive on Genetic Modalities for Rare Disease: Genetic Medicines Are Here

Moderator

Tazeen Ahmad, SMid-Cap Biotech Analyst, BofA Global Research

  • Treat once or repeat therapy?

Patricia Musolino, MD, PhD, MGH

 

Panelists

Faraz Ali, Tenaya Therpeutics

  • genetic therapy for a genetic mutation – NOVEL approach
  • 400 mutation related to cardiomyopathy
  • 2018 – gene therapy was an innovation
  • genetic medicine Cardiology introducing opportunities wiht validation that did not exist
  • find novel targets Partnerships are a must to have
  • Viral therapies vs gene therapy

Lucas Harrington, PhD, Co-Founder & CSO, Mammoth Biosciences

  • How to turm Genome 2012 to therapy?
  • targeting: Taking risk Patient interaction with treatment
  • variation between Rare diseases some are very small some are not small – incentive to investors
  • The field will grow fast

Raju Prasad, PhD, Chief Financial Officer, CRISPR Therapeutics

  • various indications
  • FDA Approval
  • Gene editing technology for rare diseases
  • LPA for RNA therapy
  • incentive to investors
  • Important for investor to understand the siize of the market, CRISPR can be a technology for a large market size
  • Sickle cell disease – market is large and therapy can be made affordable

 

Sandi See Tai, MD, Chief Development Officer, Lexeo Therapeutics

  • cardiomyopathy
  • protective gene
  • Early genetic testing
  • Educating patients

5:20 PM – 6:30 PM

Picasso Terrace and Harborside Lawns 1 & 2

Tuesday, September 24, 2024

8:00 AM – 8:55 AM

Picasso Ballroom

The Transforming World

Introducer

Liz Everett Krisberg, Head of Bank of America Institute

  • Record attendance this year
  • Introduction to Haim

Panelist

Haim Israel

Head of Global Thematic Investing Research, BofA Global Research

  • Concept of the Future and for the Future: Short-term and long-term
  • Humanity achievements in Ten Year: Data, Processing power and BRAIN – Long-term becomes Short-term – Last 10 years: 2012, 2014 solar system, 2015 medicine, 2019 blackhole, 2023 core of sun – star was created hotter than core sun
  • 2022, 2024 – galaxy picture of the universe
  • Volume of data created every month in terrabyts every 18 month data is duplicating itself.
  • Olny 1% is used – imagine 2% or 3%
  • Processing power since Apollo 11 [one trillion] – getting cheaper – cost for calculation went down 16,000 fold since 1995
  • AMMOUNT of DATA goes up and Cost of COMPUTATION goes down – price per giga byte
  • Projections for the next 100 years
  • Negative for people and Negative for Companies who are concerned with quarterly financial data
  • Companies: Walmart, Alphabet, Home Depot – DATA larger that COuntries
  • Living in defining moment: started by iPhone revolution and 2023 by AI revolution – 6x outpaced Moore’s Law by GPT by 3000x
  • 18 months into AI revolution – GPT in use
  • The next 10 years:
  1. Aging population
  2. 2024 – birth rate low in US, Japan, CHina, S. Korea – Pension system will decline in size
  3. 2.2 millions new material were created by DeepMind at Alphabet by simulation of AI on molecule
  4. Microsoft in 80 hours identified 18 materials winners for Batteries using AI from 32 million material candidates
  5. AI- weather calculations in minutes 1,000x faster, cheaper and more accurate
  6. 2025 – GPT-6 AI surpass Human Brain
  7. China is a big player in AI
  8. Cyber CRIME is the 3rd largest economy in the World. Hackers are using ChatGPT to create fake pictures leading to ZERO privacy
  • PRIVACY: Deepfakes up 62x, social media
  • 2024 – Global Grid – needs much more energy because AI consumes so much energy
  • Metals shortages: Nickel, Copper,
  • Scarcity of water for 2/3 of the planet
  • data centers consume water more than Japan
  • 2025 – Genomics Data sequencing bigger that X.com or Youtube
  • 2027 – Peak oil demand: needed to be scalable, cheaper 25%
  • 2028 – 5G networks reaches full capacity, 6G will be needed
  • 2029 – 25x more satellites in Orbit than today
  • 2029 – Personalized AI medicines and treatments will manipulate death and revive LONGEVITY – AI will generate drugs and all treatments
  • 2030Generative AI:  re-skill 1 Billion people
  • 2035 – Fusion energy, known technology since the atomic bomb, how to keep it stable in plasma state of material – not yet achieved, it is clean, cheap: to Power the World – equivalent of 11 barrels of oil
  • Large cities: Cable diameter 17cm wide to power a large city
  • AI will change scarcity into abundance
  • 2037 – Artifitial SUPER Intelligence – AI to outsmart Life
  • Quantum computer – Consortium of NASA and other governmental agencies and Google on quantum computer design
  • 2024 the most interesting year in human history

 

Concurrent Events

  • 9:00 AM – 9:45 AM

    Current and Future States of Immunology

    Moderators

    Caroline Sokol, MD, PhD, Assistant Physician, Massachusetts General Hospital;, Assistant Professor, Harvard Medical School

    Alec Stranahan, PhD, SMid-Cap Biotech Analyst, BofA Global Research

    Panelists

    Dong Feng Chen, MD, PhD, Associate Scientist, Massachusetts Eye and Ear;, Associate Professor, Harvard Medical School

    Steven Grinspoon, MD, Chief, Metabolism Unit, Massachusetts General Hospital; Professor of Medicine, Harvard Medical School

    Alexandra-Chloé Villani, PhD, Investigator, Massachusetts General Hospital; Assistant Professor, Harvard Medical School

  • 9:00 AM – 9:45 AM

    Therapeutic Psychedelics – Opportunities and Impact

    Moderators

    Maurizio Fava, MD

    Chair, Department of Psychiatry, Massachusetts General Hospital;

    Slater Family Professor of Psychiatry, Harvard Medical School

    Jason Gerberry

    Specialty Pharma and SMid-Cap Biotech Analyst, BofA Global Research

    Kerry Ressler, MD, PhD

    Chief Scientific Officer, McLean Hospital;

    Professor of Psychiatry, Harvard Medical School

    Panelists

    Cristina Cusin, MD

    Director, MGH Ketamine Clinic and Psychiatrist, Depression Clinical and Research Program, Massachusetts General Hospital;

    Associate Professor in Psychiatry, Harvard Medical School

    Daniel Karlin, MD

    Chief Medical Officer, MindMed

    John Krystal, MD

    Chair, Department of Psychiatry, Yale School of Medicine

    Jennifer Warner-Schmidt, PhD

    Vice President, Scientific Affairs, Transcend Therapeutics

  • 9:00 AM – 9:45 AM

    Innovations Advancing Community Health Equity

    Moderators

    Allen Lutz

    Health Care Services Analyst, BofA Global Research

    Elsie Taveras, MD

    Chief Community Health & Health Equity Officer, Mass General Brigham;

    Conrad Taff Endowed Chair and Professor of Pediatrics, Harvard Medical School

    Panelists

    Rebecca Mishuris, MD

    Chief Medical Information Officer, Mass General Brigham;

    Member of the Faculty, Harvard Medical School

    Claire-Cecile Pierre, MD

    Vice President, Community Health Programs, Mass General Brigham;

    Instructor in Medicine, Harvard Medical School

    Jorge Rodriguez, MD

    Clinician-investigator, Brigham and Women’s Hospital;

    Assistant Professor, Harvard Medical School

    Prabhjot Singh, MD, PhD

    Senior Advisor, Strategic Initiatives Peterson Health Technology Institute

  • 9:00 AM – 9:45 AM

    Earliest Detection

    Moderators

    James Brink, MD

    Enterprise Chief, Radiology, Mass General Brigham;

    Juan M. Taveras Professor of Radiology, Harvard Medical School

    David Louis, MD

    Enterprise Chief, Pathology, Mass General Brigham

    Benjamin Castleman Professor of Pathology, Harvard Medical School

    Jason Zemansky, PhD

    SMid-Cap Biotech Analyst, BofA Global Research

    Panelists

    Jasmeer Chhatwal, MD, PhD

    Associate Neurologist, Massachusetts General Hospital;

    Associate Professor of Neurology, Harvard Medical School

    Pradeep Natarajan, MD

    Director of Preventive Cardiology, Paul & Phyllis Fireman Endowed Chair in Vascular Medicine, Massachusetts General Hospital;

    Associate Professor of Medicine, Harvard Medical School

    Yakeel Quiroz, PhD

    Director, Familial Dementia Neuroimaging Lab and Director, Multicultural Alzheimer’s Prevention Program, Massachusetts General Hospital;

    Paul B. and Sandra M. Edgerley MGH Research Scholar;

    Associate Professor, Harvard Medical School

    Heidi Rehm, PhD

    Chief Genomics Officer, Massachusetts General Hospital;

    Professor of Pathology, Harvard Medical School

  • 9:00 AM – 9:45 AM

    Women’s Health Technology Revolution

    Moderators

    Tazeen Ahmad

    SMid-Cap Biotech Analyst, BofA Global Research

    Hadine Joffe, MD

    Executive Director of the Connors Center for Women’s Health and Gender Biology;

    Interim Chair, Department of Psychiatry, Brigham and Women’s Hospital;

    Paula A. Johnson Professor of Psychiatry in the Field of Women’s Health, Harvard Medical School

    Panelists

    Keith Isaacson, MD

    Director of Minimally Invasive Gynecologic Surgery and Infertility, Newton Wellesley Hospital;

    Associate Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School

    Nawal Nour, MD

    Chair, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital;

    Associate Professor, Kate Macy Ladd Professorship, Harvard Medical School

    Kaveeta Vasisht, MD, PharmD

    Associate Commissioner, Women’s Health, U.S. Food and Drug Administration

    Alice Zheng, MD

    Principal, RH Capital

9:50 AM – 10:15 AM

Picasso Ballroom

Fireside

Fireside Chat

Moderator

David Brown, MD, President, Academic Medical Centers, Mass General Brigham; Mass General Trustees Professor of Emergency Medicine, Harvard Medical School

  • Hoe do you balance Private medicine with Public not for profit HealthCare
  • Healthcare delivery system can achieve that much in Human health
  • Resources for Equity: housing and services: Capacity and COst
  • Evolution of care close to home catalyst of the Pandemic – How government think about the right patient for the right care level
  • MGB 40-60 In-patients at Home – Largest Program in the State  – product needs to scale across all population though some do not have food security at home

Panelist

Kate Walsh, Secretary of Health and Human Services, State of Massachusetts

  • Stuart Bankrupcy – pstioents and providers involvement – structure challenges
  • Race and ethnicity – disparities, access and equity
  • Identify the challenge for Race and ethnicity
  • Focus to identify resources
  • Medicare & Medicaid – Human needs equity involve housing, food and home care – Public and Private sector cooperation
  • Pay for Performance
  • MA vs NYC – resources for welcoming new populations to the State of MA
  • Help finding Housing vs Shelter people
  • MA is the only State in the Union that is a Shelter State
  • People in our COuntry LEGALLY are in and out of shelters, new arrivals of skilled labor – temporary assistance to get jobs that we can’t find people to fill: CNA as example
  • MA has a community of shelters and medical center in the communities
  • Services for people that are at risk due to past life in home countries
  • Support for kids that do not speak English
  • Care and location: Keep care at home or SNF at home or in the community
  • Low income person at Home Hospital vs at MGB ?
  • Autist kids becoming Adult – how to care for ?

 

10:15 AM – 10:40 AM

Picasso Ballroom

Fireside

Fireside Chat

Moderators

Alec Stranahan, PhD, SMid-Cap Biotech Analyst, BofA Global Research

Teresa Gomez-Isla, MD, PhD, MGH, Neurology, Memory division

  • Altzheimer’s biomarkers
  • Clinical trials lessons on drug benefits

Panelist

David Hyman, MD, Chief Medical Officer, Eli Lilly and Company

  • Cardio-metabolic – medicines redefining disease by medicines benefit to patients
  • Investment in manufacturing medicines for Obesity, demand continue to expand
  • Oral small molecule and scaling focus on Sleep apnea, half of the population have metabolic disease and heart failure
  • Extension Program with sustained weigh loss in pre-diabetes progressing into maintained weigh loss
  • Invest in R&D in the cardio-metabolic
  • Listed to community feedback on experience how the drugs in AD affected patients in the Community – learning about challenges in delivery innovation in AD – irreversible neurodegenerative diseases – prevent not to loose the patients entirely – brain function
  • Targeted therapies, genetic therapies
  • Past life Oncologist – delivered innovations into Cancer patients – genetic medicines
  • AD medicines are not accessible even to people of means, Drug delivery using PET spinal injections
  • Ten years horizons at Eli Lilly is common
  • Obligation to provide scientific evidence from clinical trials
  • Inventory of patients qualification to participate in Clinical trials
  • Oncology: Interactions in biologics, cell therapies, conjucate compounds
  • Renewal of Targeting antigens
  • In Oncology: Proportions of patients get long term disease control by molecules developed in Academic Centers.
  • Eli Lilly acquired a BioPharma with manufacturing capabilities
  • Innovations are core vs discount cash-flow, strategy is to look at the science due to capacity to develop innovations

10:40 AM – 11:20 AM

Picasso Ballroom

Disruptors

The Disruptors: Metabolic Power…Need It…Want it

Moderator

Alec Stranahan, PhD, SMid-Cap Biotech Analyst, BofA Global Research

Caroline Apovian, MD, MGH, HMS

  • Last ten years, from metabolic lessons of Bariatric patients
  • Treat obesity before surgery
  • product composition
  • multidisciplinary approach to obesity needs to be like in Oncology – multiple dsciplines
  • Bariatric and weigh regain like stent stenosis after surgery
  • Obesity dysfunction inflammation Gut-Brain transfer of hormones from the gut do not reach the brain to carb hunger socieaty is not signaled in the Brain and eating continued to mitigate hunger
  • Insurance must cover
  • Obesity Medicine – training 25 new practitioners to treat Obesity – Standards of Care, life style change
  • Primary care providers do not have resources to treat Life style component of
  • To reduce mortality by 20% by Bariatric surgery – No reduce of mortality by stenting – THAT I DISAGREE with

 

Panelists

David Hyman, MD, Chief Medical Officer, Eli Lilly and Company

  • non-peptide agonist, bariatric level for obesity
  • peptide injecting device
  • hormones and peptids activan inhibitor
  • hundred of million of people – scaling up
  • Adolescence with obesity will develop CVD, NASH
  • Epidemic of obesity the medicines are combating the epidemic
  • Vials, differential pricing, orals vs injectables
  • Productivity of work force, coverage by employers health insurance vs Government to handle coverage
  • 10 additional drug

Xiayang Qiu, PhD, CEO, Regor Therapeutics

  • six years ago, great opportunity peptide and biologics for lifetime disease of obesity
  • cardiovascular favorably = affected by reduction in weigh
  • Medicines that works start early at age 35

Harith Rajagopalan, MD, PhD, CEO & Co-Founder, Fractyl Health

  • Diet & Life Style
  • Eli Lilly and Novo Nordik – have great drugs
  • Patients stop using them before they see the benefit
  • durable long term of mentainance long-tern to stay on the drug
  • Past life coronary cardiologist: PCI vs surgery choice of care angioplasty vs open heart surgery
  • Bariatric surgery vs great medicines
  • may be angioplasty for Bariatric patients
  • Obesity is different than CVD
  • BC-BS coverage of obesity drugs because weight is gained back vs Statins – continual use control cholestrol
  • maintenance drugs in the field of Obesity are needed
  • cost of drugs will come down
  • more evidence on obesity drugs will affect Formulary

 

11:20 AM – 12:00 PM

Picasso Ballroom

The Innovation Gap: The Broader Impact of Metabolic Drugs on Related Diseases

Moderator

Jason Zemansky, PhD, SMid-Cap Biotech Analyst, BofA Global Research

Patrick Ellinor, MD, PhD, MGH, HMS

Panelists

Craig Basson, MD, PhD, Chief Medical Officer, Bitterroot Bio

  • 17,000 patients obese no DM
  • prior CVD followed 3 yrs of treatment 6% mortality during the Trial
  • Death from CVD endpoint
  • weight at joining the trial, loss during the trial, benefir from the drug’
  • improve CVD not weigh loss
  • mechanism of Inflammation – drug, reduced atherosclerosis and reduced plaque and cytokins and inflammation improve CVD status
  • combination of life style and drugs GI axis systemic
  • cardiac artery disease: cholesterol, inhibit inflammatory signals plaque build on top of itself – approaches to remove debris macrophages in the plaque for artherosclerosis mechanism as CVD risk

Joshua Cohen, Co-CEO, Amylyx Pharmaceuticals

  • Bariatric surgery lower obesity
  • genetics, eating habits,
  • GLP-1 agonist developed

Punit Dhillon, CEO, Skye Bioscience

  • Phase II study combination therapy CVD and Obesity
  • optimize body composition – more productive on the body periphery
  • subtypes metabolic gains
  • Pharmacotherapy for obesity: mechanisms complementary life style change is a must have for long-term benefits
  • weight loss as a start before obesity treatment
  • co-morbidities of obesity

Justin Klee, Co-CEO, Amylyx Pharmaceuticals

  • Parkinson’s CNS peripheral Brain access therapies
  • revolution in metabolic disease treatment options, more studies for pathways to target the right patients for the right treatment
  • GLP-1 is energy regulator, Hypoglycemia is very dangerous

Rohan Palekar, CEO, 89bio

  • applications to obesity – data support
  • bariatric surgery intervention is not enough, NASH will not be impacted only by the surgery
  • NASH is a disease taking 25 years to develop
  • risk of fibrosis to set in Cirrhosis which is not curable

 

Concurrent Events

  • 12:15 PM – 1:00 PM

    ARPA-H: Opening New Frontiers in Health Innovations

    Panel of 5

    Glioblastoma Treatment Reinvented

    Moderators

    E. Antonio Chiocca, MD, PhD

    Chair, Department of Neurosurgery, Brigham and Women’s Hospital;

    Harvey W. Cushing Professor of Neurosurgery, Harvard Medical School

    Charlie Yang, PhD

    Large/SMid-Cap Biotech and Major Pharma Analyst, BofA Global Research

    Panelists

    Natalie Artzi, PhD

    Associate Professor of Medicine, Brigham and Women’s Hospital & Harvard Medical School

    Bryan Choi, MD, PhD

    Associate Director, Center for Brain Tumor Immunology and Immunotherapy, Massachusetts General Hospital;

    Assistant Professor of Neurosurgery, Harvard Medical School

    Alexandra Golby, MD

    Neurosurgeon;

    Director of Image-guided Neurosurgery, Brigham and Women’s Hospital;

    Professor of Neurosurgery, Professor of Radiology, Harvard Medical School

  • 12:15 PM – 1:00 PM

    Healthcare Corporate Venture

    Moderator

    Roger Kitterman

    Senior Vice President, Ventures and Business Development & Licensing, Mass General Brigham

    Managing Partner, Mass General Brigham Ventures

    Panelists

    Rahul Ballal, PhD

    CEO, Mediar Therapeutics

    Tim Luker, PhD

    VP, Ventures & West Coast Head, Eli Lilly

    James Mawson

    CEO, Global Corporate Venturing

  • 12:15 PM – 1:00 PM

    Inflammation Pathways

    Moderators

    Tazeen Ahmad

    SMid-Cap Biotech Analyst, BofA Global Research

    Katherine Liao, MD

    Associate Physician, Department of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital;

    Associate Professor of Medicine and Biomedical Informatics, Harvard Medical School

    Panelists

    Jessica Allegretti, MD

    Director, Crohn’s and Colitis Center, Brigham and Women’s Hospital;

    Associate Professor of Medicine, Harvard Medical School

    Andrew Luster, MD, PhD

    Chief, Division of Rheumatology, Allergy and Immunology;

    Director, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital;

    Persis, Cyrus and Marlow B. Harrison Professor of Medicine, Harvard Medical School

    Thorsten Mempel, MD, PhD

    Associate Director, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital;

    Professor of Medicine, Harvard Medical School

  • 12:15 PM – 1:00 PM

    Hospital at Home

    Moderators

    Joanna Gajuk

    Health Care Facilities and Managed Care Analyst, BofA Global Research

    Heather O’Sullivan, MS, RN, AGNP

    President, Mass General Brigham Healthcare at Home

    Panelists

    O’Neil Britton, MD

    Chief Integration Officer & Executive Vice President, Mass General Brigham

    Jatin Dave, MD

    Chief Medical Officer, MassHealth;

    Director of Clinical Affairs, UMass Chan Medical School

    Chemu Lang’at

    Chief Operating Officer, Best Buy Health

1:05 PM – 1:45 PM

Picasso Ballroom

Pioneering Digital Transformation

Moderator

Liz Kwo, MD, Chief Commercial Officer, Everly Health

  • Infrastructure
  • AI used for

Panelists

Anna Åsberg, Vice President, AstraZeneca Pharmaceuticals

  • Massive data bases organize
  •  AI to augment intelligence inside the data

Tyler Bryson, Corporate Vice President, US Health & Public Sector Industries, Microsoft Corporation

  • Do we have platforms to serve new problem
  • Regulatory changes require visiting use cases
  • Pharma has the research data, providers have EMR – Microsoft builds new models using that data
  • Tumor imaging data was processed and new pattern recognition done on data of these tumors. New patterns are now a subject for research, just identified inside the data
  • Trust in Healthcare
  • NYC and Microsoft developed a System for small businesses to access city resources
  • Works with Academic institutions: Programs at Harvard and Princeton to train students by Microsoft employees on MIcrosoft AI technologies that as they graduate there will be trained new AI-trained employees
  • collaborations

Aditya Bhasin, BofA

  • AI in Banking: Bias, security
  • AI virtual system analytics to provide insight for scaling

Jane Moran, MGH

  • Network, Data structure needs updates
  • technology to help clinicians
  • care team to work with Generative AI to assist in e-mail reading and problem solving
  • Healthcare equity – avoid Bias
  • AI is not an answer to every problem
  • innovate at scale: using Epic and Microsoft
  • Clinical data structure for LLM, AI to renovate administrative processes inside MGH
  • Data structure for transperancy
  • Digital Rounds like Medical ROunds audit problems
  • equity in data

1:45 PM – 2:25 PM

Picasso Ballroom

Capital Formation: Putting Money to Work – State of Affairs in Capital Markets

Moderators

John Bishai, PhD, BofA

  • valuations went down

Brendan Singleton, Healthcare Equity Capital Markets, BofA Securities

  • what impact Capital flow

Emma Somers-Roy, Chief Investment Officer, Mass General Brigham

Panelists

Chris Garabedian, Chairman & CEO, Xontogeny; Venture Portfolio Manager, Perceptive Advisors

  • Valuations done with comparables for IPO
  • Not quick to invest in companies, responsible behavior
  • Private rounds, Biotech and Pharma strategic partners
  • M&A stable requires are exciting valuation
  • foundations, institutional investors – level of interest is related to valuations number of years to exit
  • Peak sale, Public markets different than Private markets
  • Obesity is a crowd space, diferentiation is important
  • Exit tow ways: year for IPO natural acquirer – Who is he??
  • Cancer was a dominant now CNS, Cardio-metabolic, ophthalmology
  • size of market – Cancer was attractive, less in 2024
  • Early venture investor: 50-100MM valuation to 2Bil
  • CMS has discounting since profits are been realize at present time
  • Patents`
  • Presidential election
  • investors scarce pushed fewer mega rounds 100MM financing requires early clinical data
  • Hedge fund very conservative with valuations
  • Downsize in Biotech is over

Arjun Goyal, MD, Vida Ventures

  • Investment in private markets
  • 2019-2021 – IPOs on narratives and proof of concept, only only, no financials
  • M&A or Partnering – financial risk clinical data point
  • validation of team success
  • size of market is very important
  • Innovation matters always in Pharma, prospects for Biotech very bright
  • what is HOT in a moment
  • combination therapies
  • Life cycle: compound right gene, financing history, fundamentals
  • calibration of market valuations

 

2:25 PM – 2:50 PM

Picasso Ballroom

Fireside

Lessons Learned Shaping New Horizons: Visionary Change Agent Perspectives

Moderator

Yvonne Hao, Secretary of Economic Development, Commonwealth of Massachusetts

  • accelerate AI adoption by nurses, How do you do that??
  • Public private partnerships
  • If you have a blank slate – do it differently

Great impact of Cleveland Clinic

Panelists

Delos “Toby” Cosgrove, MD, Executive Advisor; former CEO & President, Cleveland Clinic

  • Housing, education, research beyond healthcare
  • Reduce cost in healthcare, call centers by AI: equipment to measure BP every 4 hours
  • Technology is approved 13 years to become standard of care
  • COST in healthcare requires SALVATION
  • mistakes by leadership
  • Regulators have their share in current situation of Healthcare
  •  Leadership in Health care must change

Marc Harrison, MD, Co-founder & CEO, Health Assurance Transformation Corp. (HATCo)

  • collaborate with competitors
  • AI is a tool not a solution
  • Streamline processes to reduce costs
  • Government should not solve the Healthcare problem
  • Residents are victims of leaders mistakes
  • Only healthcare industry sees the medical records of all the population
  • gene therapy, innovations to change healthcare and get financial solvency

2:50 PM – 3:15 PM

Picasso Ballroom

Fireside

Fireside Chat

Moderators

Andrew Bressler, Washington Healthcare Policy Analyst, BofA Global Research

  • What is coming up in the next two years
  • Are you growing and Hiring?

Yvonne Hao, Secretary of Economic Development, Commonwealth of Massachusetts

  • AI – what is the potential for Healthcare
  • MA to work with ARPA-H

Panelist

Renee Wegrzyn, PhD, Director, Advanced Research Projects Agency for Health – A Federal Governmental Agency

  • ARPA-H Model was introduce under the Advanced Research Projects Agency for Health
  • Hired 21 Program Managers to manage Health initiatives in research
  • Health is not a partizan affair
  • Bring young innovators, mantored by experiences healthcare professionals
  • cellular therapeutics is an example selected to advanced the field
  • Data driven – looking at +100 project approved by government agency
  • Governtment, Academia, Private sector – SOLICITATIONS for solving a research problem
  • Technical merit in judging applications
  • Value-baced pricing – data to influence policy FDA, NIH collaboration
  • FDA to finance projects spending
  • Pediatrics
  • President announced a program for ARPA-H to work on
  • Investors are welcome to review proof of concepts of ARPA-H
  • Return on Investment for all Americans’ Tax payers money
  • Yes, growing and hiring. $1.5 milion budget

 

 

3:15 PM – 3:20 PM

First Look

3:20 PM – 3:35 PM

Selector of Winner: Doug Marshall & Paul Anderson, MD, PhD

 

3:35 PM – 4:15 PM

Picasso Ballroom

Disruptors

The Disruptors: The Biologic Revolution in Radiotherapies

Moderator

John Bishai, PhD, Global Healthcare Investment Banking, BofA Securities

Umar Mahmood, MD, PhD, MGH, HMS

Panelists

Amos Hedt, Chief Business Strategy Officer, Perspective Therapeutics

  • imaging used to deliver the therapeutics before the drug touch the patient to calculate toxicity
  • PL-1 combined with radiotherapy synergistics results
  • immunogenic combination therapy, in presence of these agents, immune response reaction in the immune cells

Matthew Roden, PhD, President & CEO, Aktis Oncology

  • Conjugates – delivery direct to tumors
  • Opportunity two targets: (1) SSTA2 marker (2) xx
  • WHen agent inside the tumor, shrinkage and no emergence of cell nascent 
  •  optimization design
  • Treatment break for patients and families

Philip Kantoff, MD, Co-Founder & CEO, Convergent Therapeutics

  • Radio-pharmeceutics : 10 days half-life carrier not a target for small molecules Data on 120 patient, namo robust response synergy of antibody and molecule
  • image alphas
  • durable responses

Matt Vincent, PhD, AdvanCell Isotopes

  • ROS species generated in the tumor
  • peptides, protein binders
  • paradigm shift in delivery of oncology therapeutics directly to tumors

Lena Janes, PhD, Abdera Therapeutics

  • isotope will deliver the payload without damaging the DNA and healthy tissue
  • target different types of tumors, different half-life
  • Radiation therapy using isotopes id one of two modalities: tumor in and tumor out approach
  • screen for patient for the translational therapy
  • Next generation of products will come, now it is the beginning of these agents

4:20 PM – 4:45 PM

Picasso Ballroom

Fireside

Fireside Chat

Moderator

Michael Ryskin, Life Science Tools & Diagnostics Analyst, BofA Global Research

  • Precision Medicine was it a paradigm shift??
  • Acquisition of manufacturing capabilities
  • research, manufacturinf line blurred
  • WHat excites you the most

Panelist

Marc Casper, Chairman, President & CEO, Thermo Fisher Scientific

  • Enabling Life sceinces, Pharmaceutical industries $1.5Billion internal investment annually
  • AI increasing knowledge
  • How is Precision Medicine applied? Sequencing in Cancer accelerated the Genomics information in use for 24 hours response of the sequence – adopted around the World.
  • at MGH lung cancers are treated with genomic sequencing
  • identification of the patients suitability for a targeted treatment
  • treatment during pregnacy at home vs hospitalization
  • History of company: Tools first: Mass spectrometry, one year for one sequence, protein identification and carrying to Mass spectrometry
  • Interactions need understanding acquiring electro spectrometry allowing analytical chemistry on proteins
  • Broad range of products: Clinical research to meet regulatory requirements entry into Reagents products.
  • Clinical Trials made effective by Thermo Scientific Products
  • Capabilities in registries, patient safety in psoriasis
  • Large role in experimental medicine drives efficiency in LABS
  • SIze of customers: small Biotech and large Pharma
  • Manufacture medicines: work with partnersbuilt by acquisitions small molecules,
  • 100 engagements research, supply chain making medicines available at sites
  • Role for AI at Thermo Scientific:
  1. Productivity – Cost effective for processes in use by 120,000 employees
  2. Super customer interaction perfected by interogations with internal manuals to provide answers quickly
  3. Improvement of products
  • Excitement Points: Responsiveness to COVID pandemic
  • New medicine development

4:50 PM – 5:30 PM

Picasso Ballroom

The Reemergence of ADCs, Precision Medicine, T-cell engagers, and Bispecifics: Oncology at Its Finest

 

Moderators

John Bishai, PhD, BofA

  • Approach to AI
  • Strategy regarding clinical trial design, vs molecule design

Justin Gainor, MD, MGH, HMS

  • How strategies are developed and then modified?
  • immune therapies work better open new paradeigm

Panelists

Moitreyee Chatterjee-Kishore, PhD, Head of Development, Immuno-Oncology and Cancer Cell Therapy, Astellas Pharma Inc.

  • cancer – first line of treatment vs 2nd and 3rd
  • Precision medicine more precise
  • mix and match immunotherapy and other modalities
  • small molecule early on
  • molecule formulation is science and art
  • Stratify the patient population early on
  • Help needed to design better trials
  • Research is key for molecule design

Niall Martin, PhD, CEO, Artios Pharma

  • peptide chemistry
  • molecule design had options several are applied
  • biomarker driven event in development cycle
  • strategy of biomarkers – lack structure
  • effect of combination therapy on survival?

Chris Varma, PhD, Co-founder, Chairman & CEO, Frontier Medicines

 

5:30 PM – 8:30 PM

South Lawn Tent

Attendee Reception and Dinner

Moderator

Anne Oxrider

Senior Vice President, Benefits Executive, Bank of America

Panelist

Deepak Chopra, MD

Founder, The Chopra Foundation

Wednesday, September 25, 2024

8:30 AM – 8:55 AM

Picasso Ballroom

Fireside

Fireside Chat

Moderators

David Ting, MD, Associate Clinical Director for Innovation, Mass General Cancer Center; Associate Professor of Medicine, Harvard Medical School

  • Innovation is the foundation of the future
  • Creative thinking vs one agent and one target
  • Openness is much appreciated

Jason Zemansky, PhD, SMid-Cap Biotech Analyst, BofA Global Research

  • On WSJ article on M&A in Biotech attributing decline in M&A of Biotech companies due to LACK of Innovations
  • Q from audience: organizational structure and innovation
  • Vision on leveraging Partnerships

Panelist

Tadaaki Taniguchi, MD, PhD, Chief Medical Officer, Astellas Pharma

  • Pharma and Biotech heavy betting on new medicines in Oncology
  • Astellas Pharma is different than other Pharma companies
  • We focus on Oncology and in combination therapies as a priority
  • Investment pay attention to Leadership priorities
  • One product vs BEST combination therapy for best treatment and outcomes
  • Innovations come from anywhere
  • ADCs: Target, payload emerged recently by a partnership
  • Collaborations: several pathways, several modalities, several combinations therapies
  • Partnership requires greater flexibility
  • Created Small flexible Labs to enable to innovate with Partners, “we can’t innovate alone”

9:00 AM – 9:40 AM

Picasso Ballroom

Disruptors

The Disruptors: The Role of Pathway Inhibition in Inflammation and Inflammatory Diseases

Moderators

Tazeen Ahmad, SMid-Cap Biotech Analyst, BofA Global Research

  • Are you using AI
  • Neuroinflammation

Cynthia Lemere, PhD, BWH, HMS

  • What systems are primarily impacted by the Immunes system
  • Drug delivery for inflammation huge area
  • Getting antibodies to the Brain
  • Precision medicine, genetics,specific person with specific immune disease

Panelists

Jo Viney, PhD, Cofounder, President & CEO, Seismic Therapeutic

  • Pandemics highlighted the impact of the immune system
  • Targeting cytokines in specific locations – hew approach
  • Modalities on hand: protein degradation mediation by bringing two cells together
  • AI is used for Patient stratification
  • AI to be used in Pathways involved in disease process to identify Biologics, PROTAC,
  • AI and ML for training models from interaction between proteins
  • ChatGPT to predict interactions among proteins
  • Immune disease and remission bust the immune system to improve quality of life of patient undergoing interventions
  • T-cell engaggers – in cases of refractory – great approach for boosting the immune system: removal of antibidies, recycling antibodies,
  • Two ends: Cell depletion vs Early detection
  • Therapy is every 6 months, cell depletion takes 3 months to come back.
  • Target immune system in the periphery,
  • Immune system in neurodegenerative diseases: Parkinson’s local modulation to penetrate neurological system
  • Markers to cross the BBB or not cross in neurological diseases
  • Immune disease is POLYGENIC multiple o=etiologies, mutation, genetics, which cell and which pathway to target a therapeutics: Biologics
  • Patient stratification is key for Precision Medicine at the cell level
  • T-cell, B-cell, Cytokines and antibodies mediated disease
  • ADGs degradation

9:45 AM – 10:10 AM

Picasso Ballroom

H. Jeffrey Wilkins, MD, Abcuro
  • Inflammation play a role in activating the immune system
  • zin the days of Medical School: inhibition of cytokines
  • Today: specificity to target cells for depletion
  • Specific biomarkers for response to therapies
  • cell types by mutations and physiology and causality in the inflammation area: we know why they have inflammation we need to learn interventions for inflammation
  • Asthma in the 40s as an inflammatory disease
  • assess treatment of inflammation
  • Neuro-inflammation – not well understood
  • What is the cause that drive the disease: understanding encephalitis?
NiranJana Nagarajan, PhD, MGB Ventures
  • Biology is the driver not AI
  • depletion of cells in a certain stage
  • Translation from disease to other diseases in the case of cell therapy potential – active area companies are trying solutions
  • Inflammation is a huge challenge to treat

 

Fireside

Fireside Chat

Moderators

Daniel Kuritzkes, MD, Chief, Division of Infectious Diseases, Brigham and Women’s Hospital; Harriet Ryan Albee Professor of Medicine, Harvard Medical School

  • Pathways in vaccine design
  • How to educate population on Vaccines
  • other approaches than vaccines

Alec Stranahan, PhD, SMid-Cap Biotech Analyst, BofA Global Research

  • Vaccine approval
  • Next generation vaccines

Panelist

Stéphane Bancel, CEO, Moderna

  • Vaccine design: long term vaccines weakens in aged population
  • data on role of AVV in Multiple Sclerosis
  • working on in the US vs France, Netherland in Europe different approaches
  • Vaccine for HIV
  • Vaccine was approved last year for children, pharmacies shortage
  • Season of FLu three times more vaccines in use
  • Employees run vaccine clinics on site
  • Vaccines not related to COVID
  • Misinformation from COVID vaccine
  • 5% of COVID hospitalized were on the booster
  • Combination vaccines for high risk populations
  • Healthcare providers need to be involved in Education, many do not have an interest in the education on vaccines
  • Local stories from Vaccine manufectures and developer to be used in education in the communities
  • Individual DNA cancer celll signature of the cancer  – data over time for development of vaccine to cancer many more tumor types are needed
  • Checkpoints in early disease
  • biopsy are too expensive
  • Side effect studies going on
  • mono-therapy vs immunotherapy costs involved
  • Naive virus to get into the Liver two diseases – cassets for sose management
  • Recombinant antibodies technology from the 70s
  • PD-1
  • COVID – was nto in the plan for development – design in silicon in two weeks – no change after this design
  • 10:10 AM – 10:20 AM

10:20 AM – 11:00 AM

Picasso Ballroom

The Innovation Gap: Understanding the Role of Cell Therapies in Autoimmune Disease

Moderator

Charlie Yang, PhD

Large/SMid-Cap Biotech and Major Pharma Analyst, BofA Global Research

  • TCM
  • CAR-T
  • advantages of each cell type

Angele Shen, MGB Innovations

  • CAR-T
  • What would be a quick breakthrough?

Panelists

Jeff Bluestone, PhD, CEO & President, Sonoma Biotherapeutics

  • Cell therapy for cell depletion elimination of B-cells like its role in Multiple Sclerosis
  • Working with regulatory T-cells
  • Population of cells to study: T-cells master regulator in multiple ways – produce metabolic factors, infection tone in activation of other cells
  • Biology of cell: RNA, DNA
  • TCR – target antigens in tissues they are in in immune suppression
  • FInding the right peptide bindes to a certain MAC
  • CAR-T – recornize the cells in the local milieu like in patients with RA as an autoimmune disease
  • Clinical models ascertain cell types involvement leading to clinical trial insights then to therapies on a decision tree
  • recent data on CAR-T immune response in allogeneic for potential use in neurodegenerative diseases
  • patients and companies over react on immune therapy: Patients and Science vs hype
  • next generation: POC,
  • Gene therapy specificities vs Cell therapies – each approach will develop a different drug
  • FDA and NIH has in 11/2023 a meeting on Regulation of Cell therapy on stability and their approach to immune disease where there are already several drugs
  • approvals challenges companies
  • Price, too expensive a treatment is cell therapy

Chad Cowan, PhD, Executive Advisor, Century Therapeutics

  • use Natural Killer cells to elicit long-term immune response, T-cells,
  • active Beta cells]Regulatory monitoring use
  • DM – regulatory cells made from Stem cells
  • mission durable response
  • Clinical issues – not easy way for treatment wiht a cell line and bioreactors and modalities less similar to autologoous celles
  • CAR-T in oncology lessons now are transferred to Immune disease
  • Cell therapy requires technologies to mature multiple modalities and multiple drugs not one cell therapy for all immune diseases
  • Stability of the therapy vs rejection by immune system
  • FDA making cells is not as making drugs – higher level of scrutiny for cell therapy
  • SYNTHETIC BIOLOGY on B-cells for future breakthrough

Samantha Singer, President & CEO, Abata Therapeutics

  • Immune response involve many cell types in many diseases
  • Oncology the use of T-cells as tissue residents staying in tissue long time
  • Specific biology of the disease and regulatory cells receptors optimizing TCR presentation in pathology of tissue residents phyno types
  • activate in nervous system or in pancreas – intersection of cell biology with disease biology
  • Market feasibility – scaling, biology, pathology for reimbursement
  • antibody therapy may be appropriate than cell therapy is only a novel option
  • Cell manufacturing requires optimization of process, companies commercializing across all cell types
  • comprehensive approach for systemic immune suppression
  • : healthy tissue vs diseased tissue with cell theray implanted cells as residents in tissue
  • clinical data on product performance and on the biology reactions

11:00 AM – 11:40 AM

Picasso Ballroom

Unmet Clinical Needs: 100 Harvard KOLs Weigh In

Moderators

Jose Florez, MD, PhD, Physician-in-Chief and Chair, Department of Medicine, Massachusetts General Hospital; Professor, Harvard Medical School

  • 40 minutes to deal with big needs collected from 100 faculties at Harvard Medical School
  • The ten issues on one slide
  • How could we use compute to distill data

Bruce Levy, MD, Physician-In-Chief and Co-Chair, Department of Medicine, Brigham and Women’s Hospital; Parker B. Francis Professor of Medicine, Harvard Medical School

  • Transformation from the Present to the Future
  • identifying the needs
  • Infectious diseases: Rapid diagnostics need
  • resistance to antibiotics and metabolic reactions endogenous
  • Pandemics globally of diseases erradicated in the past: Pox, polio
  • Improving health in Geriatrics, not population growing but geriatric population growing. Beyong age 60 a citizen will use 1 or 2 physicians each
  • 7,000 diseases, Genetic diseases requires integration and innovations in therapy
  • Innovations in Home devices

Panelists

Rox Anderson, MD, Lancer Endowed Chair of Dermatology;, Director, Wellman Center for Photomedicine, MGH; Professor of Dermatology, HMS

  • Access to data across institutions

Nicole Davis, PhD, Biomedical Communications

  • We asked 104 expert practitioners, content collected was analyzed
  1. detection early
  2. keeping the Human brain healthy
  3. geriatrics Medicine, aging and compound effects on health system with aging and Health equity
  • Bias in Data

Jean-François Formela, MD, Partner, Atlas Venture

  • genetic information used in therapeutics design

Steven Greenberg, MD, Neurologist, Brigham and Women’s Hospital; Professor of Neurology, Harvard Medical School

  • Human genome completed in 1999, human genetic diseases were discovered learn about the disease at the tissue level with genomics and a system approach
  • Pathogenic drivers, systme integration by therapeutics approaches to pathways multiple cytokines in allergic reactions Pfizer had two biomarkers and therapies for systemic biology of disease
  • Pediatrics has its own challenges
  • Imaging medicine
  • Living longer at a lower cost  – HOW TO ACHIEVE THAT?
  • growth abnormality in children: Body growth and Skull shrink

John Lepore, MD, CEO, ProFound Therapeutics;, CEO-Partner, Flagship Pioneering

  • Pathway, targeting therapy to patients in a System biological approach
  • Database of systme biology has missing components not included in the Human genome project – completion of the Data
  • Definition of End points needs revisiting
  • Identifying specific populations vs getting quickly to market
  • Diseases of aging: Muscles diseases – how to promote improvement in muscle mass

CONCLUSIONS

  1. Gray Tsunami
  2. Brain health
  3. Cancer treatment paradigm shift
  4. Fibrosis in many diseases
  5. infectious disease in changing World
  6. Equity in HC
  7. Clinical Data is VAST
  8. Systemic view of Human disease
  9. New approaches to Psychaitry
  10. Rare disease treatment needs a charter

In addition,

  • new generation of pain treatment
  • skin treatment new drugs
  • Chronic disease: improve treatment and prevention.
  • Obesity medicine – new discipline in a new Era

11:45 AM – 12:30 PM

Picasso Ballroom

Fireside

Fireside Chat

Moderators

Tazeen Ahmad, SMid-Cap Biotech Analyst, BofA Global Research

  • FDA sets criteria  – How is that done?
  • Autoimmune disease therapies – What is in the horizon?

 

Paul Anderson, MD, PhD, Chief Academic Officer, Mass General Brigham;

  • drug development
  • drug pricing in Europe
  • New book
  • RA needs more medicines

UNCONTROLLED SPREAD

In Uncontrolled Spread, a New York Times Best Seller, Dr. Scott Gottlieb identifies the reasons why the US was caught unprepared for the pandemic and how the country can improve its strategic planning to prepare for future viral threats.

Panelist

Scott Gottlieb, MD, Physician; Former Commissioner, Food and Drug Administration (2017-2019)

  • FDA approval 1st gene therapy in his tenure
  • Price of drugs: efficatious vs time to deveop
  • competitors in the marketplace are there for market share
  • New Book: Episodes in the FDA, appproval process at FDA, Gene therapy 1st in class approved – a special moment. Back in 1980s era translated to antibodies, to T-cell pioneering work.
  • Publisher worried it will not sell very well
  • FDA had concerns about manufacturing aspects
  • In 2024 we understand Biologics on novel platforms
  • Worries that Medicare will not reimbursement  and cover the new therapies: Cell therapy
  • Statins approval had a known very large market vs Cell therapy not known which Cancer patients will benefit???
  • Black box involved in Autoimmune, studies bring exciting results
  • In 2018 – needs arise for early approved of drugs in AD, amyloid plaque – change in thinking and is controversial
  • In early 2020, change in settings of clinical trials, placido no more the only way for Randomized trials
  • Approval for AD drug vs othe indication – the process is difference (DMD a case to think about)
  • AI & NLP: Train on data of 10,000 lesions
  • FDA choose not to regulate AI the physician is in the Middle
  • Who is wrong: CHatGPT or the clinician ?
  • Data set on gene may represents NEW biologies that Physicians had not seen before
  • Data validation on medical devices and their approval after regulating them
  • Diagnostics tests: Validation Panels are involved
  • Regulated on input data vs Output data and validate the input data
  • Platforms are needed for regulation of AI involvement in the drug discovery and the drug approval process
  • investment in this platforms will be done by Whom?? It will come
  • Framework for AI at FDA: Regulatory gray data for applications and standards for output – not a novel regulatory concept
  • If AI will be applied widely, I/O accuracy is a must have
  • may be achievable soon?
  • FDA is evolutionary organization in its decision process NOT a REVOLUTIONARY organization. Simulation work started in 2003, 40 people doing that then.
  • Recently, new team in Agency working of Safety with tools and technologies that are common in Science  – Approvals to drug labels and off labels that 20 years ago would not have happened
  • Tolerance for higher prices is to support Private sector that brings the innovating drugs to market

 

SPEAKERS

C-Suite Speakers

Faraz Ali

CEO, Tenaya Therapeutics

Peter Anastasiou

CEO, Capsida Biotherapeutics

Paul Anderson, MD, PhD

Chief Academic Officer, Mass General Brigham; K. Frank Austen Professor of Medicine, Harvard Medical School

Rahul Ballal, PhD

CEO, Mediar Therapeutics

Stéphane Bancel

CEO, Moderna

Craig Basson MD, PhD

Chief Medical Officer, Bitterroot Bio

Jeff Bluestone, PhD

CEO & President, Sonoma Biotherapeutics

Albert Bourla, PhD

Chairman & CEO, Pfizer

O’Neil Britton, MD

Chief Integration Officer & Executive Vice President, Mass General Brigham

Marc Casper

Chairman, President & CEO, Thermo Fisher Scientific

Joshua Cohen

Co-CEO, Amylyx Pharmaceuticals

Delos “Toby” Cosgrove, MD

Executive Advisor; former CEO & President, Cleveland Clinic

Jatin Dave, MD

Chief Medical Officer, MassHealth; Director of Clinical Affairs, UMass Chan Medical School

Punit Dhillon

CEO, Skye Bioscience

Steve Favaloro

Chairman & CEO, Genezen

John Fish

Chairman & CEO, Suffolk

Alexandria Forbes, PhD

CEO, MeiraGTx

Niyum Gandhi

CFO & Treasurer, Mass General Brigham

Chris Garabedian

Chairman & CEO, Xontogeny; Venture Portfolio Manager, Perceptive Advisors

Lucas Harrington, PhD

Co-Founder & CSO, Mammoth Biosciences

Marc Harrison, MD

Co-founder & CEO, Health Assurance Transformation Corp. (HATCo)

Amos Hedt

Chief Business Strategy Officer, Perspective Therapeutics

Rod Hochman, MD

President & CEO, Providence

David Hyman, MD

Chief Medical Officer, Eli Lilly and Company

Philip Kantoff, MD

Co-Founder & CEO, Convergent Therapeutics

Daniel Karlin, MD

Chief Medical Officer, MindMed

Reshma Kewalramani, MD

CEO & President, Vertex Pharmaceuticals

Justin Klee

Co-CEO, Amylyx Pharmaceuticals

Anne Klibanski, MD

President & CEO, Mass General Brigham; Laurie Carrol Guthart Professor of Medicine, Harvard Medical School

Samarth Kulkarni, PhD

CEO, CRISPR Therapeutics

Liz Kwo, MD

Chief Commercial Officer, Everly Health

Adam Landman, MD

Chief Information Officer & SVP, Digital, Mass General Brigham; Associate Professor of Emergency Medicine, Harvard Medical School

Chemu Lang’at

Chief Operating Officer, Best Buy Health

Paul LaViolette

Managing Partner & COO, SV Health Investors

John Lepore, MD

CEO, ProFound Therapeutics; CEO-Partner, Flagship Pioneering

Christopher Longhurst, MD

Chief Medical & Digital Officer, UC San Diego Health

Kevin Mahoney

CEO, University of Pennsylvania Health System

Niall Martin, PhD

CEO, Artios Pharma

James Mawson

CEO, Global Corporate Venturing

Mark McKenna

Chairman & CEO, Mirador Therapeutics

Jane Moran

Chief Information and Digital Officer, Mass General Brigham

William Morris, MD

Chief Medical Information Officer, Google Cloud

Rohan Palekar

CEO, 89bio

Raju Prasad, PhD

Chief Financial Officer, CRISPR Therapeutics

Xiayang Qiu, PhD

CEO, Regor Therapeutics

Harith Rajagopalan MD, PhD

CEO & Co-Founder, Fractyl Health

Shiv Rao, MD

CEO & Founder, Abridge

Kerry Ressler, MD, PhD

Chief Scientific Officer, McLean Hospital; Professor of Psychiatry, Harvard Medical School

Matthew Roden, PhD

President & CEO, Aktis Oncology

Sandi See Tai, MD

Chief Development Officer, Lexeo Therapeutics

Samantha Singer

President & CEO, Abata Therapeutics

Joanne Smith-Farrell, PhD

CEO & Director, Be Biopharma

Emma Somers-Roy

Chief Investment Officer, Mass General Brigham

Adam Steensberg, MD

President & CEO, Zealand Pharma

Tadaaki Taniguchi, MD, PhD

Chief Medical Officer, Astellas Pharma

Elsie Taveras, MD

Chief Community Health & Health Equity Officer, Mass General Brigham; Conrad Taff Endowed Chair and Professor of Pediatrics, Harvard Medical School

Jo Viney, PhD

Cofounder, President & CEO, Seismic Therapeutic

Ron Walls, MD

Chief Operating Officer, Mass General Brigham; Neskey Family Professor of Emergency Medicine, Harvard Medical School

Christophe Weber

President & CEO, Takeda

Fraser Wright, PhD

Chief Gene Therapy Officer, Kriya Therapeutics

Speakers

Anna Åsberg

Vice President, AstraZeneca Pharmaceuticals

Tazeen Ahmad

SMid-Cap Biotech Analyst, BofA Global Research

Jessica Allegretti, MD

Director, Crohn’s and Colitis Center, Brigham and Women’s Hospital; Associate Professor of Medicine, Harvard Medical School

Rox Anderson, MD

Lancer Endowed Chair of Dermatology; Director, Wellman Center for Photomedicine, MGH; Professor of Dermatology, HMS

Katherine Andriole, PhD

Director of Academic Research and Education, Mass General Brigham Data Science Office; Associate Professor, Harvard Medical School

Caroline Apovian, MD

Co-Director, Center for Weight Management and Wellness, Brigham and Women’s Hospital; Professor of Medicine, Harvard Medical School

Vanita Aroda, MD

Director, Diabetes Clinical Research, Brigham and Women’s Hospital; Associate Professor, Harvard Medical School

Natalie Artzi, PhD

Associate Professor of Medicine, Brigham and Women’s Hospital & Harvard Medical School

John Bishai, PhD

Global Healthcare Investment Banking, BofA Securities

David Blumenthal, MD

Professor of Practice of Public Health and Health Policy, Harvard TH Chan School of Public Health; Research Fellow, Harvard Kennedy School of Government; Samuel O. Thier Professor of Medicine, Emeritus, Harvard Medical School

Giles Boland, MD

President, Brigham and Women’s Hospital and Brigham and Women’s Physicians Organization; Philip H. Cook Distinguished Professor of Radiology, Harvard Medical School

Andrew Bressler

Washington Healthcare Policy Analyst, BofA Global Research

James Brink, MD

Enterprise Chief, Radiology, Mass General Brigham; Juan M. Taveras Professor of Radiology, Harvard Medical School

David Brown, MD

President, Academic Medical Centers, Mass General Brigham; Mass General Trustees Professor of Emergency Medicine, Harvard Medical School

Tyler Bryson

Corporate Vice President, US Health & Public Sector Industries, Microsoft Corporation

Jonathan Carlson, MD, PhD

Director of Chemistry, Center for Systems Biology, Massachusetts General Hospital; Assistant Professor of Medicine, Harvard Medical School

Miceal Chamberlain

President of Massachusetts, Bank of America

Moitreyee Chatterjee-Kishore, PhD

Head of Development, Immuno-Oncology and Cancer Cell Therapy, Astellas Pharma Inc.

Dong Feng Chen, MD, PhD

Associate Scientist, Massachusetts Eye and Ear; Associate Professor, Harvard Medical School

Jasmeer Chhatwal, MD, PhD

Associate Neurologist, Massachusetts General Hospital; Associate Professor of Neurology, Harvard Medical School

E. Antonio Chiocca, MD, PhD

Chair, Department of Neurosurgery, Brigham and Women’s Hospital; Harvey W. Cushing Professor of Neurosurgery, Harvard Medical School

Bryan Choi, MD, PhD

Associate Director, Center for Brain Tumor Immunology and Immunotherapy, Massachusetts General Hospital; Assistant Professor of Neurosurgery, Harvard Medical School

Deepak Chopra, MD

Founder, The Chopra Foundation

Yolonda Colson, MD, PhD

Chief, Division of Thoracic Surgery, Massachusetts General Hospital; Hermes C. Grillo Professor of Surgery, Harvard Medical School

Chad Cowan, PhD

Executive Advisor, Century Therapeutics

Cristina Cusin, MD

Director, MGH Ketamine Clinic and Psychiatrist, Depression Clinical and Research Program, Massachusetts General Hospital; Associate Professor in Psychiatry, Harvard Medical School

Nicole Davis, PhD

Biomedical Communications

Marcela del Carmen, MD

President, Massachusetts General Hospital and Massachusetts General Physicians Organization (MGPO); Executive Vice President, Mass General Brigham; Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School

Gerard Doherty, MD

Surgeon-in-Chief, Mass General Brigham Cancer; Surgeon-in-Chief, Brigham and Women’s Hospital; Moseley Professor of Surgery, Harvard Medical School

Liz Everett Krisberg

Head of Bank of America Institute

Maurizio Fava, MD

Chair, Department of Psychiatry, Massachusetts General Hospital; Slater Family Professor of Psychiatry, Harvard Medical School

Keith Flaherty, MD

Director of Clinical Research, Mass General Cancer Center; Professor of Medicine, Harvard Medical School

Jose Florez, MD, PhD

Physician-in-Chief and Chair, Department of Medicine, Massachusetts General Hospital; Professor, Harvard Medical School

Jean-François Formela, MD

Partner, Atlas Venture

Fritz François, MD

Executive Vice President and Vice Dean, Chief of Hospital Operations, NYU Langone Health

Joanna Gajuk

Health Care Facilities and Managed Care Analyst, BofA Global Research

Jason Gerberry

Specialty Pharma and SMid-Cap Biotech Analyst, BofA Global Research

Gad Getz, PhD

Director of Bioinformatics, Krantz Center for Cancer Research and Department of Pathology; Paul C. Zamecnik Chair in Cancer Research, Mass General Cancer Center; Professor of Pathology, Harvard Medical School

Alexandra Golby, MD

Neurosurgeon; Director of Image-guided Neurosurgery, Brigham and Women’s Hospital; Professor of Neurosurgery, Professor of Radiology, Harvard Medical School

Allan Goldstein, MD

Chief of Pediatric Surgery, Massachusetts General Hospital; Surgeon-in-Chief, Mass General for Children; Marshall K. Bartlett Professor of Surgery, Harvard Medical School

Scott Gottlieb, MD

Physician; Former Commissioner, Food and Drug Administration (2017-2019)

David Grayzel, MD

Partner, Atlas Venture

Steven Greenberg, MD

Neurologist, Brigham and Women’s Hospital; Professor of Neurology, Harvard Medical School

Steven Grinspoon, MD

Chief, Metabolism Unit, Massachusetts General Hospital; Professor of Medicine, Harvard Medical School

Daphne Haas-Kogan, MD

Chief, Enterprise Radiation Oncology, Mass General Brigham; Professor, Harvard Medical School

Roger Hajjar, MD

Director, Gene & Cell Therapy Institute, Mass General Brigham

John Hanna, MD, PhD

Associate Professor, Brigham and Women’s Hospital & Harvard Medical School

Yvonne Hao

Secretary of Economic Development, Commonwealth of Massachusetts

Nobuhiko Hata PhD

Director, Surgical Navigation and Robotics Laboratory, Brigham and Women’s Hospital; Professor of Radiology, Harvard Medical School

Maura Healey

Governor of the Commonwealth of Massachusetts

Elizabeth Henske, MD

Director, Center for LAM Research and Clinical Care, Brigham and Women’s Hospital; Professor of Medicine, Harvard Medical School

Leigh Hochberg MD, PhD

Director of Neurotechnology and Neurorecovery, Massachusetts General Hospital; Senior Lecturer on Neurology, Harvard Medical School

Daphne Holt, MD, PhD

Director of the Resilience and Prevention Program, Massachusetts General Hospital; Associate Professor of Psychiatry, Harvard Medical School

Susan Huang, MD

EVP, Chief Executive, Providence Clinical Network, Providence Southern CA

Keith Isaacson, MD

Director of Minimally Invasive Gynecologic Surgery and Infertility, Newton Wellesley Hospital; Associate Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School

Ole Isacson, MD-PhD

Founding Director, Neuroregeneration Research Institute, McLean Hospital; Professor of Neurology and Neuroscience, Harvard Medical School

Haim Israel

Head of Global Thematic Investing Research, BofA Global Research

Farouc Jaffer, MD, PhD

Director, Coronary Intervention, Massachusetts General Hospital; Associate Professor of Medicine, Harvard Medical School

Russell Jenkins, MD, PhD

Krantz Family Center for Cancer Research, Massachusetts General Hospital; Mass General Cancer Center, Center for Melanoma; Assistant Professor of Medicine, Harvard Medical School

Hadine Joffe, MD

Executive Director of the Connors Center for Women’s Health and Gender Biology; Interim Chair, Department of Psychiatry, Brigham and Women’s Hospital; Paula A. Johnson Professor of Psychiatry in the Field of Women’s Health, Harvard Medical School

Benjamin Kann, MD

Assistant Professor, Brigham and Women’s Hospital & Harvard Medical School

Tatsuo Kawai, MD, PhD

Director of the Legorreta Center for Clinical Transplantation Tolerance, A.Benedict Cosimi Chair in Transplant Surgery, Massachusetts General Hospital; Professor of Surgery, Harvard Medical School

Albert Kim, MD

Assistant Physician, Mass General Cancer Center; Assistant Professor, Harvard Medical School

Roger Kitterman

Senior Vice President, Ventures and Business Development & Licensing, Mass General Brigham Managing Partner, Mass General Brigham Ventures

Lotte Bjerre Knudsen, DMSc

Chief Scientific Advisor, Novo Nordisk

Vesela Kovacheva, MD, PhD

Director of Translational and Clinical Research, Mass General Brigham; Assistant Professor of Anesthesia, Harvard Medical School

Jonathan Kraft

President, The Kraft Group; Board Chair, Massachusetts General Hospital

John Krystal, MD

Chair, Department of Psychiatry, Yale School of Medicine

Daniel Kuritzkes, MD

Chief, Division of Infectious Diseases, Brigham and Women’s Hospital; Harriet Ryan Albee Professor of Medicine, Harvard Medical School

Bruce Levy, MD

Physician-In-Chief and Co-Chair, Department of Medicine, Brigham and Women’s Hospital; Parker B. Francis Professor of Medicine, Harvard Medical School

Katherine Liao, MD

Associate Physician, Department of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital; Associate Professor of Medicine and Biomedical Informatics, Harvard Medical School

David Louis, MD

Enterprise Chief, Pathology, Mass General Brigham Benjamin Castleman Professor of Pathology, Harvard Medical School

Tim Luker, PhD

VP, Ventures & West Coast Head, Eli Lilly

Andrew Luster, MD, PhD

Chief, Division of Rheumatology, Allergy and Immunology; Director, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital; Persis, Cyrus and Marlow B. Harrison Professor of Medicine, Harvard Medical School

Allen Lutz

Health Care Services Analyst, BofA Global Research

Calum MacRae MD, PhD

Vice Chair for Scientific Innovation, Department of Medicine, Brigham and Women’s Hospital; Professor of Medicine, Harvard Medical School

Joren Madsen, MD, PhD

Director, MGH Transplant Center; Paul S. Russell/Warner-Lambert Professor of Surgery, Harvard Medical School

Faisal Mahmood, PhD

Associate Professor, Brigham and Women’s Hospital & Harvard Medical School

Peter Marks, MD, PhD

Director, Center for Biologics Evaluation and Research, FDA

Marcela Maus, MD, PhD

Director of Cellular Therapy and Paula O’Keeffe Chair in Cancer Research, Krantz Family Center for Cancer Research and Mass General Cancer Center; Associate Director, Gene and Cell Therapy Institute, Mass General Brigham; Associate Professor, Harvard Medical School

Thorsten Mempel, MD, PhD

Associate Director, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital; Professor of Medicine, Harvard Medical School

Rebecca Mishuris, MD

Chief Medical Information Officer, Mass General Brigham; Member of the Faculty, Harvard Medical School

Pradeep Natarajan, MD

Director of Preventive Cardiology, Paul & Phyllis Fireman Endowed Chair in Vascular Medicine, Massachusetts General Hospital; Associate Professor of Medicine, Harvard Medical School

Nawal Nour, MD

Chair, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital; Associate Professor, Kate Macy Ladd Professorship, Harvard Medical School

Heather O’Sullivan, MS, RN, AGNP

President, Mass General Brigham Healthcare at Home

Anne Oxrider

Senior Vice President, Benefits Executive, Bank of America

Claire-Cecile Pierre, MD

Vice President, Community Health Programs, Mass General Brigham; Instructor in Medicine, Harvard Medical School

Richard Pierson III, MD

Scientific Director, Center for Transplantation Sciences, Massachusetts General Hospital; Professor of Surgery, Harvard Medical School

Mark Poznansky, MD, PhD

Director, Vaccine and Immunotherapy Center, Massachusetts General Hospital; Steve and Deborah Gorlin MGH Research Scholar; Professor of Medicine, Harvard Medical School

Yakeel Quiroz, PhD

Director, Familial Dementia Neuroimaging Lab and Director, Multicultural Alzheimer’s Prevention Program, Massachusetts General Hospital; Paul B. and Sandra M. Edgerley MGH Research Scholar; Associate Professor, Harvard Medical School

Heidi Rehm, PhD

Chief Genomics Officer, Massachusetts General Hospital; Professor of Pathology, Harvard Medical School

Leonardo Riella, MD, PhD

Medical Director of Kidney Transplantation, Massachusetts General Hospital; Harold and Ellen Danser Endowed Chair in Transplantation, Harvard Medical School

Jorge Rodriguez, MD

Clinician-investigator, Brigham and Women’s Hospital; Assistant Professor, Harvard Medical School

Adam Ron

Health Care Facilities and Managed Care Analyst, BofA Global Research

David Ryan, MD

Physician-in-Chief, Mass General Brigham Cancer; Professor of Medicine, Harvard Medical School

Michael Ryskin

Life Science Tools & Diagnostics Analyst, BofA Global Research

Alkesh Shah

Head of US Equity Software Research, BofA Global Research

Angela Shen, MD

Vice President, Strategic Innovation Leaders, Mass General Brigham Innovation

Gregory Simon

President, Simonovation

Prabhjot Singh, MD, PhD

Senior Advisor, Strategic Initiatives Peterson Health Technology Institute

Brendan Singleton

Healthcare Equity Capital Markets, BofA Securities

Caroline Sokol, MD, PhD

Assistant Physician, Massachusetts General Hospital; Assistant Professor, Harvard Medical School

Daniel Solomon, MD

Matthew H. Liang Distinguished Chair in Arthritis and Population Health, Brigham and Women’s Hospital; Professor of Medicine, Harvard Medical School

Scott Solomon, MD

Director, Clinical Trials Outcomes Center; Edward D. Frohlich Distinguished Chair in Cardiovascular Pathophysiology, Brigham and Women’s Hospital; Professor of Medicine, Harvard Medical School

Fatima Cody Stanford, MD

Obesity Medicine Physician Scientist, Massachusetts General Hospital; Associate Professor of Medicine and Pediatrics, Harvard Medical School

Shannon Stott, PhD

Associate Investigator, Krantz Family Center for Cancer Research and Mass General Cancer Center; d’Arbeloff Research Scholar, Massachusetts General Hospital; Associate Investigator, Krantz Family Center for Cancer Research Harvard Medical School

Alec Stranahan, PhD

SMid-Cap Biotech Analyst, BofA Global Research

Marc Succi, MD

Executive Director, Mass General Brigham MESH Incubator; Associate Chair of Innovation & Commercialization, Mass General Brigham Radiology; Assistant Professor, Harvard Medical School

Guillermo Tearney, MD, PhD

Principal Investigator, Wellman Center for Photomedicine, Massachusetts General Hospital; Remondi Family Endowed MGH Research Institute Chair; Professor of Pathology, Harvard Medical School

David Ting, MD

Associate Clinical Director for Innovation, Mass General Cancer Center; Associate Professor of Medicine, Harvard Medical School

Raul Uppot, MD

Interventional Radiologist, Massachusetts General Hospital; Associate Professor, Harvard Medical School

Chris Varma, PhD

Co-founder, Chairman & CEO, Frontier Medicines

Kaveeta Vasisht, MD, PharmD

Associate Commissioner, Women’s Health, U.S. Food and Drug Administration

Alexandra-Chloé Villani PhD

Investigator, Massachusetts General Hospital; Assistant Professor, Harvard Medical School

Kate Walsh

Secretary of Health and Human Services, State of Massachusetts

David Walt, PhD

Professor of Pathology, Brigham and Women’s Hospital; Hansjörg Wyss Professor of Biologically Inspired Engineering, Harvard Medical School

Jennifer Warner-Schmidt, PhD

Vice President, Scientific Affairs, Transcend Therapeutics

Renee Wegrzyn, PhD

Director, Advanced Research Projects Agency for Health

Christoph Westphal, MD, PhD

General Partner, Longwood Fund

Deborah Wexler, MD

Chief, Diabetes Unit, Massachusetts General Hospital; Associate Professor of Medicine, Harvard Medical School

Charlie Yang, PhD

Large/SMid-Cap Biotech and Major Pharma Analyst, BofA Global Research

Nathan Yozwiak, PhD

Head of Research, Gene and Cell Therapy Institute, Mass General Brigham

Jason Zemansky, PhD

SMid-Cap Biotech Analyst, BofA Global Research

Alice Zheng, MD

Principal, RH Capital

We continue to confirm more speakers. Please check back regularly for updates.

Read Full Post »

Use of Systems Biology for Design of inhibitor of Galectins as Cancer Therapeutic – Strategy and Software

 

 

Curator: Stephen J. Williams, Ph.D.

Below is a slide representation of the overall mission 4 to produce a PROTAC to inhibit Galectins 1, 3, and 9.

 

Using A Priori Knowledge of Galectin Receptor Interaction to Create a BioModel of Galectin 3 Binding

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Now after collecting literature from PubMed on “galectin-3” AND “binding” to determine literature containing kinetic data we generate a WordCloud on the articles.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

This following file contains the articles needed for BioModels generation.

https://pharmaceuticalintelligence.com/wp-content/uploads/2022/12/Curating-Galectin-articles-for-Biomodels.docx

 

From the WordCloud we can see that these corpus of articles describe galectin binding to the CRD (carbohydrate recognition domain).  Interestingly there are many articles which describe van Der Waals interactions as well as electrostatic interactions.  Certain carbohydrate modifictions like Lac NAc and Gal 1,4 may be important.  Many articles describe the bonding as well as surface  interactions.  Many studies have been performed with galectin inhibitors like TDGs (thio-digalactosides) like TAZ TDG (3-deoxy-3-(4-[m-fluorophenyl]-1H-1,2,3-triazol-1-yl)-thio-digalactoside).  This led to an interesting article

Dual thio-digalactoside-binding modes of human galectins as the structural basis for the design of potent and selective inhibitors

Affiliations 2016 Jul 15;6:29457.
 doi: 10.1038/srep29457. Free PMC article

Abstract

Human galectins are promising targets for cancer immunotherapeutic and fibrotic disease-related drugs. We report herein the binding interactions of three thio-digalactosides (TDGs) including TDG itself, TD139 (3,3′-deoxy-3,3′-bis-(4-[m-fluorophenyl]-1H-1,2,3-triazol-1-yl)-thio-digalactoside, recently approved for the treatment of idiopathic pulmonary fibrosis), and TAZTDG (3-deoxy-3-(4-[m-fluorophenyl]-1H-1,2,3-triazol-1-yl)-thio-digalactoside) with human galectins-1, -3 and -7 as assessed by X-ray crystallography, isothermal titration calorimetry and NMR spectroscopy. Five binding subsites (A-E) make up the carbohydrate-recognition domains of these galectins. We identified novel interactions between an arginine within subsite E of the galectins and an arene group in the ligands. In addition to the interactions contributed by the galactosyl sugar residues bound at subsites C and D, the fluorophenyl group of TAZTDG preferentially bound to subsite B in galectin-3, whereas the same group favored binding at subsite E in galectins-1 and -7. The characterised dual binding modes demonstrate how binding potency, reported as decreased Kd values of the TDG inhibitors from μM to nM, is improved and also offer insights to development of selective inhibitors for individual galectins.

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The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells

Reporter: Stephen J. Williams, PhD.
Below is one of the first reports  on the potential mechanisms of intrinsic and acquired resistance to PROTAC therapy in cancer cells.
Proteolysis-targeting chimeras (PROTACs) are a promising new class of drugs that selectively degrade cellular proteins of interest. PROTACs that target oncogene products are avidly being explored for cancer therapies, and several are currently in clinical trials. Drug resistance is a substantial challenge in clinical oncology, and resistance to PROTACs has been reported in several cancer cell models. Here, using proteomic analysis, we found intrinsic and acquired resistance mechanisms to PROTACs in cancer cell lines mediated by greater abundance or production of the drug efflux pump MDR1. PROTAC-resistant cells were resensitized to PROTACs by genetic ablation of ABCB1 (which encodes MDR1) or by coadministration of MDR1 inhibitors. In MDR1-overexpressing colorectal cancer cells, degraders targeting either the kinases MEK1/2 or the oncogenic mutant GTPase KRASG12C synergized with the dual epidermal growth factor receptor (EGFR/ErbB)/MDR1 inhibitor lapatinib. Moreover, compared with single-agent therapies, combining MEK1/2 degraders with lapatinib improved growth inhibition of MDR1-overexpressing KRAS-mutant colorectal cancer xenografts in mice. Together, our findings suggest that concurrent blockade of MDR1 will likely be required with PROTACs to achieve durable protein degradation and therapeutic response in cancer.

INTRODUCTION

Proteolysis-targeting chimeras (PROTACs) have emerged as a revolutionary new class of drugs that use cancer cells’ own protein destruction machinery to selectively degrade essential tumor drivers (1). PROTACs are small molecules with two functional ends, wherein one end binds to the protein of interest, whereas the other binds to an E3 ubiquitin ligase (23), bringing the ubiquitin ligase to the target protein, leading to its ubiquitination and subsequent degradation by the proteasome. PROTACs have enabled the development of drugs against previously “undruggable” targets and require neither catalytic activity nor high-affinity target binding to achieve target degradation (4). In addition, low doses of PROTACs can be highly effective at inducing degradation, which can reduce off-target toxicity associated with high dosing of traditional inhibitors (3). PROTACs have been developed for a variety of cancer targets, including oncogenic kinases (5), epigenetic proteins (6), and, recently, KRASG12C proteins (7). PROTACs targeting the androgen receptor or estrogen receptor are avidly being evaluated in clinical trials for prostate cancer (NCT03888612) or breast cancer (NCT04072952), respectively.
However, PROTACs may not escape the overwhelming challenge of drug resistance that befalls so many cancer therapies (8). Resistance to PROTACs in cultured cells has been shown to involve genomic alterations in their E3 ligase targets, such as decreased expression of Cereblon (CRBN), Von Hippel Lindau (VHL), or Cullin2 (CUL2) (911). Up-regulation of the drug efflux pump encoded by ABCB1—MDR1 (multidrug resistance 1), a member of the superfamily of adenosine 5′-triphosphate (ATP)–binding cassette (ABC) transporters—has been shown to convey drug resistance to many anticancer drugs, including chemotherapy agents, kinase inhibitors, and other targeted agents (12). Recently, PROTACs were shown to be substrates for MDR1 (1013), suggesting that drug efflux represents a potential limitation for degrader therapies. Here, using degraders (PROTACs) against bromodomain and extraterminal (BET) bromodomain (BBD) proteins and cyclin-dependent kinase 9 (CDK9) as a proof of concept, we applied proteomics to define acquired resistance mechanisms to PROTAC therapies in cancer cells after chronic exposure. Our study reveals a role for the drug efflux pump MDR1 in both acquired and intrinsic resistance to protein degraders in cancer cells and supports combination therapies involving PROTACs and MDR1 inhibitors to achieve durable protein degradation and therapeutic responses.

Fig. 1. Proteomic characterization of degrader-resistant cancer cell lines.
(A) Workflow for identifying protein targets up-regulated in degrader-resistant cancer cells. Single-run proteome analysis was performed, and changes in protein levels among parent and resistant cells were determined by LFQ. m/z, mass/charge ratio. (B and C) Cell viability assessed by CellTiter-Glo in parental and dBET6- or Thal SNS 032–resistant A1847 cells treated with increasing doses of dBET6 (B) or Thal SNS 032 (C) for 5 days. Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. Growth inhibitory 50% (GI50) values were determined using Prism software. (D to G) Immunoblotting for degrader targets and downstream signaling in parental A1847 cells and their derivative dBET6-R or Thal-R cells treated with increasing doses of dBET6 or Thal SNS 032 for 4 hours. The dBET6-R and Thal-R cells were continuously cultured in 500 nM PROTAC. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 values, quantitating either (E) the dose of dBET6 that reduces BRD2, BRD3, or BRD4 or (G) the dose of Thal SNS 032 that reduces CDK9 protein levels 50% of the DMSO control treatment, were determined with Prism software. Pol II, polymerase II. (H to K) Volcano plot of proteins with increased or reduced abundance in dBET6-R (H) or Thal-R (I) A1847 cells relative to parental cells. Differences in protein log2 LFQ intensities among degrader-resistant and parental cells were determined by paired t test permutation-based adjusted P values at FDR of <0.05 using Perseus software. The top 10 up-regulated proteins in each are shown in (J) and (K), respectively. FC, fold change. (L and M) ABCB1 log2 LFQ values in dBET6-R cells from (H) and Thal-R cells from (I) compared with those in parental A1847 cells. Data are presented as means ± SD from three independent assays. By paired t test permutation-based adjusted P values at FDR of <0.05 using Perseus software, ***P ≤ 0.001. (N) Cell viability assessed by CellTiter-Glo in parental and MZ1-resistant SUM159 cells treated with increasing doses of MZ1 for 5 days. Data were analyzed as % of DMSO control, presented as means of three independent assays. GI50 values were determined using Prism software. (O and P) Immunoblotting for degrader targets and downstream signaling in parental or MZ1-R SUM159 cells treated with increasing doses of MZ1 for 24 hours. The MZ1-R cells were continuously cultured in 500 nM MZ1. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 values were determined in Prism software. (Q and R) Top 10 up-regulated proteins (Q) and ABCB1 log2 LFQ values (R) in MZ1-R cells relative to parental SUM159 cells

Fig. 2. Chronic exposure to degraders induces MDR1 expression and drug efflux activity.
(A) ABCB1 mRNA levels in parental and degrader-resistant cell lines as determined by qRT-PCR. Data are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (B) Immunoblot analysis of MDR1 protein levels in parental and degrader-resistant cell lines. Blots are representative of three independent experiments. (C to E) Immunofluorescence (“IF”) microscopy of MDR1 protein levels in A1847 dBET6-R (C), SUM159 MZ1-R (D), and Thal-R A1847 cells (E) relative to parental cells. Nuclear staining by DAPI. Images are representative of three independent experiments. Scale bars, 100 μm. (F) Drug efflux activity in A1847 dBET6-R, SUM159 MZ1-R, and Thal-R A1847 cells relative to parental cells (Par.) using rhodamine 123 efflux assays. Bars are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (G) Intracellular dBET6 levels in parental or dBET-R A1847 cells transfected with a CRBN sensor and treated with increasing concentrations of dBET6. Intracellular dBET6 levels measured using the CRBN NanoBRET target engagement assay. Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001 by Student’s t test. (H and I) FISH analysis of representative drug-sensitive parental and drug-resistant A1847 (H) and SUM159 (I) cells using ABCB1 and control XCE 7 centromere probes. Images of interphase nuclei were captured with a Metasystems Metafer microscope workstation, and the raw images were extracted and processed to depict ABCB1 signals in magenta, centromere 7 signals in cyan, and DAPI-stained nuclei in blue. (J and K) CpG methylation status of the ABCB1 downstream promoter (coordinates: chr7.87,600,166-87,601,336) by bisulfite amplicon sequencing in parent and degrader-resistant A1847 (J) and SUM159 (K) cells. Images depict the averaged percentage of methylation for each region of the promoter, where methylation status is depicted by color as follows: red, methylated; blue, unmethylated. Schematic of the ABCB1 gene with the location of individual CpG sites is shown. Graphs are representative of three independent experiments. (L and M) Immunoblot analysis of MDR1 protein levels after short-term exposure [for hours (h) or days (d) as indicated] to BET protein degraders dBET6 or MZ1 (100 nM) in A1847 (L) and SUM159 (M) cells, respectively. Blots are representative of three independent experiments. (N to P) Immunoblot analysis of MDR1 protein levels in A1847 and SUM159 cells after long-term exposure (7 to 30 days) to BET protein degraders dBET6 (N), Thal SNS 032 (O), or MZ1 (P), each at 500 nM. Blots are representative of three independent experiments. (Q and R) Immunoblot analysis of MDR1 protein levels in degrader-resistant A1847 (Q) and SUM159 (R) cells after PROTAC removal for 2 or 7 days. Blots are representative of three independent experiments.

 

Fig. 3. Blockade of MDR1 activity resensitizes degrader-resistant cells to PROTACs.
(A and B) Cell viability by CellTiter-Glo assay in parental and degrader-resistant A1847 (A) and SUM159 (B) cells transfected with control siRNA or siRNAs targeting ABCB1 and cultured for 120 hours. Data were analyzed as % of control, presented as means ± SD of three independent assays. ***P ≤ 0.001 by Student’s t test. (C and D) Immunoblot analysis of degrader targets after ABCB1 knockdown in parental and degrader-resistant A1847 (C) and SUM159 (D) cells. Blots are representative, and densitometric analyses using ImageJ are means ± SD of three blots, each normalized to the loading control, GAPDH. (E) Drug efflux activity, using the rhodamine 123 efflux assay, in degrader-resistant cells after MDR1 inhibition by tariquidar (0.1 μM). Data are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (F to H) Cell viability by CellTiter-Glo assay in parental and dBET6-R (F) or Thal-R (G) A1847 cells or MZ1-R SUM159 cells (H) treated with increasing concentrations of tariquidar. Data are % of DMSO control, presented as means ± SD of three independent assays. GI50 value determined with Prism software. (I to K) Immunoblot analysis of degrader targets after MDR1 inhibition (tariquidar, 0.1 μM for 24 hours) in parental and degrader-resistant A1847 cells (I and J) and SUM159 cells (K). Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. (L and M) A 14-day colony formation assessed by crystal violet staining of (L) A1847 cells or (M) SUM159 cells treated with degrader (0.1 μM; dBET6 or MZ1, respectively) and MDR1 inhibitor tariquidar (0.1 μM). Images are representative of three biological replicates. (N) Immunoblotting for MDR1 in SUM159 cells stably expressing FLAG-MDR1 after selection with hygromycin. (O) Long-term 14-day colony formation assay of SUM159 cells expressing FLAG-MDR1 that were treated with DMSO, MZ1 (0.1 μM), or MZ1 and tariquidar (0.1 μM) for 14 days, assessed by crystal violet staining. Representative images of three biological replicates are shown. (P and Q) RT-PCR (P) and immunoblot (Q) analysis of ABCB1 mRNA and MDR1 protein levels, respectively, in parental or MZ1-R HCT116, OVCAR3, and MOLT4 cells.

 

Fig. 4. Overexpression of MDR1 conveys intrinsic resistance to degrader therapies in cancer cells.
(A) Frequency of ABCB1 mRNA overexpression in a panel of cancer cell lines, obtained from cBioPortal for Cancer Genomics using Z-score values of >1.2 for ABCB1 mRNA levels (30). (B) Immunoblot for MDR1 protein levels in a panel of 10 cancer cell lines. Blots are representative of three independent experiments. (C) Cell viability by CellTiter-Glo assay in cancer cell lines expressing high or low MDR1 protein levels and treated with Thal SNS 032 for 5 days. Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. GI50 values were determined with Prism software. (D to F) Immunoblot analysis of CDK9 in MDR1-low (D) or MDR1-high (E) cell lines after Thal SNS 032 treatment for 4 hours. Blots are representative, and densitometric analyses using ImageJ are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value determined with Prism. (G and H) Immunoblotting of control and MDR1-knockdown DLD-1 cells treated for 4 hours with increasing concentrations of Thal SNS 032 [indicated in (H)]. Blots are representative, and densitometric analysis data are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value determined with Prism. (I) Drug efflux activity using rhodamine 123 efflux assays in DLD-1 cells treated with DMSO or 0.1 μM tariquidar. Data are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (J) Intracellular Thal SNS 032 levels, using the CRBN NanoBRET target engagement assay, in MDR1-overexpressing DLD-1 cells treated with DMSO or 0.1 μM tariquidar and increasing doses of Thal SNS 032. Data are % of DMSO control, presented as means ± SD of three independent assays. **P ≤ 0.01 and ***P ≤ 0.001 by Student’s t test. (K to N) Immunoblotting in DLD-1 cells treated with increasing doses of Thal SNS 032 (K and L) or dBET6 (M and N) alone or with tariquidar (0.1 μM) for 4 hours. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value of Thal SNS 032 for CDK9 reduction (L) or of dBET6 for BRD4 reduction (N) determined with Prism. (O to T) Bliss synergy scores based on cell viability by CellTiter-Glo assay, colony formation, and immunoblotting in DLD-1 cells treated with the indicated doses of Thal SNS 032 (O to Q) or dBET6 (R to T) alone or with tariquidar. Cells were treated for 14 days for colony formation assays and 24 hours for immunoblotting.

 

Fig. 5. Repurposing dual kinase/MDR1 inhibitors to overcome degrader resistance in cancer cells.
(A and B) Drug efflux activity by rhodamine 123 efflux assays in degrader-resistant [dBET-R (A) or Thal-R (B)] A1847 cells after treatment with tariquidar, RAD001, or lapatinib (each 2 μM). Data are means ± SD of three independent experiments. *P ≤ 0.05 by Student’s t test. (C and D) CellTiter-Glo assay for the cell viability of parental, dBET6-R, or Thal-R A1847 cells treated with increasing concentrations of RAD001 (C) or lapatinib (D). Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. GI50 values were determined with Prism software. (E to I) Immunoblot analysis of degrader targets in parental (E), dBET6-R (F and G), and Thal-R (H and I) A1847 cells treated with increasing concentrations of RAD001 or lapatinib for 4 hours. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value of dBET6 for BRD4 reduction (G) or of Thal SNS 032 for CDK9 reduction (I) determined with Prism. (J) Immunoblotting for cleaved PARP in dBET6-R or Thal-R A1847 cells treated with RAD001, lapatinib, or tariquidar (each 2 μM) for 24 hours. Blots are representative of three independent blots. (K to N) Immunoblotting for BRD4 in DLD-1 cells treated with increasing doses of dBET6 alone or in combination with either RAD001 or lapatinib [each 2 μM (K and L)] or KU-0063794 or afatinib [each 2 μM (M and N)] for 4 hours. Blots are representative of three independent experiments and, in (L), are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value for BRD4 reduction (L) determined in Prism. (O) Colony formation by DLD-1 cells treated with DMSO, dBET6 (0.1 μM), lapatinib (2 μM), afatinib (2 μM), RAD001 (2 μM), KU-0063794 (2 μM), or the combination of inhibitor and dBET6 for 14 days. Images representative of three independent assays. (P and Q) Immunoblotting for CDK9 in DLD-1 cells treated with increasing doses of Thal SNS 032 and/or RAD001 (2 μM) or lapatinib (2 μM) for 4 hours. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value for CDK9 reduction determined with Prism (Q). (R) Colony formation in DLD-1 cells treated with DMSO, Thal SNS 032 (0.5 μM), lapatinib (2 μM), and/or RAD001 (2 μM) as indicated for 14 days.

 

Fig. 6. Combining MEK1/2 degraders with lapatinib synergistically kills MDR1-overexpressing KRAS-mutant CRC cells and tumors.
(A and B) ABCB1 expression in KRAS-mutant CRC cell lines from cBioPortal (30) (A) and MDR1 abundance in select KRAS-mutant CRC cell lines (B). (C) Cell viability assessed by CellTiter-Glo in CRC cells treated with increasing doses of MS432 for 5 days, analyzed as % of DMSO control. GI50 value determined with Prism software. (D) Colony formation by CRC cells 14 days after treatment with 1 μM MS432. (E) MEK1/2 protein levels assessed by immunoblot in CRC lines SKCO1 (low MDR1) or LS513 (high MDR1) treated with increasing doses of MS432 for 4 hours. (F) Rhodamine 123 efflux in LS513 cells treated with DMSO, 2 μM tariquidar, or 2 μM lapatinib. (G and H) Immunoblotting analysis in LS513 cells treated with increasing doses of MS432 alone or in combination with tariquidar (0.1 μM) or lapatinib (5 μM) for 24 hours. DC50 value for MEK1 levels determined with Prism. (I) Immunoblotting in LS513 cells treated with DMSO, PD0325901 (0.01 μM), lapatinib (5 μM), or the combination for 48 hours. (J and K) Immunoblotting in LS513 cells treated either with DMSO, MS432 (1 μM), tariquidar (0.1 μM) (J), or lapatinib (5 μM) (K), alone or in combination. (L) Bliss synergy scores determined from cell viability assays (CellTiter-Glo) in LS513 cells treated with increasing concentrations of MS432, lapatinib, or the combination. (M and N) Colony formation by LS513 cells (M) and others (N) treated with DMSO, lapatinib (2 μM), MS432 (1 μM), or the combination for 14 days. (O and P) Immunoblotting in LS513 cells treated with increasing doses of MS934 alone (O) or combined with lapatinib (5 μM) (P) for 24 hours. (Q and R) Tumor volume of LS513 xenografts (Q) and the body weights of the tumor-bearing nude mice (R) treated with vehicle, MS934 (50 mg/kg), lapatinib (100 mg/kg), or the combination. n = 5 mice per treatment group. In (A) to (R), blots and images are representative of three independent experiments, and quantified data are means ± SD [SEM in (Q) and (R)] of three independent experiments; ***P ≤ 0.001 by Student’s t test.

 

Fig. 7. Lapatinib treatment improves KRASG12C degrader therapies in MDR1-overexpressing CRC cell lines.
(A and B) Colony formation by SW1463 (A) or SW837 (B) cells treated with DMSO, LC-2 (1 μM), or MRTX849 (1 μM) for 14 days. Images representative of three independent assays. (C to E) Immunoblotting in SW1463 cells (C and D) and SW837 cells (E) treated with DMSO, LC-2 (1 μM), tariquidar (0.1 μM) (C), or lapatinib (5 μM) (D and E) alone or in combination for 48 hours. Blots are representative of three independent experiments. (F and G) Bliss synergy scores based on CellTiter-Glo assay for the cell viability of SW1463 (F) or SW837 (G) cells treated with increasing concentrations of LC-2, lapatinib, or the combination. Data are means of three experiments ± SD. (H and I) Colony formation of SW1463 (H) or SW837 (I) cells treated as indicated (−, DMSO; LC-2, 1 μM; lapatinib, 2 μM; tariquidar, 0.1 μM) for 14 days. Images representative of three independent assays. (J) Rationale for combining lapatinib with MEK1/2 or KRASG12C degraders in MDR1-overexpressing CRC cell lines. Simultaneous blockade of MDR1 and ErbB receptor signaling overcomes degrader resistance and ErbB receptor kinome reprogramming, resulting in sustained inhibition of KRAS effector signaling.

SOURCE

Other articles in this Open Access Scientific Journal on PROTAC therapy in cancer include

Accelerating PROTAC drug discovery: Establishing a relationship between ubiquitination and target protein degradation

The Vibrant Philly Biotech Scene: Proteovant Therapeutics Using Artificial Intelligence and Machine Learning to Develop PROTACs

The Map of human proteins drawn by artificial intelligence and PROTAC (proteolysis targeting chimeras) Technology for Drug Discovery

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Accelerating PROTAC drug discovery: Establishing a relationship between ubiquitination and target protein degradation

Curator: Stephen J. Williams, Ph.D.

PROTACs have been explored in multiple disease fields with focus on only few ligases like cereblon (CRBN), Von Hippel-Lindau (VHL), IAP and MDM2. Cancer targets like androgen receptor, estrogen receptor, BTK, BCL2, CDK8 and c-MET [[6], [7], [8], [9], [10], [11]] have been successfully targeted using PROTACs. A variety of BET family (BRD2, BRD3, and BRD4)- PROTACs were designed using multiple ligases; MDM2-based BRD4 PROTAC [12], CRBN based dBET1 [13] and BETd-24-6 [14] for triple-negative breast cancer, enhanced membrane permeable dBET6 [15], and dBET57 PROTAC [16]. PROTACs for Hepatitis c virus (HCV) protease, IRAK4 and Tau [[17], [18], [19]] have been explored for viral, immune and neurodegenerative diseases, respectively. Currently, the PROTAC field expansion to vast undruggable proteome is hindered due to narrow focus on select E3 ligases. Lack of reliable tools to rapidly evaluate PROTACs based on new ligases is hindering the progress. Screening platforms designed must be physiologically relevant and represent true PROTAC cellular function, i.e., PROTAC-mediated target ubiquitination and degradation.

In the current study, we employ TUBEs as affinity capture reagents to monitor PROTAC-induced poly-ubiquitination and degradation as a measure of potency. We established and validated proof-of-concept cell-based assays in a 96-well format using PROTACS for three therapeutic targets BET family proteins, kinases, and KRAS. To our knowledge, the proposed PROTAC assays are first of its kind that can simultaneously 1) detect ubiquitination of endogenous, native protein targets, 2) evaluate the potency of PROTACs, and 3) establish a link between the UPS and protein degradation. Using these TUBE assays, we established rank order potencies between four BET family PROTACs dBET1, dBET6, BETd246 and dBET57 based on peak ubiquitination signals (“UbMax”) of the target protein. TUBE assay was successful in demonstrating promiscuous kinase PROTACs efficiency to degrade Aurora Kinase A at sub-nanomolar concentrations within 1 h. A comparative study to identify changes in the ubiquitination and degradation profile of KRAS G12C PROTACs recruiting two E3 ligases (CRBN and VHL). All of the ubiquitination and degradation profiles obtained from TUBE based assays correlate well with traditional low throughput immunoblotting. Significant correlation between DC50 obtained from protein degradation in western blotting and UbMax values demonstrates our proposed assays can aid in high-throughput screening and drastically eliminate artifacts to overcome bottlenecks in PROTAC drug discovery.

To successfully set up HTS screening with novel PROTACs without pre-existing knowledge, we recommend the following steps. 1. Identify a model PROTAC that can potentially demonstrate activity based on knowledge in PROTAC design or in vitro binding studies. 2. Perform a time course study with 2–3 doses of the model PROTAC based on affinities of the ligands selected. 3. Monitor ubiquitination and degradation profiles using plate-based assay and identify time point that demonstrates UbMax. 4. Perform a dose response at selected time point with a library of PROTACs to establish rank order potency.

INTRODUCTION

Ubiquitination is a major regulatory mechanism to maintain cellular protein homeostasis by marking proteins for proteasomal-mediated degradation [1]. Given ubiquitin’s role in a variety of pathologies, the idea of targeting the Ubiquitin Proteasome System (UPS) is at the forefront of drug discovery [2]. “Event-driven” protein degradation using the cell’s own UPS is a promising technology for addressing the “undruggable” proteome [3]. Targeted protein degradation (TPD) has emerged as a new paradigm and promising therapeutic option to selectively attack previously intractable drug targets using PROteolytic TArgeting Chimeras (PROTACs) [4]. PROTACs are heterobifunctional molecules with a distinct ligand that targets a specific E3 ligase which is tethered to another ligand specific for the target protein using an optimized chemical linker. A functional PROTAC induces a ternary E3-PROTAC-target complex, resulting in poly-ubiquitination and subsequent controlled protein degradation [5]. Ability to function at sub-stoichiometric levels for efficient degradation, a significant advantage over traditional small molecules.

PROTACs have been explored in multiple disease fields with focus on only few ligases like cereblon (CRBN), Von Hippel-Lindau (VHL), IAP and MDM2. Cancer targets like androgen receptorestrogen receptor, BTK, BCL2, CDK8 and c-MET [[6][7][8][9][10][11]] have been successfully targeted using PROTACs. A variety of BET family (BRD2, BRD3, and BRD4)- PROTACs were designed using multiple ligases; MDM2-based BRD4 PROTAC [12], CRBN based dBET1 [13] and BETd-24-6 [14] for triple-negative breast cancer, enhanced membrane permeable dBET6 [15], and dBET57 PROTAC [16]. PROTACs for Hepatitis c virus (HCV) proteaseIRAK4 and Tau [[17][18][19]] have been explored for viral, immune and neurodegenerative diseases, respectively. Currently, the PROTAC field expansion to vast undruggable proteome is hindered due to narrow focus on select E3 ligases. Lack of reliable tools to rapidly evaluate PROTACs based on new ligases is hindering the progress. Screening platforms designed must be physiologically relevant and represent true PROTAC cellular function, i.e., PROTAC-mediated target ubiquitination and degradation.

Cellular PROTAC screening is traditionally performed using cell lines harboring reporter genes and/or Western blotting. While Western blotting is easy to perform, they are low throughput, semi-quantitative and lack sensitivity. While reporter gene assays address some of the issues, they are challenged by reporter tags having internal lysines leading to artifacts. Currently, no approaches are available that can identify true PROTAC effects such as target ubiquitination and proteasome-mediated degradation simultaneously. High affinity ubiquitin capture reagents like TUBEs [20] (tandem ubiquitin binding entities), are engineered ubiquitin binding domains (UBDs) that allow for detection of ultralow levels of polyubiquitinated proteins under native conditions with affinities as low as 1 nM. The versatility and selectivity of TUBEs makes them superior to antibodies, and they also offer chain-selectivity (-K48, -K63, or linear) [21]. High throughput assays that can report the efficacy of multiple PROTACs simultaneously by monitoring PROTAC mediated ubiquitination can help establish rank order potency and guide chemists in developing meaningful structure activity relationships (SAR) rapidly.

In the current study, we employ TUBEs as affinity capture reagents to monitor PROTAC-induced poly-ubiquitination and degradation as a measure of potency. We established and validated proof-of-concept cell-based assays in a 96-well format using PROTACS for three therapeutic targets BET family proteins, kinases, and KRAS. To our knowledge, the proposed PROTAC assays are first of its kind that can simultaneously 1) detect ubiquitination of endogenous, native protein targets, 2) evaluate the potency of PROTACs, and 3) establish a link between the UPS and protein degradation. Using these TUBE assays, we established rank order potencies between four BET family PROTACs dBET1, dBET6, BETd246 and dBET57 based on peak ubiquitination signals (“UbMax”) of the target protein. TUBE assay was successful in demonstrating promiscuous kinase PROTACs efficiency to degrade Aurora Kinase A at sub-nanomolar concentrations within 1 h. A comparative study to identify changes in the ubiquitination and degradation profile of KRAS G12C PROTACs recruiting two E3 ligases (CRBN and VHL). All of the ubiquitination and degradation profiles obtained from TUBE based assays correlate well with traditional low throughput immunoblotting. Significant correlation between DC50 obtained from protein degradation in western blotting and UbMax values demonstrates our proposed assays can aid in high-throughput screening and drastically eliminate artifacts to overcome bottlenecks in PROTAC drug discovery.

Fig. 1. Schematic representation of TUBE assay to monitor PROTAC mediated cellular ubiquitination of target proteins.
Fig. 2. TUBE based assay screening of PROTACs: Jurkat cell lysates were treated with BRD3-specific PROTACs A) dBET1, B) dBET6, C) BETd24-6, and D) dBET57. Polyubiquitination profiles and Ubmax of BRD3 for each PROTAC were represented as relative CL intensity. Relative CL intensities were calculated by dividing raw CL signals from a given PROTAC dose over DMSO treated samples. Error bars represent standard deviations, n = 3.
Fig. 3. PROTAC mediated degradation of bromodomain proteins analyzed by anti-BRD3 western blotting. Dose response of PROTACs dBET1, dBET6, Betd-24-6 and dBET57 at 45 min in Jurkat cells demonstrates degradation of BRD3, Acting as loading control.

 

 

 

 

 

 

 

 

 

Fig. 4. PROTAC mediated ubiquitination and degradation of AURKA in K562 cells. (A) Time course study to evaluate intracellular ubiquitination and degradation. (B) Western blot analysis of time course study: degradation kinetics (C) A dose response study to evaluate DC50 of the promiscuous kinase PROTAC in K562 cells. (D) Western blot analysis of dose response study to monitor degradation, GAPDH as loading control. Error bars represent standard deviation, n = 3.

SOURCE

https://www.sciencedirect.com/science/article/abs/pii/S0006291X22011792

Other articles of PROTACs in this Open Access Journal Include

The Vibrant Philly Biotech Scene: Proteovant Therapeutics Using Artificial Intelligence and Machine Learning to Develop PROTACs

The Map of human proteins drawn by artificial intelligence and PROTAC (proteolysis targeting chimeras) Technology for Drug Discovery

Live Conference Coverage AACR 2020 in Real Time: Monday June 22, 2020 Late Day Sessions

From High-Throughput Assay to Systems Biology: New Tools for Drug Discovery

 

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New studies link cell cycle proteins to immunosurveillance of premalignant cells

Curator: Stephen J. Williams, Ph.D.

The following is from a Perspectives article in the journal Science by Virinder Reen and Jesus Gil called “Clearing Stressed Cells: Cell cycle arrest produces a p21-dependent secretome that initaites immunosurveillance of premalignant cells”. This is a synopsis of the Sturmlechener et al. research article in the same issue (2).

Complex organisms repair stress-induced damage to limit the replication of faulty cells that could drive cancer. When repair is not possible, tissue homeostasis is maintained by the activation of stress response programs such as apoptosis, which eliminates the cells, or senescence, which arrests them (1). Cellular senescence causes the arrest of damaged cells through the induction of cyclin-dependent kinase inhibitors (CDKIs) such as p16 and p21 (2). Senescent cells also produce a bioactive secretome (the senescence-associated secretory phenotype, SASP) that places cells under immunosurveillance, which is key to avoiding the detrimental inflammatory effects caused by lingering senescent cells on surrounding tissues. On page 577 of this issue, Sturmlechner et al. (3) report that induction of p21 not only contributes to the arrest of senescent cells, but is also an early signal that primes stressed cells for immunosurveillance.Senescence is a complex program that is tightly regulated at the epigenetic and transcriptional levels. For example, exit from the cell cycle is controlled by the induction of p16 and p21, which inhibit phosphorylation of the retinoblastoma protein (RB), a transcriptional regulator and tumor suppressor. Hypophosphorylated RB represses transcription of E2F target genes, which are necessary for cell cycle progression. Conversely, production of the SASP is regulated by a complex program that involves super-enhancer (SE) remodeling and activation of transcriptional regulators such as nuclear factor κB (NF-κB) or CCAAT enhancer binding protein–β (C/EBPβ) (4).

Senescence is a complex program that is tightly regulated at the epigenetic and transcriptional levels. For example, exit from the cell cycle is controlled by the induction of p16 and p21, which inhibit phosphorylation of the retinoblastoma protein (RB), a transcriptional regulator and tumor suppressor. Hypophosphorylated RB represses transcription of E2F target genes, which are necessary for cell cycle progression. Conversely, production of the SASP is regulated by a complex program that involves super-enhancer (SE) remodeling and activation of transcriptional regulators such as nuclear factor κB (NF-κB) or CCAAT enhancer binding protein–β (C/EBPβ) (4).

Sturmlechner et al. found that activation of p21 following stress rapidly halted cell cycle progression and triggered an internal biological timer (of ∼4 days in hepatocytes), allowing time to repair and resolve damage (see the figure). In parallel, C-X-C motif chemokine 14 (CXCL14), a component of the PASP, attracted macrophages to surround and closely surveil these damaged cells. Stressed cells that recovered and normalized p21 expression suspended PASP production and circumvented immunosurveillance. However, if the p21-induced stress was unmanageable, the repair timer expired, and the immune cells transitioned from surveillance to clearance mode. Adjacent macrophages mounted a cytotoxic T lymphocyte response that destroyed damaged cells. Notably, the overexpression of p21 alone was sufficient to orchestrate immune killing of stressed cells, without the need of a senescence phenotype. Overexpression of other CDKIs, such as p16 and p27, did not trigger immunosurveillance, likely because they do not induce CXCL14 expression.In the context of cancer, senescent cell clearance was first observed following reactivation of the tumor suppressor p53 in liver cancer cells. Restoring p53 signaling induced senescence and triggered the elimination of senescent cells by the innate immune system, prompting tumor regression (5). Subsequent work has revealed that the SASP alerts the immune system to target preneoplastic senescent cells. Hepatocytes expressing the oncogenic mutant NRASG12V (Gly12→Val) become senescent and secrete chemokines and cytokines that trigger CD4+ T cell–mediated clearance (6). Despite the relevance for tumor suppression, relatively little is known about how immunosurveillance of oncogene-induced senescent cells is initiated and controlled.

Source of image: Reen, V. and Gil, J. Clearing Stressed Cells. Science Perspectives 2021;Vol 374(6567) p 534-535.

References

2. Sturmlechner I, Zhang C, Sine CC, van Deursen EJ, Jeganathan KB, Hamada N, Grasic J, Friedman D, Stutchman JT, Can I, Hamada M, Lim DY, Lee JH, Ordog T, Laberge RM, Shapiro V, Baker DJ, Li H, van Deursen JM. p21 produces a bioactive secretome that places stressed cells under immunosurveillance. Science. 2021 Oct 29;374(6567):eabb3420. doi: 10.1126/science.abb3420. Epub 2021 Oct 29. PMID: 34709885.

More Articles on Cancer, Senescence and the Immune System in this Open Access Online Scientific Journal Include

Bispecific and Trispecific Engagers: NK-T Cells and Cancer Therapy

Natural Killer Cell Response: Treatment of Cancer

Issues Need to be Resolved With ImmunoModulatory Therapies: NK cells, mAbs, and adoptive T cells

New insights in cancer, cancer immunogenesis and circulating cancer cells

Insight on Cell Senescence

Immune System Stimulants: Articles of Note @pharmaceuticalintelligence.com

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#TUBiol5227: Biomarkers & Biotargets: Genetic Testing and Bioethics

Curator: Stephen J. Williams, Ph.D.

The advent of direct to consumer (DTC) genetic testing and the resultant rapid increase in its popularity as well as companies offering such services has created some urgent and unique bioethical challenges surrounding this niche in the marketplace. At first, most DTC companies like 23andMe and Ancestry.com offered non-clinical or non-FDA approved genetic testing as a way for consumers to draw casual inferences from their DNA sequence and existence of known genes that are linked to disease risk, or to get a glimpse of their familial background. However, many issues arose, including legal, privacy, medical, and bioethical issues. Below are some articles which will explain and discuss many of these problems associated with the DTC genetic testing market as well as some alternatives which may exist.

‘Direct-to-Consumer (DTC) Genetic Testing Market to hit USD 2.5 Bn by 2024’ by Global Market Insights

This post has the following link to the market analysis of the DTC market (https://www.gminsights.com/pressrelease/direct-to-consumer-dtc-genetic-testing-market). Below is the highlights of the report.

As you can see,this market segment appears to want to expand into the nutritional consulting business as well as targeted biomarkers for specific diseases.

Rising incidence of genetic disorders across the globe will augment the market growth

Increasing prevalence of genetic disorders will propel the demand for direct-to-consumer genetic testing and will augment industry growth over the projected timeline. Increasing cases of genetic diseases such as breast cancer, achondroplasia, colorectal cancer and other diseases have elevated the need for cost-effective and efficient genetic testing avenues in the healthcare market.
 

For instance, according to the World Cancer Research Fund (WCRF), in 2018, over 2 million new cases of cancer were diagnosed across the globe. Also, breast cancer is stated as the second most commonly occurring cancer. Availability of superior quality and advanced direct-to-consumer genetic testing has drastically reduced the mortality rates in people suffering from cancer by providing vigilant surveillance data even before the onset of the disease. Hence, the aforementioned factors will propel the direct-to-consumer genetic testing market overt the forecast timeline.
 

DTC Genetic Testing Market By Technology

Get more details on this report – Request Free Sample PDF
 

Nutrigenomic Testing will provide robust market growth

The nutrigenomic testing segment was valued over USD 220 million market value in 2019 and its market will witness a tremendous growth over 2020-2028. The growth of the market segment is attributed to increasing research activities related to nutritional aspects. Moreover, obesity is another major factor that will boost the demand for direct-to-consumer genetic testing market.
 

Nutrigenomics testing enables professionals to recommend nutritional guidance and personalized diet to obese people and help them to keep their weight under control while maintaining a healthy lifestyle. Hence, above mentioned factors are anticipated to augment the demand and adoption rate of direct-to-consumer genetic testing through 2028.
 

Browse key industry insights spread across 161 pages with 126 market data tables & 10 figures & charts from the report, “Direct-To-Consumer Genetic Testing Market Size By Test Type (Carrier Testing, Predictive Testing, Ancestry & Relationship Testing, Nutrigenomics Testing), By Distribution Channel (Online Platforms, Over-the-Counter), By Technology (Targeted Analysis, Single Nucleotide Polymorphism (SNP) Chips, Whole Genome Sequencing (WGS)), Industry Analysis Report, Regional Outlook, Application Potential, Price Trends, Competitive Market Share & Forecast, 2020 – 2028” in detail along with the table of contents:
https://www.gminsights.com/industry-analysis/direct-to-consumer-dtc-genetic-testing-market
 

Targeted analysis techniques will drive the market growth over the foreseeable future

Based on technology, the DTC genetic testing market is segmented into whole genome sequencing (WGS), targeted analysis, and single nucleotide polymorphism (SNP) chips. The targeted analysis market segment is projected to witness around 12% CAGR over the forecast period. The segmental growth is attributed to the recent advancements in genetic testing methods that has revolutionized the detection and characterization of genetic codes.
 

Targeted analysis is mainly utilized to determine any defects in genes that are responsible for a disorder or a disease. Also, growing demand for personalized medicine amongst the population suffering from genetic diseases will boost the demand for targeted analysis technology. As the technology is relatively cheaper, it is highly preferred method used in direct-to-consumer genetic testing procedures. These advantages of targeted analysis are expected to enhance the market growth over the foreseeable future.
 

Over-the-counter segment will experience a notable growth over the forecast period

The over-the-counter distribution channel is projected to witness around 11% CAGR through 2028. The segmental growth is attributed to the ease in purchasing a test kit for the consumers living in rural areas of developing countries. Consumers prefer over-the-counter distribution channel as they are directly examined by regulatory agencies making it safer to use, thereby driving the market growth over the forecast timeline.
 

Favorable regulations provide lucrative growth opportunities for direct-to-consumer genetic testing

Europe direct-to-consumer genetic testing market held around 26% share in 2019 and was valued at around USD 290 million. The regional growth is due to elevated government spending on healthcare to provide easy access to genetic testing avenues. Furthermore, European regulatory bodies are working on improving the regulations set on the direct-to-consumer genetic testing methods. Hence, the above-mentioned factors will play significant role in the market growth.
 

Focus of market players on introducing innovative direct-to-consumer genetic testing devices will offer several growth opportunities

Few of the eminent players operating in direct-to-consumer genetic testing market share include Ancestry, Color Genomics, Living DNA, Mapmygenome, Easy DNA, FamilytreeDNA (Gene By Gene), Full Genome Corporation, Helix OpCo LLC, Identigene, Karmagenes, MyHeritage, Pathway genomics, Genesis Healthcare, and 23andMe. These market players have undertaken various business strategies to enhance their financial stability and help them evolve as leading companies in the direct-to-consumer genetic testing industry.
 

For example, in November 2018, Helix launched a new genetic testing product, DNA discovery kit, that allows customer to delve into their ancestry. This development expanded the firm’s product portfolio, thereby propelling industry growth in the market.

The following posts discuss bioethical issues related to genetic testing and personalized medicine from a clinicians and scientisit’s perspective

Question: Each of these articles discusses certain bioethical issues although focuses on personalized medicine and treatment. Given your understanding of the robust process involved in validating clinical biomarkers and the current state of the DTC market, how could DTC testing results misinform patients and create mistrust in the physician-patient relationship?

Personalized Medicine, Omics, and Health Disparities in Cancer:  Can Personalized Medicine Help Reduce the Disparity Problem?

Diversity and Health Disparity Issues Need to be Addressed for GWAS and Precision Medicine Studies

Genomics & Ethics: DNA Fragments are Products of Nature or Patentable Genes?

The following posts discuss the bioethical concerns of genetic testing from a patient’s perspective:

Ethics Behind Genetic Testing in Breast Cancer: A Webinar by Laura Carfang of survivingbreastcancer.org

Ethical Concerns in Personalized Medicine: BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk

23andMe Product can be obtained for Free from a new app called Genes for Good: UMich’s Facebook-based Genomics Project

Question: If you are developing a targeted treatment with a companion diagnostic, what bioethical concerns would you address during the drug development process to ensure fair, equitable and ethical treatment of all patients, in trials as well as post market?

Articles on Genetic Testing, Companion Diagnostics and Regulatory Mechanisms

Centers for Medicare & Medicaid Services announced that the federal healthcare program will cover the costs of cancer gene tests that have been approved by the Food and Drug Administration

Real Time Coverage @BIOConvention #BIO2019: Genome Editing and Regulatory Harmonization: Progress and Challenges

New York Times vs. Personalized Medicine? PMC President: Times’ Critique of Streamlined Regulatory Approval for Personalized Treatments ‘Ignores Promising Implications’ of Field

Live Conference Coverage @Medcitynews Converge 2018 Philadelphia: Early Diagnosis Through Predictive Biomarkers, NonInvasive Testing

Protecting Your Biotech IP and Market Strategy: Notes from Life Sciences Collaborative 2015 Meeting

Question: What type of regulatory concerns should one have during the drug development process in regards to use of biomarker testing? From the last article on Protecting Your IP how important is it, as a drug developer, to involve all payers during the drug development process?

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