Healthcare analytics, AI solutions for biological big data, providing an AI platform for the biotech, life sciences, medical and pharmaceutical industries, as well as for related technological approaches, i.e., curation and text analysis with machine learning and other activities related to AI applications to these industries.
Non – CME – dSTRIDE™-HR: A Functional Biomarker for In Situ, ‘real-time’ Detection and Quantification of Homologous Recombination Activity.
Magda Kordon-Kiszala, PhD, CEO and co-founder,intoDNA
12:35-12:55
Epigenetic Plasticity and Tumor Evolution: Mechanisms of Resistance in Precision Oncology
Johnathan R. Whetstine, PhD, Director, Cancer Epigenetics Institute, Director, Geonomics Resource, Fox Chase Cancer Center
Title: Epigenetic plasticity a gatekeeper to generating extrachromosomal DNA amplification and rearrangements
genetic events in cancer are actually controlled not random as he says
Fox Chase Cancer Center Epigenetics Institute; 5th year goal to understand epigenetic mechanisms to understand resistance and biomarker development; bring others and break down silos; they are expanding and hiring and bringing into a network; March 5 2026 5th Annual Symposium Philadelphia Franklin Institute
DNA amplification is also chromosomal: integrated same locus or different regions or chromosomal duplication
KDM4A epigenetic demethylase controls transiet site specific DNA re-replication; can have focal control of DNA regions
you can control regional control of like EGFR amplification
can use Cy3 to find local regions
KDM3B inhibitor promotes transiet copy gains in KMT2A/MLL
EHMT2 is lysine demethylase is a driver of this copy amplification
this demethylase can change expression locally in one hour.. very fast
demethylases are very specific for their gene locus they control and so this demethylase only controls MLL gene
doxorubicin topoisomerase inhibitor can cause LOH in MLL locus and methylase inhibitor can reverse this
over twenty combinatorial regulators so this field is just budding
11:30-12:30
Companion Diagnostics in Hereditary and Chronic Diseases – Development, Regulatory Approval, and Commercialization – Non-CME Discussion
Huw Ricketts PhD, Senior Director, CLIA Business Development, QIAGEN
Tricia Carrigan, PhD, BC Biosolutions
Arushi Agarwal, MS, Partner, Health Advances
Melissa Reuter, MS, MBA, Director, Precision Medicine Program Strategy, GSK
This is a session panel Discussion on the current state of companion diagnostic development, not just in oncology. Regulatory aspects will be discussed
Arushi: There are alot of opportunities in non-oncology areas for companion diagnostics, and time to development may be an obstacle
Huw Rickets: From a development standpoint most people are not looking at the diagnostic side but more on the therapeutic side.
Tricia: There needs to be a shift in oncology drug development world, and pharma sees developing diagnostic is too expensive.
Meliisa: They try to engage early with the agencies to understand the regulatory landscape; GSK is very strong in their oncology platform but there are gaps in diagnostics and non-oncology programs
Arushi: seems in Pharma oncology and non-oncology programs seems siloed
for non-oncology many of the biomarkers may be rare… well under 25% of population
Huw: Qiagen trying to develop diagnostics for Parkinson’s but those rare genetic diseases are easier to develop
Arushi: neurodegenerative, NASH, and immuno diseases are big areas where companies are looking to make companion diagnostics
Huw: kidney disease is a big focus to develop companion diagnostics for
12:30-12:40
Non – CME – dSTRIDE™-HR: A Functional Biomarker for In Situ, ‘real-time’ Detection and Quantification of Homologous Recombination Activity.
Magda Kordon-Kiszala, PhD, CEO and co-founder,intoDNA
Tumor board Live… Molecular profiling great for identifying synthetic lethal combinations work very well… Many oncologist not accepting recommendations of molec tumor board
Tumor board Live . Oncologists don’t always accept tumor board recommendations based on molecular profiling… Dr Baptiste at first felt constrained to use single agent but WINTER combo trial with molec profiling better
Tumor board Live… Oncologist may give pushback when molecular therapeutic targets identified.. like when methylomics give a result and tumor board suggest temazolamide
Tumor board Live… Oncologist may give pushback when molecular therapeutic targets identified.. like when methylomics give a result and tumor board suggest temazolamide
Tumor board Live… Oncologist may give pushback when molecular therapeutic targets identified.. like when methylomics give a result and tumor board suggest temazolamide
Tumor board Live… Discussion of ovarian cancer case women first presented with CRC BRCA mut but failed PARP inhibitor board is looking at immunotherapy NGS IHC performed
Tumor board Live… Molecular profiling great for identifying synthetic lethal combinations work very well… Many oncologist not accepting recommendations of molec tumor board
Dr. El-Diery welcomes all to this joint symposium with Advancing Precision Medicine and the Win Consortium, which he is currently the head of. More in the WIN Consortium: (Worldwide Innovation Network Consortium in Precision Oncology). The WIN Network is involved in setting up internationalclinical tumor board collaboration
WIN was formed on the premise that we can accomplish more together than each organization can achieve working alone. We aim to improve cancer patients’ survival and quality of life. View WIN’s history and unique attributes:
WIN members collaboratively design and carry out global studies designed to achieve breakthroughs for patients worldwide. Our distinguished Scientific Advisory Board oversees WIN studies. Current trials include:
They guide WIN’s strategic, operational, and scientific direction.
OrganizationThe WIN Consortium is organized in the following groups who collectively work together to achieve WIN’s common goals
Nigel Russell, Founder and CEO, Advancing Precision Medicine
Christopher P. Molineaux, President & Chief Executive Officer, Life Science Pennsylvania
Life Sciences Pennsylvania (LSPA) is the statewide trade association for the commonwealth’s life sciences industry. Founded in 1989, LSPA works to ensure Pennsylvania has a business and public policy climate that makes the commonwealth the most attractive location to open and operate a life sciences company. Our membership is comprised of organizations statewide, representing the entire ecosystem of the life sciences: research institutions, biotechnology, medical device, diagnostic, pharmaceutical, and investment entities, along with service providers who support the industry. Together, we unify Pennsylvania’s innovators to make the Commonwealth a global life sciences leader.
As president & CEO of Life Sciences Pennsylvania, Christopher Molineaux serves as the chief advocate and spokesman for the life sciences industry that calls Pennsylvania home. Molineaux oversees the strategic direction for the association, assuring Life Sciences Pennsylvania continues to be the catalyst that makes Pennsylvania the top location for life sciences companies.
Molineaux brings to Life Sciences Pennsylvania more than 25 years of experience in the bio-pharmaceutical and health care industries, with front-line experience in developing and executing strategies to navigate a shifting economic and political environment.
9:00-9:40
Keynote Lecture – WIN Consortium
Targeting the Achilles’ Heel of Cancer: Synthetic Lethality and Hypoxia in Precision Oncology
William Kaelin was born in New York City. He studied chemistry and mathematics at Duke University in Durham, North Carolina, and received his doctor of medicine degree there in 1982. He then did his residency at Johns Hopkins University in Baltimore, Maryland. In 2002 he became a professor at Harvard Medical School in Cambridge, Massachusetts.
Work
Animals need oxygen for the conversion of food into useful energy. The importance of oxygen has been understood for centuries, but how cells adapt to changes in levels of oxygen has long been unknown. William Kaelin, Peter Ratcliffe, and Gregg Semenza discovered how cells can sense and adapt to changing oxygen availability. During the 1990s they identified a molecular machinery that regulates the activity of genes in response to varying levels of oxygen. The discoveries may lead to new treatments of anemia, cancer and many other diseases.
TRACK 1 204BC
WIN SYMPOSIUM
MULTI-OMICS
9:40 – 10:40
SESSION 1
From Base Pairs To Better Care:
AI and Omics in Precision Oncology
9:40-10:00
Multi-Omic Profiling and Clinical Decision Support in Precision Oncology
David Spetzler, PhD, MBA, MS, President, Caris Life Sciences
10:00-10:20
Integrating Omics and AI for Next-Gen Precision Oncology
Keith T. Flaherty, MD, FAACR, Director of Clinical Research,Massachusetts General Cancer Center; Professor of Medicine, Harvard Medical School; President-Elect: 2025-2026, American Association for Cancer Research (AACR)
10:20-10:40
Real-World Data and AI in Precision Oncology: Making Data Work for Patients – Q&A
MODERATOR: Jeff Elton, PhD, Vice Chairman, Founding CEO
ConcertAI
PANELISTS: David Spetzler, PhD, MBA, MS, President, Caris Life Sciences
Keith T. Flaherty, MD, FAACR, Director of Clinical Research,Massachusetts General Cancer Center; Professor of Medicine, Harvard Medical School; President-Elect: 2025-2026, American Association for Cancer Research (AACR)
Daryl Pritchard, PhD, Interim President, Personalized Medicine Coalition
Keith T. Flaherty, MD, FAACR, Director of Clinical Research,Massachusetts General Cancer Center; Professor of Medicine, Harvard Medical School; President-Elect: 2025-2026, American Association for Cancer Research (AACR)
SESSION 3
The Shifting Landscape:
Tumor Plasticity and Resistance
12:00-12:20
Mathematical and Evolutionary Modeling in Precision Radiation Oncology
Jacob Scott, MD, DPhil, Professor and Staff Physician-Scientist, CWRU School of Medicine and Cleveland Clinic
12:20-12:40
Plasticity and Persistence: The Role of EMT in Cancer Progression and Therapy Resistance
Sendurai A. Mani, PhD, Professor of Pathology and Laboratory Medicine, Brown University; Associate Director of Translational Oncology, Brown University Legorreta Cancer Center
12:40-1:00
Targeting Molecularly Defined Subsets: Challenges in Translational Oncology
Benedito A. Carneiro, MD, MS, Director, Clinical Research Director, Cancer Drug Development; Associate Director, Division of Hematology/Oncology
Legorreta Cancer Center, Brown University Health
Conference Coverage 2025 Advancing Precision Medicine Conference, Philadelphia PA October 3-4 2025
Reporter: Stephen J. Williams, PhD
The Annual Advanced Precision Medicine Conference will be held at the Pennsylvania Convention Center October 3-4 2025 in Philadelphia PA. Advancing Precision Medicine is an organization dedicated to provide education and discourse among medical professionals to advance the field of precision therapeutics and diagnostics in cancer, cardiovascular, and other diseases. The Annual symposium is held in Philadelphia.
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.
This 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.
APM is a mission-driven team dedicated to advancing clinical practice through education in precision medicine, oncology, and pathology. Our expert-led programs bring together clinicians, pathologists, pharmacists, nurses, and researchers from across the country.
What We Offer
In 2025, we’re proud to offer three specialized event series—each tailored to a different corner of the healthcare ecosystem:
Where discovery meets application – and science transforms lives.
What’s New in 2025?
Four Specialized Tracks:
Track 1 – 2025 WIN Symposium: Progress and Challenges in Precision Oncology Presented in partnership with Advancing Precision Medicine
As the official 2025 WIN Symposium, this dedicated track will explore the evolving landscape of precision oncology, highlighting both groundbreaking advances and the ongoing challenges of translating molecular insights into clinical impact. Curated by the WIN Consortium, the program will feature global leaders in cancer research, diagnostics, and therapeutic innovation—offering a comprehensive view of how precision medicine is reshaping oncology across tumor types and care settings.
Track 2 – Day 1 – Multi-Omics Integration, Day 2 – Precision Medicine Outside of Oncology
From genomics and transcriptomics to proteomics and metabolomics—this track highlights how multi-layered data is revolutionizing systems biology and clinical decision-making.
Diving into applications across cardiovascular, neurology, rare disease, infectious disease, and other therapeutic areas where precision tools are reshaping clinical practice.
Sidney Farber Professor of Medicine at Harvard Medical School and Dana-Farber Cancer Institute
Senior Physician-Scientist at Brigham and Women’s Hospital
Howard Hughes Medical Institute Investigator
William Kaelin is the Sidney Farber Professor of Medicine at Harvard Medical School and Dana-Farber Cancer Institute, Senior Physician-Scientist at Brigham and Women’s Hospital and Howard Hughes Medical Institute Investigator. He obtained his undergraduate and M.D. degrees from Duke University and completed his training in Internal Medicine at the Johns Hopkins Hospital, where he served as chief medical resident. He was a clinical fellow in Medical Oncology at the Dana-Farber Cancer Institute and later a postdoctoral fellow in David Livingston’s laboratory, during which time he was a McDonnell Scholar.
A Nobel Laureate, Dr. Kaelin received the 2019 Nobel Prize in Physiology or Medicine. He is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, the National Academy of Medicine, the American Society of Clinical Investigation, and the American College of Physicians. He previously served on the National Cancer Institute Board of Scientific Advisors, the AACR Board of Trustees, and the Institute of Medicine National Cancer Policy Board. He is a recipient of the Paul Marks Prize for cancer research from the Memorial Sloan-Kettering Cancer Center; the Richard and Hinda Rosenthal Prize from the AACR; the Doris Duke Distinguished Clinical Scientist award; the 2010 Canada International Gairdner Award; ASCI’s Stanley J. Korsmeyer Award; the Scientific Grand Prix of the Foundation Lefoulon-Delalande; the Wiley Prize in Biomedical Sciences; the Steven C. Beering Award; the AACR Princess Takamatsu Award; the ASCO Science of Oncology Award; the Helis Award; the Albert Lasker Basic Medical Research Prize; the Massry Prize; the Harriet P. Dustan Award for Science as Related to Medicine from the American College of Physicians.
Dr. Kaelin’s research seeks to understand how, mechanistically, mutations affecting tumor-suppressor genes cause cancer. His laboratory is currently focused on studies of the VHL, RB-1, and p53 tumor suppressor genes. His long-term goal is to lay the foundation for new anticancer therapies based on the biochemical functions of such proteins. His work on the VHL protein helped to motivate the eventual successful clinical testing of VEGF inhibitors for the treatment of kidney cancer. Moreover, this line of investigation led to new insights into how cells sense and respond to changes in oxygen, and thus has implications for diseases beyond cancer, such as anemia, myocardial infarction, and stroke. His group also showed that leukemic transformation by mutant IDH was reversible, setting the stage for the development and approval of mutant IDH inhibitors, and discovered how thalidomide-like drugs kill myeloma cells by degrading two otherwise undruggable transcription factors,
A diverse group of more than 90 key opinion leaders will convene to explore the critical forces shaping the future of healthcare. Representing a range of disciplines—including genomics, bioinformatics, clinical research, biopharma, technology, and investment—these experts will lead discussions on the latest advancements and challenges in precision medicine.
Topics will include the evolution of genomic sequencing technologies, ethical considerations in managing patient data, the integration of AI in diagnostics, and strategies for translating innovation into clinical practice. The inclusion of investors and strategic partners will also bring a vital perspective on funding models, commercialization pathways, and the acceleration of cutting-edge therapies. Together, these voices will offer a comprehensive view of the trends transforming personalized healthcare on a global scale.
Networking Opportunities
Our precision medicine event, hosting over 500 attendees, offers invaluable networking opportunities. Bringing together professionals, researchers, and industry leaders, the event facilitates engaging discussions, knowledge-sharing, and potential partnerships, driving advancements in precision medicine.
Why Exhibit
Exhibiting at the event provides a unique opportunity to showcase your cutting-edge solutions and connect with key stakeholders in the rapidly advancing field of personalized healthcare. As an exhibitor, you’ll gain visibility among industry leaders, researchers, and professionals, allowing you to forge strategic partnerships, highlight your contributions to precision medicine, and stay at the forefront of innovations shaping the future of healthcare. Don’t miss the chance to position your company as a leader in this dynamic and transformative space, driving meaningful collaborations and contributing to the advancement of precision medicine.
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
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
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
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
2024 Nobel Prize in Physiology or Medicine jointly to Victor Ambros and Gary Ruvkun for the discovery of microRNA and its role in post-transcriptional gene regulation
Reporter: Aviva Lev-Ari, PhD, RN
Updated 10/22/2024
The revolution in our understanding of transcriptional regulation and dark regions of the genome
The genome of higher eukaryotes are comprised of multiple exonic and intronic regions, with coding and noncoding DNA respectively. Much of the DNA sequence between exonic regions of genes, the sequences encoding the amino acids of a polypeptide, was considered either promoter regions regulating an exonic sequence or ‘junk DNA’, which had merely separated exons and their regulatory elements. It was not considered that this dark DNA or junk DNA was important in regulating transcription of genes. It was felt that most gene regulation occurred in promoter regions by response element factors which bound to specific sequences within these regions.
MicroRNA (miRNA), originally discovered in Caenorhabditis elegans, is found in most eukaryotes, including humans [1–3]. It is predicted that miRNA account for 1-5% of the human genome and regulate at least 30% of protein-coding genes [4–8]. To date, 940 distinct miRNAs molecules have been identified within the human genome [9–12] (http://microrna.sanger.ac.uk accessed July 20, 2010). Although little is currently known about the specific targets and biological functions of miRNA molecules thus far, it is evident that miRNA plays a crucial role in the regulation of gene expression controlling diverse cellular and metabolic pathways.
MiRNA are small, evolutionary conserved, single-stranded, non-coding RNA molecules that bind target mRNA to prevent protein production by one of two distinct mechanisms. Mature miRNA is generated through two-step cleavage of primary miRNA (pri-miRNA), which incorporates into the effector complex RNA-induced silencing complex (RISC). The miRNA functions as a guide by base-pairing with target mRNA to negatively regulate its expression. The level of complementarity between the guide and mRNA target determines which silencing mechanism will be employed; cleavage of target messenger RNA (mRNA) with subsequent degradation or translation inhibition
Fig. (1). MicroRNA maturation and function.
Figure. miRNA maturation and function. Source: Macfarlane LA, Murphy PR. MicroRNA: Biogenesis, Function and Role in Cancer. Curr Genomics. 2010 Nov;11(7):537-61. doi: 10.2174/138920210793175895.
The following is an interview in the journal Journal of Cellular Biology with Dr, Victor Ambros on his discovery of miRNA.
Source: Ambros V. Victor Ambros: the broad scope of microRNAs. Interview by Caitlin Sedwick. J Cell Biol. 2013 May 13;201(4):492-3. doi: 10.1083/jcb.2014pi. PMID: 23671307; PMCID: PMC3653358.
Once, we thought we understood all there was to know about how gene expression is regulated: A cell can tinker with the expression level of a given protein’s messenger RNA by modifying the activity, abundance, and type of transcription factors in the nucleus or with the RNA’s stability once it is made. But then came a surprising story about a short RNA in C. elegans called lin-4, which didn’t encode a protein but prevented expression of the protein encoded by another gene, lin-14, through antisense binding to lin-14 mRNA (1, 2). Today, we know that lin-4 was just the first example of a large number of small RNAs, called microRNAs, which regulate the expression of various other proteins in a similar way.
Victor Ambros, whose lab published that first story about lin-4, has been studying microRNAs (3, 4) and their regulation (5, 6) ever since, pushing forward our understanding of this powerful mechanism. We called him at his office at the University of Massachusetts Medical School to get some perspective on microRNAs and his career and to learn about some of the latest developments in his lab.
“That shared discovery is one of the most precious moments in my career.”
FROM FARM TO LAB TABLE
How did you end up doing a PhD with David Baltimore?
I was the first scientist in my family. My dad was an immigrant from Poland. He came to the States just after World War II and met my mom. They got married, moved to a farm in Vermont, and started farming. My siblings and I grew up amongst the cows and pigs and helped with the haying and cutting corn, stuff like that.
When I was about nine, I got interested in science, and after that I always wanted to be a scientist. I was an amateur astronomer; I built a telescope and started to imagine that I could actually do astronomy or physics as an occupation. But I quickly changed my mind when I reached college, in part because I realized that my math skills weren’t really up to the task of being a physicist and also because I discovered molecular biology and genetics and just fell in love with both subjects. David taught one of the advanced biology classes I took as an undergraduate at MIT, and that probably had some influence on my decision to work with him. After college, I worked as a technician in David’s lab for a year. I liked it a lot and stayed on in his lab when I entered graduate school at MIT. I was lucky because I had gotten a little bit of traction on a project and continued on that as a grad student, so I ended up finishing grad school fairly efficiently.
Had you any idea at the time what the nature of the lin-4 mutant was?
The assumption was that it was a protein product. I mean, nobody ever thought that there would be any other kind of regulator. There really wasn’t any reason to imagine that there were any other kinds of molecules necessary, other than proteins, to carry out everything that’s done in a cell—especially with regard to the regulation of gene expression. The complexity of gene regulation by proteins alone was so enormous that I never imagined—and nobody I knew imagined—that we needed to look for new kinds of regulatory molecules. The realization that lin-4 was antisense to the 3′-untranslated region of lin-14 was totally the result of communication between Gary and me. That shared discovery is one of the most precious moments in my career. But at the time I didn’t realize that this might be the first example of a general mechanism for regulating gene expression because I was prone to thinking that whatever I was studying in the worm was not generally applicable. It wasn’t until genome sequences were made available that the prevalence of this mechanism became clear.
THE RIGHT CONTEXT
You’ve moved to studying processes that modulate microRNA function…
One protein we’ve studied is called Nhl-2. It’s an example of an emerging class of proteins that can modulate, positively or negatively, the RNA-induced silencing complex (RISC) that inhibits mRNAs targeted by microRNAs. This class of genes may have either general effects on RISC activity or, in some cases, more specific effects. One area of interest in the lab right now is trying to understand the specific outcomes for the regulation of particular microRNAs. Do they always interact with all their targets, or is their activity on some targets promoted or inhibited at the expense of other targets? Can their interaction with certain targets be modified depending on context? We’re using genetic and genomic approaches to identify new modulatory cofactors.
Watch Video
Victor Ambros was born in 1953 in Hanover, New Hampshire, USA. He received his PhD from Massachusetts Institute of Technology (MIT), Cambridge, MA, in 1979 where he also did postdoctoral research 1979-1985. He became a Principal Investigator at Harvard University, Cambridge, MA in 1985. He was Professor at Dartmouth Medical School from 1992-2007 and he is now Silverman Professor of Natural Science at the University of Massachusetts Medical School, Worcester, MA.
Gary Ruvkun was born in Berkeley, California, USA in 1952. He received his PhD from Harvard University in 1982. He was a postdoctoral fellow at Massachusetts Institute of Technology (MIT), Cambridge, MA, 1982-1985. He became a Principal Investigator at Massachusetts General Hospital and Harvard Medical School in 1985, where he is now Professor of Genetics.
This year’s Nobel Prize honors two scientists for their discovery of a fundamental principle governing how gene activity is regulated.
The information stored within our chromosomes can be likened to an instruction manual for all cells in our body. Every cell contains the same chromosomes, so every cell contains exactly the same set of genes and exactly the same set of instructions. Yet, different cell types, such as muscle and nerve cells, have very distinct characteristics. How do these differences arise? The answer lies in gene regulation, which allows each cell to select only the relevant instructions. This ensures that only the correct set of genes is active in each cell type.
Victor Ambros and Gary Ruvkun were interested in how different cell types develop. They discovered microRNA, a new class of tiny RNA molecules that play a crucial role in gene regulation. Their groundbreaking discovery revealed a completely new principle of gene regulation that turned out to be essential for multicellular organisms, including humans. It is now known that the human genome codes for over one thousand microRNAs. Their surprising discovery revealed an entirely new dimension to gene regulation. MicroRNAs are proving to be fundamentally important for how organisms develop and function.
Ambros and Ruvkun were interested in genes that control the timing of activation of different genetic programs, ensuring that various cell types develop at the right time. They studied two mutant strains of worms, lin-4 and lin-14, that displayed defects in the timing of activation of genetic programs during development. The laureates wanted to identify the mutated genes and understand their function. Ambros had previously shown that the lin-4 gene appeared to be a negative regulator of the lin-14 gene. However, how the lin-14 activity was blocked was unknown. Ambros and Ruvkun were intrigued by these mutants and their potential relationship and set out to resolve these mysteries.
Ambros and Ruvkun performed further experiments showing that the lin-4 microRNA turns off lin-14 by binding to the complementary sequences in its mRNA, blocking the production of lin-14 protein. A new principle of gene regulation, mediated by a previously unknown type of RNA, microRNA, had been discovered! The results were published in 1993 in two articles in the journal Cell.
Ruvkun cloned let-7, a second gene encoding a microRNA. The gene is conserved in evolution, and it is now known that microRNA regulation is universal among multicellular organisms.
Andrew Z. Fire and Craig C. Mello, awarded the Nobel Prize in 2006, described RNA interference, where specific mRNA-molecules are inactivated by adding double-stranded RNA to cells.
Mutations in one of the proteins required for microRNA production result in the DICER1 syndrome, a rare but severe syndrome linked to cancer in various organs and tissues.
Eight Subcellular Pathologies driving Chronic Metabolic Diseases – Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics: Impact on Pharmaceuticals in Use
In this curation we wish to present two breaking through goals:
Goal 1:
Exposition of a new direction of research leading to a more comprehensive understanding of Metabolic Dysfunctional Diseases that are implicated in effecting the emergence of the two leading causes of human mortality in the World in 2023: (a) Cardiovascular Diseases, and (b) Cancer
Goal 2:
Development of Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics for these eight subcellular causes of chronic metabolic diseases. It is anticipated that it will have a potential impact on the future of Pharmaceuticals to be used, a change from the present time current treatment protocols for Metabolic Dysfunctional Diseases.
According to Dr. Robert Lustig, M.D, an American pediatric endocrinologist. He is Professor emeritus of Pediatrics in the Division of Endocrinology at the University of California, San Francisco, where he specialized in neuroendocrinology and childhood obesity, there are eight subcellular pathologies that drive chronic metabolic diseases.
These eight subcellular pathologies can’t be measured at present time.
In this curation we will attempt to explore methods of measurement for each of these eight pathologies by harnessing the promise of the emerging field known as Bioelectronics.
Unmeasurable eight subcellular pathologies that drive chronic metabolic diseases
Glycation
Oxidative Stress
Mitochondrial dysfunction [beta-oxidation Ac CoA malonyl fatty acid]
Insulin resistance/sensitive [more important than BMI], known as a driver to cancer development
Membrane instability
Inflammation in the gut [mucin layer and tight junctions]
Epigenetics/Methylation
Autophagy [AMPKbeta1 improvement in health span]
Diseases that are not Diseases: no drugs for them, only diet modification will help
Image source
Robert Lustig, M.D. on the Subcellular Processes That Belie Chronic Disease
These eight Subcellular Pathologies driving Chronic Metabolic Diseases are becoming our focus for exploration of the promise of Bioelectronics for two pursuits:
Will Bioelectronics be deemed helpful in measurement of each of the eight pathological processes that underlie and that drive the chronic metabolic syndrome(s) and disease(s)?
IF we will be able to suggest new measurements to currently unmeasurable health harming processes THEN we will attempt to conceptualize new therapeutic targets and new modalities for therapeutics delivery – WE ARE HOPEFUL
In the Bioelecronics domain we are inspired by the work of the following three research sources:
Michael Levin is an American developmental and synthetic biologist at Tufts University, where he is the Vannevar Bush Distinguished Professor. Levin is a director of the Allen Discovery Center at Tufts University and Tufts Center for Regenerative and Developmental Biology. Wikipedia
THE VOICE of Dr. Justin D. Pearlman, MD, PhD, FACC
PENDING
THE VOICE of Stephen J. Williams, PhD
Ten TakeAway Points of Dr. Lustig’s talk on role of diet on the incidence of Type II Diabetes
25% of US children have fatty liver
Type II diabetes can be manifested from fatty live with 151 million people worldwide affected moving up to 568 million in 7 years
A common myth is diabetes due to overweight condition driving the metabolic disease
There is a trend of ‘lean’ diabetes or diabetes in lean people, therefore body mass index not a reliable biomarker for risk for diabetes
Thirty percent of ‘obese’ people just have high subcutaneous fat. the visceral fat is more problematic
there are people who are ‘fat’ but insulin sensitive while have growth hormone receptor defects. Points to other issues related to metabolic state other than insulin and potentially the insulin like growth factors
At any BMI some patients are insulin sensitive while some resistant
Visceral fat accumulation may be more due to chronic stress condition
Fructose can decrease liver mitochondrial function
A methionine and choline deficient diet can lead to rapid NASH development
Entering the last day of the American College of Cardiology’s annual conference, the Big Pharma is trotting out new phase 2 data of its anti-PCSK9 drug, finding that it reduced particular kinds of cholesterol by up to 61% compared to placebo.
Meanwhile, expanded phase 3 data of sotatercept, added onto background therapy, has exceeded the expectations of Chief Medical Officer Eliav Barr, M.D. “It just hits the right receptor,” he said in an interview with Fierce Biotech.
Sotatercept was the prized jewel in the company’s $11.5 billion purchase of Acceleron Pharma in 2021. The cardio med aimed at treating pulmonary arterial hypertension improved patients’ six-minute walk distance by more than 40 meters after 24 weeks compared to placebo, hitting the primary endpoint of the 323-patient trial.
The therapy also reduced the risk of clinical worsening or death by 84% compared to placebo for a median follow-up of 32.7 weeks, according to the conference presentation.What’s more, sotatercept had a slightly lower discontinuation rate due to treatment-related side effects than placebo patients.
While sotatercept has accrued much of the acclaim for the cardio team, Barr was also riding the high of positive phase 2 data from the company’s oral PCSK9 inhibitor to treat high cholesterol. The trial compared four doses of MK-0616 in patients with high cholesterol compared to placebo; all four were found to significantly reduce LDL cholesterol levels.
The highest dose of the med reduced levels of this cholesterol by more than 60% compared to placebo and the number of side effects across all dose levels was consistent with placebo.
The data is naturally a critical checkpoint as Barr and Merck tout the value of the first oral version of the therapy class currently dominated by Amgen’s Repatha and Regeneron’s Praluent. Next on the clinical docket is a phase 3 trial slated for the second half of the year, but Barr also hopes to launch a cardiovascular outcomes trial before year-end as well.
Cholesterol Lowering Novel PCSK9 drugs: Praluent [Sanofi and Regeneron] vs Repatha [Amgen] – which drug cuts CV risks enough to make it cost-effective?
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