Funding, Deals & Partnerships: BIOLOGICS & MEDICAL DEVICES; BioMed e-Series; Medicine and Life Sciences Scientific Journal – http://PharmaceuticalIntelligence.com
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
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 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.
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.
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
The Vibrant Philly Biotech Scene: Proteovant Therapeutics Using Artificial Intelligence and Machine Learning to Develop PROTACs
Reporter:Stephen J. Williams, Ph.D.
It has been a while since I have added to this series but there have been a plethora of exciting biotech startups in the Philadelphia area, and many new startups combining technology, biotech, and machine learning. One such exciting biotech is Proteovant Therapeutics, which is combining the new PROTAC (Proteolysis-Targeting Chimera) technology with their in house ability to utilize machine learning and artificial intelligence to design these types of compounds to multiple intracellular targets.
PROTACs (which actually is under a trademark name of Arvinus Operations, but is also refered to as Protein Degraders. These PROTACs take advantage of the cell protein homeostatic mechanism of ubiquitin-mediated protein degradation, which is a very specific targeted process which regulates protein levels of various transcription factors, protooncogenes, and receptors. In essence this regulated proteolyic process is needed for normal cellular function, and alterations in this process may lead to oncogenesis, or a proteotoxic crisis leading to mitophagy, autophagy and cellular death. The key to this technology is using chemical linkers to associate an E3 ligase with a protein target of interest. E3 ligases are the rate limiting step in marking the proteins bound for degradation by the proteosome with ubiquitin chains.
A review of this process as well as PROTACs can be found elsewhere in articles (and future articles) on this Open Access Journal.
Protevant have made two important collaborations:
Oncopia Therapeutics: came out of University of Michigan Innovation Hub and lab of Shaomeng Wang, who developed a library of BET and MDM2 based protein degraders. In 2020 was aquired by Riovant Sciences.
Riovant Sciences: uses computer aided design of protein degraders
Proteovant Company Description:
Proteovant is a newly launched development-stage biotech company focusing on discovery and development of disease-modifying therapies by harnessing natural protein homeostasis processes. We have recently acquired numerous assets at discovery and development stages from Oncopia, a protein degradation company. Our lead program is on track to enter IND in 2021. Proteovant is building a strong drug discovery engine by combining deep drugging expertise with innovative platforms including Roivant’s AI capabilities to accelerate discovery and development of protein degraders to address unmet needs across all therapeutic areas. The company has recently secured $200M funding from SK Holdings in addition to investment from Roivant Sciences. Our current therapeutic focus includes but is not limited to oncology, immunology and neurology. We remain agnostic to therapeutic area and will expand therapeutic focus based on opportunity. Proteovant is expanding its discovery and development teams and has multiple positions in biology, chemistry, biochemistry, DMPK, bioinformatics and CMC at many levels. Our R&D organization is located close to major pharmaceutical companies in Eastern Pennsylvania with a second site close to biotech companies in Boston area.
The ubiquitin proteasome system (UPS) is responsible for maintaining protein homeostasis. Targeted protein degradation by the UPS is a cellular process that involves marking proteins and guiding them to the proteasome for destruction. We leverage this physiological cellular machinery to target and destroy disease-causing proteins.
Unlike traditional small molecule inhibitors, our approach is not limited by the classic “active site” requirements. For example, we can target transcription factors and scaffold proteins that lack a catalytic pocket. These classes of proteins, historically, have been very difficult to drug. Further, we selectively degrade target proteins, rather than isozymes or paralogous proteins with high homology. Because of the catalytic nature of the interactions, it is possible to achieve efficacy at lower doses with prolonged duration while decreasing dose-limiting toxicities.
Biological targets once deemed “undruggable” are now within reach.
Roivant develops transformative medicines faster by building technologies and developing talent in creative ways, leveraging the Roivant platform to launch “Vants” – nimble and focused biopharmaceutical and health technology companies. These Vants include Proteovant but also Dermovant, ImmunoVant,as well as others.
Roivant’s drug discovery capabilities include the leading computational physics-based platform for in silico drug design and optimization as well as machine learning-based models for protein degradation.
The integration of our computational and experimental engines enables the rapid design of molecules with high precision and fidelity to address challenging targets for diseases with high unmet need.
Our current modalities include small molecules, heterobifunctionals and molecular glues.
Roivant Unveils Targeted Protein Degradation Platform
– First therapeutic candidate on track to enter clinical studies in 2021
– Computationally-designed degraders for six targets currently in preclinical development
– Acquisition of Oncopia Therapeutics and research collaboration with lab of Dr. Shaomeng Wang at the University of Michigan to add diverse pipeline of current and future compounds
– Clinical-stage degraders will provide foundation for multiple new Vants in distinct disease areas
– Platform supported by $200 million strategic investment from SK Holdings
Other articles in this Vibrant Philly Biotech Scene on this Online Open Access Journal include:
2021 Virtual World Medical Innovation Forum, Mass General Brigham, Gene and Cell Therapy, VIRTUAL May 19–21, 2021
The 2021 Virtual World Medical Innovation Forum will focus on the growing impact of gene and cell therapy. Senior healthcare leaders from all over look to shape and debate the area of gene and cell therapy. Our shared belief: no matter the magnitude of change, responsible healthcare is centered on a shared commitment to collaborative innovation–industry, academia, and practitioners working together to improve patients’ lives.
About the World Medical Innovation Forum
Mass General Brigham is pleased to present the World Medical Innovation Forum (WMIF) virtual event Wednesday, May 19 – Friday, May 21. This interactive web event features expert discussions of gene and cell therapy (GCT) and its potential to change the future of medicine through its disease-treating and potentially curative properties. The agenda features 150+ executive speakers from the healthcare industry, venture, startups, life sciences manufacturing, consumer health and the front lines of care, including many Harvard Medical School-affiliated researchers and clinicians. The annual in-person Forum will resume live in Boston in 2022. The World Medical Innovation Forum is presented by Mass General Brigham Innovation, the global business development unit supporting the research requirements of 7,200 Harvard Medical School faculty and research hospitals including Massachusetts General, Brigham and Women’s, Massachusetts Eye and Ear, Spaulding Rehab and McLean Hospital. Follow us on Twitter: twitter.com/@MGBInnovation
Accelerating the Future of Medicine with Gene and Cell Therapy What Comes Next
Co-Chairs identify the key themes of the Forum – set the stage for top GCT opportunities, challenges, and where the field might take medicine in the future. Moderator: Susan Hockfield, PhD
President Emerita and Professor of Neuroscience, MIT
Hope that CGT emerging, how the therapies work, neuro, muscular, ocular, genetic diseases of liver and of heart revolution for the industry 900 IND application 25 approvals Economic driver Skilled works, VC disease. Modality one time intervention, long duration of impart, reimbursement, ecosystem to be built around CGT
FDA works by indications and risks involved, Standards and expectations for streamlining manufacturing, understanding of process and products
payments over time payers and Innovators relations Moderator: Julian Harris, MD
Partner, Deerfield
Promise of CGT realized, what part?
FDA role and interaction in CGT
Manufacturing aspects which is critical Speaker: Dave Lennon, PhD
President, Novartis Gene Therapies
Hope that CGT emerging, how the therapies work, neuro, muscular, ocular, genetic diseases of liver and of heart revolution for the industry 900 IND application 25 approvals Economic driver Skilled works, VC disease. Modality one time intervention, long duration of impart, reimbursement, ecosystem to be built around CGT
FDA works by indications and risks involved, Standards and expectations for streamlining manufacturing, understanding of process and products
payments over time payers and Innovators relations
GCT development for rare diseases is driven by patient and patient-advocate communities. Understanding their needs and perspectives enables biomarker research, the development of value-driving clinical trial endpoints and successful clinical trials. Industry works with patient communities that help identify unmet needs and collaborate with researchers to conduct disease natural history studies that inform the development of biomarkers and trial endpoints. This panel includes patients who have received cutting-edge GCT therapy as well as caregivers and patient advocates. Moderator: Patricia Musolino, MD, PhD
Co-Director Pediatric Stroke and Cerebrovascular Program, MGH
Assistant Professor of Neurology, HMS
What is the Power of One – the impact that a patient can have on their own destiny by participating in Clinical Trials Contacting other participants in same trial can be beneficial Speakers: Jack Hogan
Parkinson patient Constraints by regulatory on participation in clinical trial advance stage is approved participation Patients to determine the level of risk they wish to take Information dissemination is critical Barbara Lavery
Chief Program Officer, ACGT Foundation
Advocacy agency beginning of work Global Genes educational content and out reach to access the information
Patient has the knowledge of the symptoms and recording all input needed for diagnosis by multiple clinicians Early application for CGTDan Tesler
Clinical Trial Patient, BWH/DFCC
Experimental Drug clinical trial patient participation in clinical trial is very important to advance the state of scienceSarah Beth Thomas, RN
Professional Development Manager, BWH
Outcome is unknown, hope for good, support with resources all advocacy groups,
Process at FDA generalize from 1st entry to rules more generalizable Speaker: Peter Marks, MD, PhD
Director, Center for Biologics Evaluation and Research, FDA
Last Spring it became clear that something will work a vaccine by June 2020 belief that enough candidates the challenge manufacture enough and scaling up FDA did not predicted the efficacy of mRNA vaccine vs other approaches expected to work
Recover Work load for the pandemic will wean & clear, Gene Therapies IND application remained flat in the face of the pandemic Rare diseases urgency remains Consensus with industry advisory to get input gene therapy Guidance T-Cell therapy vs Regulation best thinking CGT evolve speedily flexible gained by Guidance
Immune modulators, Immunotherapy Genome editing can make use of viral vectors future technologies nanoparticles and liposome encapsulation
big pharma has portfolios of therapeutics not one drug across Tx areas: cell, gene iodine therapy
collective learning infrastructure features manufacturing at scale early in development Acquisitions strategy for growth # applications for scaling Rick Modi
CEO, Affinia Therapeutics
Copy, paste EDIT from product A to B novel vectors leverage knowledge varient of vector, coder optimization choice of indication is critical exploration on larger populations Speed to R&D and Speed to better gene construct get to clinic with better design vs ASAP
Data sharing clinical experience with vectors strategies patients selection, vector selection, mitigation, patient type specific Louise Rodino-Klapac, PhD
AAV based platform 15 years in development same disease indication vs more than one indication stereotype, analytics as hurdle 1st was 10 years 2nd was 3 years
Safety to clinic vs speed to clinic, difference of vectors to trust
Recent AAV gene therapy product approvals have catalyzed the field. This new class of therapies has shown the potential to bring transformative benefit to patients. With dozens of AAV treatments in clinical studies, all eyes are on the field to gauge its disruptive impact.
The panel assesses the largest challenges of the first two products, the lessons learned for the broader CGT field, and the extent to which they serve as a precedent to broaden the AAV modality.
Is AAV gene therapy restricted to genetically defined disorders, or will it be able to address common diseases in the near term?
Lessons learned from these first-in-class approvals.
Challenges to broaden this modality to similar indications.
Reflections on safety signals in the clinical studies?
Tissue types additional administrations, tech and science, address additional diseases, more science for photoreceptors a different tissue type underlying pathology novelties in last 10 years
Laxterna success to be replicated platform, paradigms measurement visual improved
More science is needed to continue develop vectors reduce toxicity,
AAV can deliver different cargos reduce adverse events improve vectorsRon Philip
Chief Operating Officer, Spark Therapeutics
The first retinal gene therapy, voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics), was approved by the FDA in 2017.Meredith Schultz, MD
Executive Medical Director, Lead TME, Novartis Gene Therapies
Impact of cell therapy beyond muscular dystrophy, translational medicine, each indication, each disease, each group of patients build platform unlock the promise
Monitoring for Safety signals real world evidence remote markers, home visits, clinical trial made safer, better communication of information
AAV a complex driver in Pharmacology durable, vector of choice, administer in vitro, gene editing tissue specificity, pharmacokinetics side effects and adverse events manufacturability site variation diversify portfolios,
This panel will address the advances in the area of AAV gene therapy delivery looking out the next five years. Questions that loom large are: How can biodistribution of AAV be improved? What solutions are in the wings to address immunogenicity of AAV? Will patients be able to receive systemic redosing of AAV-based gene therapies in the future? What technical advances are there for payload size? Will the cost of manufacturing ever become affordable for ultra-rare conditions? Will non-viral delivery completely supplant viral delivery within the next five years?What are the safety concerns and how will they be addressed? Moderators: Xandra Breakefield, PhD
Ataxia requires therapy targeting multiple organ with one therapy, brain, spinal cord, heart several IND, clinical trials in 2022Mathew Pletcher, PhD
SVP, Head of Gene Therapy Research and Technical Operations, Astellas
Work with diseases poorly understood, collaborations needs example of existing: DMD is a great example explain dystrophin share placedo data
Continue to explore large animal guinea pig not the mice, not primates (ethical issues) for understanding immunogenicity and immune response Manny Simons, PhD
CEO, Akouos
AAV Therapy for the fluid of the inner ear, CGT for the ear vector accessible to surgeons translational work on the inner ear for gene therapy right animal model
Biology across species nerve ending in the cochlea
engineer out of the caspid, lowest dose possible, get desired effect by vector use, 2022 new milestones
The GCT M&A market is booming – many large pharmas have made at least one significant acquisition. How should we view the current GCT M&A market? What is its impact of the current M&A market on technology development? Are these M&A trends new are just another cycle? Has pharma strategy shifted and, if so, what does it mean for GCT companies? What does it mean for patients? What are the long-term prospects – can valuations hold up? Moderator: Adam Koppel, MD, PhD
Managing Director, Bain Capital Life Sciences
What acquirers are looking for??
What is the next generation vs what is real where is the industry going? Speakers:
Debby Baron,
Worldwide Business Development, Pfizer
CGT is an important area Pfizer is active looking for innovators, advancing forward programs of innovation with the experience Pfizer has internally
Scalability and manufacturing regulatory conversations, clinical programs safety in parallel to planning getting drug to patients
ALS – Man 1in 300, Women 1 in 400, next decade increase 7%
10% ALS is heredity 160 pharma in ALS space, diagnosis is late 1/3 of people are not diagnosed, active community for clinical trials Challenges: disease heterogeneity cases of 10 years late in diagnosis. Clinical Trials for ALS in Gene Therapy targeting ASO1 protein therapies FUS gene struck youngsters
Cell therapy for ACTA2 Vasculopathy in the brain and control the BP and stroke – smooth muscle intima proliferation. Viral vector deliver aiming to change platform to non-viral delivery rare disease , gene editing, other mutations of ACTA2 gene target other pathway for atherosclerosis
Oncolytic viruses represent a powerful new technology, but so far an FDA-approved oncolytic (Imlygic) has only occurred in one area – melanoma and that what is in 2015. This panel involves some of the protagonists of this early success story. They will explore why and how Imlygic became approved and its path to commercialization. Yet, no other cancer indications exist for Imlygic, unlike the expansion of FDA-approved indication for immune checkpoint inhibitors to multiple cancers. Why? Is there a limitation to what and which cancers can target? Is the mode of administration a problem?
No other oncolytic virus therapy has been approved since 2015. Where will the next success story come from and why? Will these therapies only be beneficial for skin cancers or other easily accessible cancers based on intratumoral delivery?
The panel will examine whether the preclinical models that have been developed for other cancer treatment modalities will be useful for oncolytic viruses. It will also assess the extent pre-clinical development challenges have slowed the development of OVs. Moderator: Nino Chiocca, MD, PhD
Neurosurgeon-in-Chief and Chairman, Neurosurgery, BWH
Harvey W. Cushing Professor of Neurosurgery, HMS
Challenges of manufacturing at Amgen what are they? Speakers: Robert Coffin, PhD
Chief Research & Development Officer, Replimune
2002 in UK promise in oncolytic therapy GNCSF
Phase III melanoma 2015 M&A with Amgen
oncolytic therapy remains non effecting on immune response
data is key for commercialization
do not belief in systemic therapy achieve maximum immune response possible from a tumor by localized injection Roger Perlmutter, MD, PhD
Chairman, Merck & Co.
response rates systemic therapy like PD1, Keytruda, OPTIVA well tolerated combination of Oncolytic with systemic
Physician, Dana Farber-Brigham and Women’s Cancer Center
Assistant Professor of Medicine, HMS
Which person gets oncolytics virus if patient has immune suppression due to other indications
Safety of oncolytic virus greater than Systemic treatment
series biopsies for injected and non injected tissue and compare Suspect of hot tumor and cold tumors likely to have sme response to agent unknown all potential
There are currently two oncolytic virus products on the market, one in the USA and one in China. As of late 2020, there were 86 clinical trials 60 of which were in phase I with just 2 in Phase III the rest in Phase I/II or Phase II. Although global sales of OVs are still in the ramp-up phase, some projections forecast OVs will be a $700 million market by 2026. This panel will address some of the major questions in this area:
What regulatory challenges will keep OVs from realizing their potential? Despite the promise of OVs for treating cancer only one has been approved in the US. Why has this been the case? Reasons such have viral tropism, viral species selection and delivery challenges have all been cited. However, these are also true of other modalities. Why then have oncolytic virus approaches not advanced faster and what are the primary challenges to be overcome?
Will these need to be combined with other agents to realize their full efficacy and how will that impact the market?
Why are these companies pursuing OVs while several others are taking a pass?
In 2020 there were a total of 60 phase I trials for Oncolytic Viruses. There are now dozens of companies pursuing some aspect of OV technology. This panel will address:
How are small companies equipped to address the challenges of developing OV therapies better than large pharma or biotech?
Will the success of COVID vaccines based on Adenovirus help the regulatory environment for small companies developing OV products in Europe and the USA?
Is there a place for non-viral delivery and other immunotherapy companies to engage in the OV space? Would they bring any real advantages?
Systemic delivery Oncolytic Virus IV delivery woman in remission
Collaboration with Regeneron
Data collection: Imageable reporter secretable reporter, gene expression
Field is intense systemic oncolytic delivery is exciting in mice and in human, response rates are encouraging combination immune stimulant, check inhibitors
Few areas of potential cancer therapy have had the attention and excitement of CAR-T. This panel of leading executives, developers, and clinician-scientists will explore the current state of CAR-T and its future prospects. Among the questions to be addressed are:
Is CAR-T still an industry priority – i.e. are new investments being made by large companies? Are new companies being financed? What are the trends?
What have we learned from first-generation products, what can we expect from CAR-T going forward in novel targets, combinations, armored CAR’s and allogeneic treatment adoption?
Early trials showed remarkable overall survival and progression-free survival. What has been observed regarding how enduring these responses are?
Most of the approvals to date have targeted CD19, and most recently BCMA. What are the most common forms of relapses that have been observed?
Is there a consensus about what comes after these CD19 and BCMA trials as to additional targets in liquid tumors? How have dual-targeted approaches fared?
The potential application of CAR-T in solid tumors will be a game-changer if it occurs. The panel explores the prospects of solid tumor success and what the barriers have been. Questions include:
How would industry and investor strategy for CAR-T and solid tumors be characterized? Has it changed in the last couple of years?
Does the lack of tumor antigen specificity in solid tumors mean that lessons from liquid tumor CAR-T constructs will not translate well and we have to start over?
Whether due to antigen heterogeneity, a hostile tumor micro-environment, or other factors are some specific solid tumors more attractive opportunities than others for CAR-T therapy development?
Given the many challenges that CAR-T faces in solid tumors, does the use of combination therapies from the start, for example, to mitigate TME effects, offer a more compelling opportunity.
Executive Director, Head of Cell Therapy Research, Exploratory Immuno-Oncology, NIBR
2017 CAR-T first approval
M&A and research collaborations
TCR tumor specific antigens avoid tissue toxicity Knut Niss, PhD
CTO, Mustang Bio
tumor hot start in 12 month clinical trial solid tumors , theraties not ready yet. Combination therapy will be an experimental treatment long journey checkpoint inhibitors to be used in combination maintenance Lipid tumor Barbra Sasu, PhD
CSO, Allogene
T cell response at prostate cancer
tumor specific
cytokine tumor specific signals move from solid to metastatic cell type for easier infiltration
Where we might go: safety autologous and allogeneic Jay Short, PhD
Chairman, CEO, Cofounder, BioAlta, Inc.
Tumor type is not enough for development of therapeutics other organs are involved in the periphery
difficult to penetrate solid tumors biologics activated in the tumor only, positive changes surrounding all charges, water molecules inside the tissue acidic environment target the cells inside the tumor and not outside
The modes of GCT manufacturing have the potential of fundamentally reordering long-established roles and pathways. While complexity goes up the distance from discovery to deployment shrinks. With the likelihood of a total market for cell therapies to be over $48 billion by 2027, groups of products are emerging. Stem cell therapies are projected to be $28 billion by 2027 and non-stem cell therapies such as CAR-T are projected be $20 billion by 2027. The manufacturing challenges for these two large buckets are very different. Within the CAR-T realm there are diverging trends of autologous and allogeneic therapies and the demands on manufacturing infrastructure are very different. Questions for the panelists are:
Help us all understand the different manufacturing challenges for cell therapies. What are the trade-offs among storage cost, batch size, line changes in terms of production cost and what is the current state of scaling naïve and stem cell therapy treatment vs engineered cell therapies?
For cell and gene therapy what is the cost of Quality Assurance/Quality Control vs. production and how do you think this will trend over time based on your perspective on learning curves today?
Will point of care production become a reality? How will that change product development strategy for pharma and venture investors? What would be the regulatory implications for such products?
How close are allogeneic CAR-T cell therapies? If successful what are the market implications of allogenic CAR-T? What are the cost implications and rewards for developing allogeneic cell therapy treatments?
Global Head of Product Development, Gene & Cell Therapy, Catalent
2/3 autologous 1/3 allogeneic CAR-T high doses and high populations scale up is not done today quality maintain required the timing logistics issues centralized vs decentralized allogeneic are health donors innovations in cell types in use improvements in manufacturing
China embraced gene and cell therapies early. The first China gene therapy clinical trial was in 1991. China approved the world’s first gene therapy product in 2003—Gendicine—an oncolytic adenovirus for the treatment of advanced head and neck cancer. Driven by broad national strategy, China has become a hotbed of GCT development, ranking second in the world with more than 1,000 clinical trials either conducted or underway and thousands of related patents. It has a booming GCT biotech sector, led by more than 45 local companies with growing IND pipelines.
In late 1990, a T cell-based immunotherapy, cytokine-induced killer (CIK) therapy became a popular modality in the clinic in China for tumor treatment. In early 2010, Chinese researchers started to carry out domestic CAR T trials inspired by several important reports suggested the great antitumor function of CAR T cells. Now, China became the country with the most registered CAR T trials, CAR T therapy is flourishing in China.
The Chinese GCT ecosystem has increasingly rich local innovation and growing complement of development and investment partnerships – and also many subtleties.
This panel, consisting of leaders from the China GCT corporate, investor, research and entrepreneurial communities, will consider strategic questions on the growth of the gene and cell therapy industry in China, areas of greatest strength, evolving regulatory framework, early successes and products expected to reach the US and world market. Moderator: Min Wu, PhD
Managing Director, Fosun Health Fund
What are the area of CGT in China, regulatory similar to the US Speakers: Alvin Luk, PhD
CEO, Neuropath Therapeutics
Monogenic rare disease with clear genomic target
Increase of 30% in patient enrollment
Regulatory reform approval is 60 days no delayPin Wang, PhD
CSO, Jiangsu Simcere Pharmaceutical Co., Ltd.
Similar starting point in CGT as the rest of the World unlike a later starting point in other biologicalRichard Wang, PhD
CEO, Fosun Kite Biotechnology Co., Ltd
Possibilities to be creative and capitalize the new technologies for innovating drug
Support of the ecosystem by funding new companie allowing the industry to be developed in China
Autologous in patients differences cost challengeTian Xu, PhD
Vice President, Westlake University
ICH committee and Chinese FDA -r regulation similar to the US
Difference is the population recruitment, in China patients are active participants in skin disease
Active in development of transposome
Development of non-viral methods, CRISPR still in D and transposome
In China price of drugs regulatory are sensitive Shunfei Yan, PhD
The COVID vaccine race has propelled mRNA to the forefront of biomedicine. Long considered as a compelling modality for therapeutic gene transfer, the technology may have found its most impactful application as a vaccine platform. Given the transformative industrialization, the massive human experience, and the fast development that has taken place in this industry, where is the horizon? Does the success of the vaccine application, benefit or limit its use as a therapeutic for CGT?
How will the COVID success impact the rest of the industry both in therapeutic and prophylactic vaccines and broader mRNA lessons?
How will the COVID success impact the rest of the industry both on therapeutic and prophylactic vaccines and broader mRNA lessons?
Beyond from speed of development, what aspects make mRNA so well suited as a vaccine platform?
Will cost-of-goods be reduced as the industry matures?
How does mRNA technology seek to compete with AAV and other gene therapy approaches?
Many years of mRNA pivoting for new diseases, DARPA, nucleic Acids global deployment of a manufacturing unit on site where the need arise Elan Musk funds new directions at Moderna
How many mRNA can be put in one vaccine: Dose and tolerance to achieve efficacy
45 days for Personalized cancer vaccine one per patient
Hemophilia has been and remains a hallmark indication for the CGT. Given its well-defined biology, larger market, and limited need for gene transfer to provide therapeutic benefit, it has been at the forefront of clinical development for years, however, product approval remains elusive. What are the main hurdles to this success? Contrary to many indications that CGT pursues no therapeutic options are available to patients, hemophiliacs have an increasing number of highly efficacious treatment options. How does the competitive landscape impact this field differently than other CGT fields? With many different players pursuing a gene therapy option for hemophilia, what are the main differentiators? Gene therapy for hemophilia seems compelling for low and middle-income countries, given the cost of currently available treatments; does your company see opportunities in this market? Moderator: Nancy Berliner, MD
Safety concerns, high burden of treatment CGT has record of safety and risk/benefit adoption of Tx functional cure CGT is potent Tx relative small quantity of protein needs be delivered
Potency and quality less quantity drug and greater potency
risk of delivery unwanted DNA, capsules are critical
analytics is critical regulator involvement in potency definition
Director, Center for Rare Neurological Diseases, MGH
Associate Professor, Neurology, HMS
Single gene disorder NGS enable diagnosis, DIagnosis to Treatment How to know whar cell to target, make it available and scale up Address gap: missing components Biomarkers to cell types lipid chemistry cell animal biology
crosswalk from bone marrow matter
New gene discovered that causes neurodevelopment of stagnant genes Examining new Biology cell type specific biomarkers
The American Diabetes Association estimates 30 million Americans have diabetes and 1.5 million are diagnosed annually. GCT offers the prospect of long-sought treatment for this enormous cohort and their chronic requirements. The complexity of the disease and its management constitute a grand challenge and highlight both the potential of GCT and its current limitations.
Islet transplantation for type 1 diabetes has been attempted for decades. Problems like loss of transplanted islet cells due to autoimmunity and graft site factors have been difficult to address. Is there anything different on the horizon for gene and cell therapies to help this be successful?
How is the durability of response for gene or cell therapies for diabetes being addressed? For example, what would the profile of an acceptable (vs. optimal) cell therapy look like?
Advanced made, Patient of Type 1 Outer and Inner compartments of spheres (not capsule) no immune suppression continuous secretion of enzyme Insulin independence without immune suppression
Volume to have of-the-shelf inventory oxegenation in location lymphatic and vascularization conrol the whole process modular platform learning from others
Keep eyes open, waiting the Pandemic to end and enable working back on all the indications
Portfolio of MET, Mimi Emerging Therapies
Learning from the Pandemic – operationalize the practice science, R&D leaders, new collaboratives at NIH, FDA, Novartis
Pursue programs that will yield growth, tropic diseases with Gates Foundation, Rising Tide pods for access CGT within Novartis Partnership with UPenn in Cell Therapy
Cost to access to IP from Academia to a Biotech CRISPR accessing few translations to Clinic
Protein degradation organization constraint valuation by parties in a partnership
Novartis: nuclear protein lipid nuclear particles, tamplate for Biotech to collaborate
Game changing: 10% of the Portfolio, New frontiers human genetics in Ophthalmology, CAR-T, CRISPR, Gene Therapy Neurological and payloads of different matter
The Voice of Dr. Seidman – Her abstract is cited below
The ultimate opportunity presented by discovering the genetic basis of human disease is accurate prediction and disease prevention. To enable this achievement, genetic insights must enable the identification of at-risk
individuals prior to end-stage disease manifestations and strategies that delay or prevent clinical expression. Genetic cardiomyopathies provide a paradigm for fulfilling these opportunities. Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, diastolic dysfunction with normal or enhanced systolic performance and a unique histopathology: myocyte hypertrophy, disarray and fibrosis. Dilated cardiomyopathy (DCM) exhibits enlarged ventricular volumes with depressed systolic performance and nonspecific histopathology. Both HCM and DCM are prevalent clinical conditions that increase risk for arrhythmias, sudden death, and heart failure. Today treatments for HCM and DCM focus on symptoms, but none prevent disease progression. Human molecular genetic studies demonstrated that these pathologies often result from dominant mutations in genes that encode protein components of the sarcomere, the contractile unit in striated muscles. These data combined with the emergence of molecular strategies to specifically modulate gene expression provide unparalleled opportunities to silence or correct mutant genes and to boost healthy gene expression in patients with genetic HCM and DCM. Many challenges remain, but the active and vital efforts of physicians, researchers, and patients are poised to ensure success.
Cyprus Island, kidney disease by mutation causing MUC1 accumulation and death BRD4780 molecule that will clear the misfolding proteins from the kidney organoids: pleuripotent stem cells small molecule developed for applications in the other cell types in brain, eye, gene mutation build mechnism for therapy clinical models transition from Academia to biotech
One of the most innovative segments in all of healthcare is the development of GCT driven therapies for rare and ultra-rare diseases. Driven by a series of insights and tools and funded in part by disease focused foundations, philanthropists and abundant venture funding disease after disease is yielding to new GCT technology. These often become platforms to address more prevalent diseases. The goal of making these breakthroughs routine and affordable is challenged by a range of issues including clinical trial design and pricing.
What is driving the interest in rare diseases?
What are the biggest barriers to making breakthroughs ‘routine and affordable?’
What is the role of retrospective and prospective natural history studies in rare disease? When does the expected value of retrospective disease history studies justify the cost?
Related to the first question, what is the FDA expecting as far as controls in clinical trials for rare diseases? How does this impact the collection of natural history data?
The power of GCT to cure disease has the prospect of profoundly improving the lives of patients who respond. Planning for a disruption of this magnitude is complex and challenging as it will change care across the spectrum. Leading chief executives shares perspectives on how the industry will change and how this change should be anticipated. Moderator: Meg Tirrell
Senior Health and Science Reporter, CNBC
CGT becoming staple therapy what are the disruptors emerging Speakers: Lisa Dechamps
SVP & Chief Business Officer, Novartis Gene Therapies
Reimagine medicine with collaboration at MGH, MDM condition in children
The Science is there, sustainable processes and systems impact is transformational
Value based pricing, risk sharing Payers and Pharma for one time therapy with life span effect
Head, Pharmaceuticals Research & Development, Bayer AG
CGT – 2016 and in 2020 new leadership and capability
Disease Biology and therapeutics
Regenerative Medicine: CGT vs repair building pipeline in ophthalmology and cardiovascular
During Pandemic: Deliver Medicines like Moderna, Pfizer – collaborations between competitors with Government Bayer entered into Vaccines in 5 days, all processes had to change access innovations developed over decades for medical solutions
GCT represents a large and growing market for novel therapeutics that has several segments. These include Cardiovascular Disease, Cancer, Neurological Diseases, Infectious Disease, Ophthalmology, Benign Blood Disorders, and many others; Manufacturing and Supply Chain including CDMO’s and CMO’s; Stem Cells and Regenerative Medicine; Tools and Platforms (viral vectors, nano delivery, gene editing, etc.). Bayer’s pharma business participates in virtually all of these segments. How does a Company like Bayer approach the development of a portfolio in a space as large and as diverse as this one? How does Bayer approach the support of the production infrastructure with unique demands and significant differences from its historical requirements? Moderator:
EVP, Pharmaceuticals, Head of Cell & Gene Therapy, Bayer AG
CGT will bring treatment to cure, delivery of therapies
Be a Leader repair, regenerate, cure
Technology and Science for CGT – building a portfolio vs single asset decision criteria development of IP market access patients access acceleration of new products
Bayer strategy: build platform for use by four domains
Gener augmentation
Autologeneic therapy, analytics
Gene editing
Oncology Cell therapy tumor treatment: What kind of cells – the jury is out
Of 23 product launch at Bayer no prediction is possible some high some lows
Gene delivery uses physical, chemical, or viral means to introduce genetic material into cells. As more genetically modified therapies move closer to the market, challenges involving safety, efficacy, and manufacturing have emerged. Optimizing lipidic and polymer nanoparticles and exosomal delivery is a short-term priority. This panel will examine how the short-term and long-term challenges are being tackled particularly for non-viral delivery modalities. Moderator: Natalie Artzi, PhD
Gene editing was recognized by the Nobel Committee as “one of gene technology’s sharpest tools, having a revolutionary impact on life sciences.” Introduced in 2011, gene editing is used to modify DNA. It has applications across almost all categories of disease and is also being used in agriculture and public health.
Today’s panel is made up of pioneers who represent foundational aspects of gene editing. They will discuss the movement of the technology into the therapeutic mainstream.
Successes in gene editing – lessons learned from late-stage assets (sickle cell, ophthalmology)
When to use what editing tool – pros and cons of traditional gene-editing v. base editing. Is prime editing the future? Specific use cases for epigenetic editing.
When we reach widespread clinical use – role of off-target editing – is the risk real? How will we mitigate? How practical is patient-specific off-target evaluation?
There are several dozen companies working to develop gene or cell therapies for Sickle Cell Disease, Beta Thalassemia, and Fanconi Anemia. In some cases, there are enzyme replacement therapies that are deemed effective and safe. In other cases, the disease is only managed at best. This panel will address a number of questions that are particular to this class of genetic diseases:
What are the pros and cons of various strategies for treatment? There are AAV-based editing, non-viral delivery even oligonucleotide recruitment of endogenous editing/repair mechanisms. Which approaches are most appropriate for which disease?
How can companies increase the speed of recruitment for clinical trials when other treatments are available? What is the best approach to educate patients on a novel therapeutic?
How do we best address ethnic and socio-economic diversity to be more representative of the target patient population?
How long do we have to follow up with the patients from the scientific, patient’s community, and payer points of view? What are the current FDA and EMA guidelines for long-term follow-up?
Where are we with regards to surrogate endpoints and their application to clinically meaningful endpoints?
What are the emerging ethical dilemmas in pediatric gene therapy research? Are there challenges with informed consent and pediatric assent for trial participation?
Are there differences in reimbursement policies for these different blood disorders? Clearly durability of response is a big factor. Are there other considerations?
Oligonucleotide drugs have recently come into their own with approvals from companies such as Biogen, Alnylam, Novartis and others. This panel will address several questions:
How important is the delivery challenge for oligonucleotides? Are technological advancements emerging that will improve the delivery of oligonucleotides to the CNS or skeletal muscle after systemic administration?
Will oligonucleotides improve as a class that will make them even more effective? Are further advancements in backbone chemistry anticipated, for example.
Will oligonucleotide based therapies blaze trails for follow-on gene therapy products?
Are small molecules a threat to oligonucleotide-based therapies?
Beyond exon skipping and knock-down mechanisms, what other roles will oligonucleotide-based therapies take mechanistically — can genes be activating oligonucleotides? Is there a place for multiple mechanism oligonucleotide medicines?
Are there any advantages of RNAi-based oligonucleotides over ASOs, and if so for what use?
What is occurring in the GCT venture capital segment? Which elements are seeing the most activity? Which areas have cooled? How is the investment market segmented between gene therapy, cell therapy and gene editing? What makes a hot GCT company? How long will the market stay frothy? Some review of demographics — # of investments, sizes, etc. Why is the market hot and how long do we expect it to stay that way? Rank the top 5 geographic markets for GCT company creation and investing? Are there academic centers that have been especially adept at accelerating GCT outcomes? Do the business models for the rapid development of coronavirus vaccine have any lessons for how GCT technology can be brought to market more quickly? Moderator: Meredith Fisher, PhD
The promise of stem cells has been a highlight in the realm of regenerative medicine. Unfortunately, that promise remains largely in the future. Recent breakthroughs have accelerated these potential interventions in particular for treating neurological disease. Among the topics the panel will consider are:
Stem cell sourcing
Therapeutic indication growth
Genetic and other modification in cell production
Cell production to final product optimization and challenges
The dynamics of venture/PE investing and IPOs are fast evolving. What are the drivers – will the number of investors grow will the size of early rounds continue to grow? How is this reflected in GCT target areas, company design, and biotech overall? Do patients benefit from these trends? Is crossover investing a distinct class or a little of both? Why did it emerge and what are the characteristics of the players? Will SPACs play a role in the growth of the gene and cell therapy industry. What is the role of corporate investment arms eg NVS, Bayer, GV, etc. – has a category killer emerged? Are we nearing the limit of what the GCT market can absorb or will investment capital continue to grow unabated? Moderator: Roger Kitterman
Nearly one hundred senior Mass General Brigham Harvard faculty contributed to the creation of this group of twelve GCT technologies that they believe will breakthrough in the next two years. The Disruptive Dozen identifies and ranks the GCT technologies that will be available on at least an experimental basis to have the chance of significantly improving health care. 11:35 AM – 11:45 AM
Computer connection to the iCloud of WordPress.com FROZE completely at 10:30AM EST and no file update was possible. COVERAGE OF MAY 21, 2021 IS RECORDED BELOW FOLLOWING THE AGENDA BY COPY AN DPASTE OF ALL THE TWEETS I PRODUCED ON MAY 21, 2021 8:30 AM – 8:55 AM
What is occurring in the GCT venture capital segment? Which elements are seeing the most activity? Which areas have cooled? How is the investment market segmented between gene therapy, cell therapy and gene editing? What makes a hot GCT company? How long will the market stay frothy? Some review of demographics — # of investments, sizes, etc. Why is the market hot and how long do we expect it to stay that way? Rank the top 5 geographic markets for GCT company creation and investing? Are there academic centers that have been especially adept at accelerating GCT outcomes? Do the business models for the rapid development of coronavirus vaccine have any lessons for how GCT technology can be brought to market more quickly? Moderator: Meredith Fisher, PhD
The promise of stem cells has been a highlight in the realm of regenerative medicine. Unfortunately, that promise remains largely in the future. Recent breakthroughs have accelerated these potential interventions in particular for treating neurological disease. Among the topics the panel will consider are:
Stem cell sourcing
Therapeutic indication growth
Genetic and other modification in cell production
Cell production to final product optimization and challenges
The dynamics of venture/PE investing and IPOs are fast evolving. What are the drivers – will the number of investors grow will the size of early rounds continue to grow? How is this reflected in GCT target areas, company design, and biotech overall? Do patients benefit from these trends? Is crossover investing a distinct class or a little of both? Why did it emerge and what are the characteristics of the players? Will SPACs play a role in the growth of the gene and cell therapy industry. What is the role of corporate investment arms eg NVS, Bayer, GV, etc. – has a category killer emerged? Are we nearing the limit of what the GCT market can absorb or will investment capital continue to grow unabated? Moderator: Roger Kitterman
Nearly one hundred senior Mass General Brigham Harvard faculty contributed to the creation of this group of twelve GCT technologies that they believe will breakthrough in the next two years. The Disruptive Dozen identifies and ranks the GCT technologies that will be available on at least an experimental basis to have the chance of significantly improving health care. 11:35 AM – 11:45 AM
The co-chairs convene to reflect on the insights shared over the three days. They will discuss what to expect at the in-person GCT focused May 2-4, 2022 World Medical Innovation Forum.
The co-chairs convene to reflect on the insights shared over the three days. They will discuss what to expect at the in-person GCT focused May 2-4, 2022 World Medical Innovation Forum.Christine Seidman, MD
Cyprus Island, kidney disease by mutation causing MUC1 accumulation and death BRD4780 molecule that will clear the misfolding proteins from the kidney organoids: pleuripotent stem cells small molecule developed for applications in the other cell types in brain, eye, gene mutation build mechnism for therapy clinical models transition from Academia to biotech
One of the most innovative segments in all of healthcare is the development of GCT driven therapies for rare and ultra-rare diseases. Driven by a series of insights and tools and funded in part by disease focused foundations, philanthropists and abundant venture funding disease after disease is yielding to new GCT technology. These often become platforms to address more prevalent diseases. The goal of making these breakthroughs routine and affordable is challenged by a range of issues including clinical trial design and pricing.
What is driving the interest in rare diseases?
What are the biggest barriers to making breakthroughs ‘routine and affordable?’
What is the role of retrospective and prospective natural history studies in rare disease? When does the expected value of retrospective disease history studies justify the cost?
Related to the first question, what is the FDA expecting as far as controls in clinical trials for rare diseases? How does this impact the collection of natural history data?
The power of GCT to cure disease has the prospect of profoundly improving the lives of patients who respond. Planning for a disruption of this magnitude is complex and challenging as it will change care across the spectrum. Leading chief executives shares perspectives on how the industry will change and how this change should be anticipated. Moderator: Meg Tirrell
Senior Health and Science Reporter, CNBC
CGT becoming staple therapy what are the disruptors emerging Speakers: Lisa Dechamps
SVP & Chief Business Officer, Novartis Gene Therapies
Reimagine medicine with collaboration at MGH, MDM condition in children
The Science is there, sustainable processes and systems impact is transformational
Value based pricing, risk sharing Payers and Pharma for one time therapy with life span effect
Head, Pharmaceuticals Research & Development, Bayer AG
CGT – 2016 and in 2020 new leadership and capability
Disease Biology and therapeutics
Regenerative Medicine: CGT vs repair building pipeline in ophthalmology and cardiovascular
During Pandemic: Deliver Medicines like Moderna, Pfizer – collaborations between competitors with Government Bayer entered into Vaccines in 5 days, all processes had to change access innovations developed over decades for medical solutions
GCT represents a large and growing market for novel therapeutics that has several segments. These include Cardiovascular Disease, Cancer, Neurological Diseases, Infectious Disease, Ophthalmology, Benign Blood Disorders, and many others; Manufacturing and Supply Chain including CDMO’s and CMO’s; Stem Cells and Regenerative Medicine; Tools and Platforms (viral vectors, nano delivery, gene editing, etc.). Bayer’s pharma business participates in virtually all of these segments. How does a Company like Bayer approach the development of a portfolio in a space as large and as diverse as this one? How does Bayer approach the support of the production infrastructure with unique demands and significant differences from its historical requirements? Moderator:
EVP, Pharmaceuticals, Head of Cell & Gene Therapy, Bayer AG
CGT will bring treatment to cure, delivery of therapies
Be a Leader repair, regenerate, cure
Technology and Science for CGT – building a portfolio vs single asset decision criteria development of IP market access patients access acceleration of new products
Bayer strategy: build platform for use by four domains
Gener augmentation
Autologeneic therapy, analytics
Gene editing
Oncology Cell therapy tumor treatment: What kind of cells – the jury is out
Of 23 product launch at Bayer no prediction is possible some high some lows
Gene delivery uses physical, chemical, or viral means to introduce genetic material into cells. As more genetically modified therapies move closer to the market, challenges involving safety, efficacy, and manufacturing have emerged. Optimizing lipidic and polymer nanoparticles and exosomal delivery is a short-term priority. This panel will examine how the short-term and long-term challenges are being tackled particularly for non-viral delivery modalities. Moderator: Natalie Artzi, PhD
Gene editing was recognized by the Nobel Committee as “one of gene technology’s sharpest tools, having a revolutionary impact on life sciences.” Introduced in 2011, gene editing is used to modify DNA. It has applications across almost all categories of disease and is also being used in agriculture and public health.
Today’s panel is made up of pioneers who represent foundational aspects of gene editing. They will discuss the movement of the technology into the therapeutic mainstream.
Successes in gene editing – lessons learned from late-stage assets (sickle cell, ophthalmology)
When to use what editing tool – pros and cons of traditional gene-editing v. base editing. Is prime editing the future? Specific use cases for epigenetic editing.
When we reach widespread clinical use – role of off-target editing – is the risk real? How will we mitigate? How practical is patient-specific off-target evaluation?
There are several dozen companies working to develop gene or cell therapies for Sickle Cell Disease, Beta Thalassemia, and Fanconi Anemia. In some cases, there are enzyme replacement therapies that are deemed effective and safe. In other cases, the disease is only managed at best. This panel will address a number of questions that are particular to this class of genetic diseases:
What are the pros and cons of various strategies for treatment? There are AAV-based editing, non-viral delivery even oligonucleotide recruitment of endogenous editing/repair mechanisms. Which approaches are most appropriate for which disease?
How can companies increase the speed of recruitment for clinical trials when other treatments are available? What is the best approach to educate patients on a novel therapeutic?
How do we best address ethnic and socio-economic diversity to be more representative of the target patient population?
How long do we have to follow up with the patients from the scientific, patient’s community, and payer points of view? What are the current FDA and EMA guidelines for long-term follow-up?
Where are we with regards to surrogate endpoints and their application to clinically meaningful endpoints?
What are the emerging ethical dilemmas in pediatric gene therapy research? Are there challenges with informed consent and pediatric assent for trial participation?
Are there differences in reimbursement policies for these different blood disorders? Clearly durability of response is a big factor. Are there other considerations?
Oligonucleotide drugs have recently come into their own with approvals from companies such as Biogen, Alnylam, Novartis and others. This panel will address several questions:
How important is the delivery challenge for oligonucleotides? Are technological advancements emerging that will improve the delivery of oligonucleotides to the CNS or skeletal muscle after systemic administration?
Will oligonucleotides improve as a class that will make them even more effective? Are further advancements in backbone chemistry anticipated, for example.
Will oligonucleotide based therapies blaze trails for follow-on gene therapy products?
Are small molecules a threat to oligonucleotide-based therapies?
Beyond exon skipping and knock-down mechanisms, what other roles will oligonucleotide-based therapies take mechanistically — can genes be activating oligonucleotides? Is there a place for multiple mechanism oligonucleotide medicines?
Are there any advantages of RNAi-based oligonucleotides over ASOs, and if so for what use?
Computer connection to the iCloud of WordPress.com FROZE completely at 10:30AM EST and no file update was possible. COVERAGE OF MAY 21, 2021 IS RECORDED BELOW FOLLOWING THE AGENDA BY COPY AN DPASTE OF ALL THE TWEETS I PRODUCED ON MAY 21, 2021
What is occurring in the GCT venture capital segment? Which elements are seeing the most activity? Which areas have cooled? How is the investment market segmented between gene therapy, cell therapy and gene editing? What makes a hot GCT company? How long will the market stay frothy? Some review of demographics — # of investments, sizes, etc. Why is the market hot and how long do we expect it to stay that way? Rank the top 5 geographic markets for GCT company creation and investing? Are there academic centers that have been especially adept at accelerating GCT outcomes? Do the business models for the rapid development of coronavirus vaccine have any lessons for how GCT technology can be brought to market more quickly? Moderator: Meredith Fisher, PhD
Partner, Mass General Brigham Innovation Fund
Strategies, success what changes are needed in the drug discovery process Speakers:
Bring disruptive frontier as a platform with reliable delivery CGT double knock out disease cure all change efficiency and scope human centric vs mice centered right scale of data converted into therapeutics acceleratetion
Innovation in drugs 60% fails in trial because of Toxicology system of the future deal with big diseases
Moderna is an example in unlocking what is inside us Microbiome and beyond discover new drugs epigenetics
Manufacturing change is not a new clinical trial FDA need to be presented with new rethinking for big innovations Drug pricing cheaper requires systematization How to systematically scaling up systematize the discovery and the production regulatory innovations
The promise of stem cells has been a highlight in the realm of regenerative medicine. Unfortunately, that promise remains largely in the future. Recent breakthroughs have accelerated these potential interventions in particular for treating neurological disease. Among the topics the panel will consider are:
Stem cell sourcing
Therapeutic indication growth
Genetic and other modification in cell production
Cell production to final product optimization and challenges
Director, Neuroregeneration Research Institute, McLean
Professor, Neurology and Neuroscience, MGH, HMS
Opportunities in the next generation of the tactical level Welcome the oprimism and energy level of all Translational medicine funding stem cells enormous opportunities
Ear inside the scall compartments and receptors responsible for hearing highly differentiated tall ask to identify cell for anticipated differentiation
The dynamics of venture/PE investing and IPOs are fast evolving. What are the drivers – will the number of investors grow will the size of early rounds continue to grow? How is this reflected in GCT target areas, company design, and biotech overall? Do patients benefit from these trends? Is crossover investing a distinct class or a little of both? Why did it emerge and what are the characteristics of the players? Will SPACs play a role in the growth of the gene and cell therapy industry. What is the role of corporate investment arms eg NVS, Bayer, GV, etc. – has a category killer emerged? Are we nearing the limit of what the GCT market can absorb or will investment capital continue to grow unabated? Moderator: Roger Kitterman
VP, Venture, Mass General Brigham
Saturation reached or more investment is coming in CGT
Pharmacologic agent in existing cause another disorders locomo-movement related
efficacy Autologous cell therapy transplantation approach program T cells into dopamine generating neurons greater than Allogeneic cell transplantation
Current market does not have delivery mechanism that a drug-delivery is the solution Trials would fail on DELIVERY
Immune suppressed patients during one year to avoid graft rejection Autologous approach of Parkinson patient genetically mutated reprogramed as dopamine generating neuron – unknowns are present
Circuitry restoration
Microenvironment disease ameliorate symptoms – education of patients on the treatment
Nearly one hundred senior Mass General Brigham Harvard faculty contributed to the creation of this group of twelve GCT technologies that they believe will breakthrough in the next two years. The Disruptive Dozen identifies and ranks the GCT technologies that will be available on at least an experimental basis to have the chance of significantly improving health care. 11:35 AM – 11:45 AM
The co-chairs convene to reflect on the insights shared over the three days. They will discuss what to expect at the in-person GCT focused May 2-4, 2022 World Medical Innovation Forum.
ALL THE TWEETS PRODUCED ON MAY 21, 2021 INCLUDE THE FOLLOWING:
Bob Carter, MD, PhD Chairman, Department of Neurosurgery, MGH William and Elizabeth Sweet, Professor of Neurosurgery, HMS Neurogeneration REVERSAL or slowing down?
Penelope Hallett, PhD NRL, McLean Assistant Professor Psychiatry, HMS efficacy Autologous cell therapy transplantation approach program T cells into dopamine genetating cells greater than Allogeneic cell transplantation
Roger Kitterman VP, Venture, Mass General Brigham Saturation reached or more investment is coming in CGT Multi OMICS and academia originated innovations are the most attractive areas
Peter Kolchinsky, PhD Founder and Managing Partner, RA Capital Management Future proof for new comers disruptors Ex Vivo gene therapy to improve funding products what tool kit belongs to
Chairman, Department of Neurosurgery, MGH, Professor of Neurosurgery, HMS Cell therapy for Parkinson to replace dopamine producing cells lost ability to produce dopamine skin cell to become autologous cells reprogramed
Kapil Bharti, PhD Senior Investigator, Ocular and Stem Cell Translational Research Section, NIH Off-th-shelf one time treatment becoming cure Intact tissue in a dish is fragile to maintain metabolism to become like semiconductors
Ole Isacson, MD, PhD Director, Neuroregeneration Research Institute, McLean Professor, Neurology and Neuroscience, MGH, HMS Opportunities in the next generation of the tactical level Welcome the oprimism and energy level of all
Erin Kimbrel, PhD Executive Director, Regenerative Medicine, Astellas In the ocular space immunogenecity regulatory communication use gene editing for immunogenecity Cas1 and Cas2 autologous cells
Nabiha Saklayen, PhD CEO and Co-Founder, Cellino scale production of autologous cells foundry using semiconductor process in building cassettes by optic physicists
Joe Burns, PhD VP, Head of Biology, Decibel Therapeutics Ear inside the scall compartments and receptors responsible for hearing highly differentiated tall ask to identify cell for anticipated differentiation control by genomics
Kapil Bharti, PhD Senior Investigator, Ocular and Stem Cell Translational Research Section, NIH first drug required to establish the process for that innovations design of animal studies not done before
Robert Nelsen Managing Director, Co-founder, ARCH Venture Partners Manufacturing change is not a new clinical trial FDA need to be presented with new rethinking for big innovations Drug pricing cheaper requires systematization
David Berry, MD, PhD CEO, Valo Health GP, Flagship Pioneering Bring disruptive frontier platform reliable delivery CGT double knockout disease cure all change efficiency scope human centric vs mice centered right scale acceleration
Kush Parmar, MD, PhD Managing Partner, 5AM Ventures build it yourself, benefit for patients FIrst Look at MGB shows MEE innovation on inner ear worthy investment
Robert Nelsen Managing Director, Co-founder, ARCH Venture Partners Frustration with supply chain during the Pandemic, GMC anticipation in advance CGT rapidly prototype rethink and invest proactive investor .edu and Pharma
Thriving Vaccines and Research: Weizmann Institute Coronavirus Research Development
Reporter:Amandeep Kaur, B.Sc., M.Sc.
In early February, Prof. Eran Segal updated in one of his tweets and mentioned that “We say with caution, the magic has started.”
The article reported that this statement by Prof. Segal was due to decreasing cases of COVID-19, severe infection cases and hospitalization of patients by rapid vaccination process throughout Israel. Prof. Segal emphasizes in another tweet to remain cautious over the country and informed that there is a long way to cover and searching for scientific solutions.
A daylong webinar entitled “COVID-19: The epidemic that rattles the world” was a great initiative by Weizmann Institute to share their scientific knowledge about the infection among the Israeli institutions and scientists. Prof. Gideon Schreiber and Dr. Ron Diskin organized the event with the support of the Weizmann Coronavirus Response Fund and Israel Society for Biochemistry and Molecular Biology. The speakers were invited from the Hebrew University of Jerusalem, Tel-Aviv University, the Israel Institute for Biological Research (IIBR), and Kaplan Medical Center who addressed the molecular structure and infection biology of the virus, treatments and medications for COVID-19, and the positive and negative effect of the pandemic.
The article reported that with the emergence of pandemic, the scientists at Weizmann started more than 60 projects to explore the virus from different range of perspectives. With the help of funds raised by communities worldwide for the Weizmann Coronavirus Response Fund supported scientists and investigators to elucidate the chemistry, physics and biology behind SARS-CoV-2 infection.
Prof. Avi Levy, the coordinator of the Weizmann Institute’s coronavirus research efforts, mentioned “The vaccines are here, and they will drastically reduce infection rates. But the coronavirus can mutate, and there are many similar infectious diseases out there to be dealt with. All of this research is critical to understanding all sorts of viruses and to preempting any future pandemics.”
The following are few important projects with recent updates reported in the article.
Mapping a hijacker’s methods
Dr. Noam Stern-Ginossar studied the virus invading strategies into the healthy cells and hijack the cell’s systems to divide and reproduce. The article reported that viruses take over the genetic translation system and mainly the ribosomes to produce viral proteins. Dr. Noam used a novel approach known as ‘ribosome profiling’ as her research objective and create a map to locate the translational events taking place inside the viral genome, which further maps the full repertoire of viral proteins produced inside the host.
She and her team members grouped together with the Weizmann’s de Botton Institute and researchers at IIBR for Protein Profiling and understanding the hijacking instructions of coronavirus and developing tools for treatment and therapies. Scientists generated a high-resolution map of the coding regions in the SARS-CoV-2 genome using ribosome-profiling techniques, which allowed researchers to quantify the expression of vital zones along the virus genome that regulates the translation of viral proteins. The study published in Nature in January, explains the hijacking process and reported that virus produces more instruction in the form of viral mRNA than the host and thus dominates the translation process of the host cell. Researchers also clarified that it is the misconception that virus forced the host cell to translate its viral mRNA more efficiently than the host’s own translation, rather high level of viral translation instructions causes hijacking. This study provides valuable insights for the development of effective vaccines and drugs against the COVID-19 infection.
Like chutzpah, some things don’t translate
Prof. Igor Ulitsky and his team worked on untranslated region of viral genome. The article reported that “Not all the parts of viral transcript is translated into protein- rather play some important role in protein production and infection which is unknown.” This region may affect the molecular environment of the translated zones. The Ulitsky group researched to characterize that how the genetic sequence of regions that do not translate into proteins directly or indirectly affect the stability and efficiency of the translating sequences.
Initially, scientists created the library of about 6,000 regions of untranslated sequences to further study their functions. In collaboration with Dr. Noam Stern-Ginossar’s lab, the researchers of Ulitsky’s team worked on Nsp1 protein and focused on the mechanism that how such regions affect the Nsp1 protein production which in turn enhances the virulence. The researchers generated a new alternative and more authentic protocol after solving some technical difficulties which included infecting cells with variants from initial library. Within few months, the researchers are expecting to obtain a more detailed map of how the stability of Nsp1 protein production is getting affected by specific sequences of the untranslated regions.
The landscape of elimination
The article reported that the body’s immune system consists of two main factors- HLA (Human Leukocyte antigen) molecules and T cells for identifying and fighting infections. HLA molecules are protein molecules present on the cell surface and bring fragments of peptide to the surface from inside the infected cell. These peptide fragments are recognized and destroyed by the T cells of the immune system. Samuels’ group tried to find out the answer to the question that how does the body’s surveillance system recognizes the appropriate peptide derived from virus and destroy it. They isolated and analyzed the ‘HLA peptidome’- the complete set of peptides bound to the HLA proteins from inside the SARS-CoV-2 infected cells.
After the analysis of infected cells, they found 26 class-I and 36 class-II HLA peptides, which are present in 99% of the population around the world. Two peptides from HLA class-I were commonly present on the cell surface and two other peptides were derived from coronavirus rare proteins- which mean that these specific coronavirus peptides were marked for easy detection. Among the identified peptides, two peptides were novel discoveries and seven others were shown to induce an immune response earlier. These results from the study will help to develop new vaccines against new coronavirus mutation variants.
Gearing up ‘chain terminators’ to battle the coronavirus
Prof. Rotem Sorek and his lab discovered a family of enzymes within bacteria that produce novel antiviral molecules. These small molecules manufactured by bacteria act as ‘chain terminators’ to fight against the virus invading the bacteria. The study published in Nature in January which reported that these molecules cause a chemical reaction that halts the virus’s replication ability. These new molecules are modified derivates of nucleotide which integrates at the molecular level in the virus and obstruct the works.
Prof. Sorek and his group hypothesize that these new particles could serve as a potential antiviral drug based on the mechanism of chain termination utilized in antiviral drugs used recently in the clinical treatments. Yeda Research and Development has certified these small novel molecules to a company for testing its antiviral mechanism against SARS-CoV-2 infection. Such novel discoveries provide evidences that bacterial immune system is a potential repository of many natural antiviral particles.
Resolving borderline diagnoses
Currently, Real-time Polymerase chain reaction (RT-PCR) is the only choice and extensively used for diagnosis of COVID-19 patients around the globe. Beside its benefits, there are problems associated with RT-PCR, false negative and false positive results and its limitation in detecting new mutations in the virus and emerging variants in the population worldwide. Prof. Eran Elinavs’ lab and Prof. Ido Amits’ lab are working collaboratively to develop a massively parallel, next-generation sequencing technique that tests more effectively and precisely as compared to RT-PCR. This technique can characterize the emerging mutations in SARS-CoV-2, co-occurring viral, bacterial and fungal infections and response patterns in human.
The scientists identified viral variants and distinctive host signatures that help to differentiate infected individuals from non-infected individuals and patients with mild symptoms and severe symptoms.
In Hadassah-Hebrew University Medical Center, Profs. Elinav and Amit are performing trails of the pipeline to test the accuracy in borderline cases, where RT-PCR shows ambiguous or incorrect results. For proper diagnosis and patient stratification, researchers calibrated their severity-prediction matrix. Collectively, scientists are putting efforts to develop a reliable system that resolves borderline cases of RT-PCR and identify new virus variants with known and new mutations, and uses data from human host to classify patients who are needed of close observation and extensive treatment from those who have mild complications and can be managed conservatively.
Moon shot consortium refining drug options
The ‘Moon shot’ consortium was launched almost a year ago with an initiative to develop a novel antiviral drug against SARS-CoV-2 and was led by Dr. Nir London of the Department of Chemical and Structural Biology at Weizmann, Prof. Frank von Delft of Oxford University and the UK’s Diamond Light Source synchroton facility.
To advance the series of novel molecules from conception to evidence of antiviral activity, the scientists have gathered support, guidance, expertise and resources from researchers around the world within a year. The article reported that researchers have built an alternative template for drug-discovery, full transparency process, which avoids the hindrance of intellectual property and red tape.
The new molecules discovered by scientists inhibit a protease, a SARS-CoV-2 protein playing important role in virus replication. The team collaborated with the Israel Institute of Biological Research and other several labs across the globe to demonstrate the efficacy of molecules not only in-vitro as well as in analysis against live virus.
Further research is performed including assaying of safety and efficacy of these potential drugs in living models. The first trial on mice has been started in March. Beside this, additional drugs are optimized and nominated for preclinical testing as candidate drug.
Genetic scissors: a tool for rewriting the code of life
Emmanuelle Charpentier and Jennifer A. Doudna have discovered one of gene technology’s sharpest tools: the CRISPR/Cas9 genetic scissors. Using these, researchers can change the DNA of animals, plants and microorganisms with extremely high precision. This technology has had a revolutionary impact on the life sciences, is contributing to new cancer therapies and may make the dream of curing inherited diseases come true.
Researchers need to modify genes in cells if they are to find out about life’s inner workings. This used to be time-consuming, difficult and sometimes impossible work. Using the CRISPR/Cas9 genetic scissors, it is now possible to change the code of life over the course of a few weeks.
“There is enormous power in this genetic tool, which affects us all. It has not only revolutionised basic science, but also resulted in innovative crops and will lead to ground-breaking new medical treatments,” says Claes Gustafsson, chair of the Nobel Committee for Chemistry.
As so often in science, the discovery of these genetic scissors was unexpected. During Emmanuelle Charpentier’s studies of Streptococcus pyogenes, one of the bacteria that cause the most harm to humanity, she discovered a previously unknown molecule, tracrRNA. Her work showed that tracrRNA is part of bacteria’s ancient immune system, CRISPR/Cas, that disarms viruses by cleaving their DNA.
Charpentier published her discovery in 2011. The same year, she initiated a collaboration with Jennifer Doudna, an experienced biochemist with vast knowledge of RNA. Together, they succeeded in recreating the bacteria’s genetic scissors in a test tube and simplifying the scissors’ molecular components so they were easier to use.
In an epoch-making experiment, they then reprogrammed the genetic scissors. In their natural form, the scissors recognise DNA from viruses, but Charpentier and Doudna proved that they could be controlled so that they can cut any DNA molecule at a predetermined site. Where the DNA is cut it is then easy to rewrite the code of life.
Since Charpentier and Doudna discovered the CRISPR/Cas9 genetic scissors in 2012 their use has exploded. This tool has contributed to many important discoveries in basic research, and plant researchers have been able to develop crops that withstand mould, pests and drought. In medicine, clinical trials of new cancer therapies are underway, and the dream of being able to cure inherited diseases is about to come true. These genetic scissors have taken the life sciences into a new epoch and, in many ways, are bringing the greatest benefit to humankind.
Emmanuelle Charpentier, born 1968 in Juvisy-sur-Orge, France. Ph.D. 1995 from Institut Pasteur, Paris, France. Director of the Max Planck Unit for the Science of Pathogens, Berlin, Germany.
Jennifer A. Doudna, born 1964 in Washington, D.C, USA. Ph.D. 1989 from Harvard Medical School, Boston, USA. Professor at the University of California, Berkeley, USA and Investigator, Howard Hughes Medical Institute.
Other Articles on the Nobel Prize in this Open Access Journal Include:
June 22-24: Free Registration for AACR Members, the Cancer Community, and the Public
This virtual meeting will feature more than 120 sessions and 4,000 e-posters, including sessions on cancer health disparities and the impact of COVID-19 on clinical trials
This Virtual Meeting is Part II of the AACR Annual Meeting. Part I was held online in April and was centered only on clinical findings. This Part II of the virtual meeting will contain all the Sessions and Abstracts pertaining to basic and translational cancer research as well as clinical trial findings.
Chemicals known to cause cancer are used and released to the environment in large volumes, exposing people where they live, work, play, and go to school. The science establishing an important role for such exposures in the development of cancers continues to strengthen, yet cancer prevention researchers are largely unfamiliar with the data drawn upon in identifying carcinogens and making decisions about their use. Characterizing and reducing harmful exposures and accelerating the devel
Julia Brody, Kathryn Z. Guyton, Polly J. Hoppin, Bill Walsh, Mary H. Ward
During carcinoma progression, initially benign epithelial cells acquire the ability to invade locally and disseminate to distant tissues by activating epithelial-mesenchymal transition (EMT). EMT is a cellular process during which epithelial cells lose their epithelial features and acquire mesenchymal phenotypes and behavior. Growing evidence supports the notion that EMT programs during tumor progression are usually activated to various extents and often partial and reversible, thus pr
Jean-Paul Thiery, Heide L Ford, Jing Yang, Geert Berx
Cellular senescence is a stable cell growth arrest that is broadly recognized to act as a barrier against tumorigenesis. Senescent cells acquire a senescence-associated secretory phenotype (SASP), a transcriptional response involving the secretion of inflammatory cytokines, immune modulators, and proteases that can shape the tumor microenvironment. The SASP can initially stimulate tumor immune surveillance and reinforce growth arrest. However, if senescent cells are not removed by the
The focus of this educational session will be on recent developments in cell-free DNA (cfDNA) analysis that have the potential to impact the care of cancer patients. Tumors continually shed DNA into the circulation, where it can be detected as circulating tumor DNA (ctDNA). Analysis of ctDNA has become a routine part of care for a subset of patients with advanced malignancies. However, there are a number of exciting potential applications that have promising preliminary data but that h
Michael R Speicher, Maximilian Diehn, Aparna Parikh
This session will describe how advances in understanding cancer genomes and in genetic testing technologies are being translated to the clinic. The speakers will illustrate the clinical impact of genomic discoveries for diagnostics and treatment of common tumor types in adults and in children. Cutting-edge technologies for characterization of patient and tumor genomes will be described. New insights into the importance of patient factors for cancer risk and outcome, including predispos
Heather L. Hampel, Gordana Raca, Jaclyn Biegel, Jeffrey M Trent
The U.S. Food and Drug Administration relies on data from clinical trials to determine whether medical products are safe and effective. Ideally, patients enrolled in those trials are representative of the population in which the product will be used if approved, including people of different ages, races, ethnic groups, and genders. Unfortunately, with few patients enrolling in clinical trials, many groups are not well-represented in clinical trials. This session will explore challenges
Ajay K. Nooka, Nicole J. Gormley, Kenneth C Anderson, Ruben A. Mesa, Daniel J. George, Yelak Biru, RADM Richardae Araojo, Lola A. Fashoyin-Aje
This educational session will cover the exciting emerging field of targeted protein degradation. Key learning topics will include: 1. an introduction to the technology and its relevance to oncology; 2. PROTACS, degraders, and CELMoDs; 3. enzymology and protein-protein interactions in targeted protein degraders; 4. examples of differentiated biology due to degradation vs. inhibition; 5. how to address questions of specificity; and 6. how the field is approaching challenges in optimizing therapies
George Burslem, Mary Matyskiela, Lyn H. Jones, Stewart L Fisher, Andrew J Phillips
Bioinformatics and Systems Biology, Experimental and Molecular Therapeutics, Drug Development, Molecular and Cellular Biology/Genetics
Obstacles and opportunities for protein degradation drug discovery
Lyn H. Jones
PROTACs ubiquitin mediated by E3 ligases; first discovered by DeShaies and targeted to specific proteins
PROTACs used in drug discovery against a host of types of targets including kinases and membrane receptors
PROTACs can be modular but lack molecular structural activity relationships
can use chemical probes for target validation
four requirements: candidate exposure at site of action (for example lipophilicity for candidates needed to cross membranes and accumulate in lysosomes), target engagement (ternary occupancy as measured by FRET), functional pharmacology, relevant phenotype
PROTACs hijack the proteosomal degradation system
Proteolysis-targeting chimeras as therapeutics and tools for biological discovery
George Burslem
first PROTAC developed to coopt the VHL ubiquitin ligase system which degrades HIF1alpha but now modified for EREalpha
in screen for potential PROTACS there were compounds which bound high affinity but no degradation so phenotypic screening very important
when look at molecular dynamics can see where PROTAC can add additional protein protein interaction, verifed by site directed mutagenesis
able to target bcr-Abl
he says this is a rapidly expanding field because of all the new E3 ligase targets being discovered
Expanding the horizons of cereblon modulators
Mary Matyskiela
Translating cellular targeted protein degradation to in vivo models using an enzymology framework
Stewart L Fisher
new targeting compounds have an E3 ligase binding domain, a target binding domain and a linker domain
in vivo these compounds are very effective; BRD4 degraders good invitro and in vivo with little effect on body weight
degraders are essential activators of E3 ligases as these degraders bring targets in close proximity so activates a catalytic cycle of a multistep process (has now high turnover number)
in enzymatic pathway the degraders make a productive complex so instead of a kcat think of measuring a kprod or productivity of degraders linked up an E3 ligase
the degraders are also affecting the rebound protein synthesis; so Emax never to zero and see a small rebound of protein synthesis
Drug combinations remain the gold standard for treating cancer, as they significantly outperform single agents. However, due to the enormous size of drug combination space, it is virtually impossible to interrogate all possible combinations. This session will discuss approaches to identify novel combinations using both experimental and computational approaches. Speakers will discuss i) approaches to drug screening in cell lines, the impact of the microenvironment, and attempts to more
Bence Szalai, James E Korkola, Lisa Tucker-Kellogg, Jeffrey W Tyner
Cancer stem cells are a subpopulation of cells with a high capacity for self-renewal, differentiation and resistance to therapy. In this session, we will define cancer stem cells, discuss cellular plasticity, interactions between cancer stem cells and the tumor microenvironment, and mechanisms that contribute to therapeutic resistance.
Robert S Kerbel, Dolores Hambardzumyan, Jennifer S. Yu
This session will cover the fundamentals as well as the major advances made in the field of molecular imaging. Topics covered will include the basics for optical, nuclear, and ultrasound imaging; the pros and cons of each modality; and the recent translational advancements. Learning objectives include the fundamentals of each imaging modality, recent advances in the technology, the processes involved to translate an imaging agent from bench to bedside, and how molecular imaging can gui
Julie Sutcliffe, Summer L Gibbs, Mark D Pagel, Katherine W Ferrara
Tumor-associated endothelium is a gatekeeper that coordinates the entry and egress of innate and adaptive immune cells within the tumor microenvironment. This is achieved, in part, via the coordinated expression of chemokines and cell adhesion molecules on the endothelial cell surface that attract and retain circulating leukocytes. Crosstalk between adaptive immune cells and the tumor endothelium is therefore essential for tumor immune surveillance and the success of immune-based thera
Dai Fukumura, Maria M Steele, Wen Jiang, Andrew C Dudley
T-cell immunotherapy in the form of immune checkpoint blockade or cellular T-cell therapies has been tremendously successful in some types of cancer. This success has opened the door to consider what other modalities or types of immune cells can be harnessed for exert antitumor functions. In this session, experts in their respective fields will discuss topics including novel approaches in immunotherapy, including NK cells, macrophage, and viral oncotherapies.
Evanthia Galanis, Kerry S Campbell, Milan G Chheda, Jennifer L Guerriero
Carcinomas develop metastases and resistance to therapy as a result of interaction with tumor microenvironment, composed of various nonmalignant cell types. Understanding the complexity and origins of tumor stromal cells is a prerequisite for development of effective treatments. The link between obesity and cancer progression has revealed the engagement of adipose stromal cells (ASC) and adipocytes from adjacent fat tissue. However, the molecular mechanisms through which they stimulate
Guojun Wu, Matteo Ligorio, Mikhail Kolonin, Maria T Diaz-Meco
The term “cancer” encompasses hundreds of distinct disease entities involving almost every possible site in the human body. Effectively interrogating cancer, either in animals models or human specimens, requires a deep understanding of the involved organ. This includes both the normal cellular constituents of the affected tissue as well as unique aspects of tissue-specific tumorigenesis. It is critical to “Know Thy Organ” when studying cancer. This session will focus on two of the most
Trudy G Oliver, Hossein Borghaei, Laura Delong Wood, Howard C Crawford
Good clinical trial design has always had to balance the competing interests of effectively and convincingly answering the question with the limitations imposed by scarce resources, complex logistics, and risks and potential benefits to participants. New targeted therapies, immuno-oncology, and novel combination treatments add new challenges on top of the old ones. This session will introduce these concerns and 1) suggest ways to consider what outcomes are relevant, 2) how we can best
Mary W. Redman, Nolan A. Wages, Susan G Hilsenbeck, Karyn A. Goodman
The sequencing of human cancers now provides a landscape of the genetic alterations that occur in human cancer, and increasingly knowledge of somatic genetic alterations is becoming part of the evaluation of cancer patients. In some cases, this information leads directly to the selection of particular therapeutic approaches; however, we still lack the ability to decipher the significance of genetic alterations in many cancers. This session will focus on recent developments that permit the identification of molecular targets in specific cancers. This information, coupled with genomic characterization of cancer, will facilitate the development of new therapeutic agents and provide a path to implement precision cancer medicine to all patients.
William C Hahn, Mark A Dawson, Mariella Filbin, Michael Bassik
Genome-scale CRISPR screens in 3D spheroids identify cancer vulnerabilities
Michael Bassik
Utilizing single-cell RNAseq and CRISPR screens to target cancer stem cells in pediatric brain tumors
Mariella Filbin
many gliomas are defined by discreet mutational spectra that also discriminates based on age and site as well (for example many cortical tumors have mainly V600E Braf mutations while thalamus will be FGFR1
they did single cell RNAseq on needle biopsy from 7 gliomas which gave about 3500 high quality single cells; obtained full length RNA
tumors clustered mainly where the patient it came from but had stromal cell contamination probably so did a deconvolution? Copy number variation showed which were tumor cells and did principle component analysis
it seems they used a human glioma model as training set
identified a stem cell like glioma cell so concentrated on the genes altered in these for translational studies
developed multiple PDX models from patients
PDX transcriptome closest to patient transcriptome but organoid grown in serum free very close while organoids grown in serum very distinct transcriptome
developed a CRISPR barcoded library to determine genes for survival genes
pulled out BMI1 and EZH2 (polycomb complex proteins) as good targets
Virtual Methods Workshop
Prevention Research, Survivorship, Clinical Research Excluding Trials, Epidemiology
Through this Education Session we will use examples from ongoing research to provide an overview of implementation science approaches to cancer prevention and control research. We draw on examples to highlight study design approaches, research methods, and real-world solutions when applying implementation science to achieve health equity. Approaches to defining change in the care setting and measuring sustained changes are also emphasized. Using real examples of patient navigation prog
Graham A Colditz, Sanja Percac-Lima, Nathalie Huguet
This session will consider the use of real-world evidence in the context of oncology clinical trials affected by the COVID-19 pandemic. Key aspects of the FDA’s recent “Guidance on Conduct of Clinical Trials of Medical Products of Medical Products during COVID-19 Public Health Emergency” will be discussed, including telemedicine, accounting for missing data, obtaining laboratory tests and images locally, using remote informed consent procedures, and additional considerations for contin
Wendy Rubinstein, Paul G. Kluetz, Amy P. Abernethy, Jonathan Hirsch, C.K. Wang
Targeting chromatin remodeling-associated genetic vulnerabilities in cancer: PBRM1 defects are synthetic lethal with PARP and ATR inhibitors
Presenter/AuthorsRoman Merial Chabanon, Daphné Morel, Léo Colmet-Daage, Thomas Eychenne, Nicolas Dorvault, Ilirjana Bajrami, Marlène Garrido, Suzanna Hopkins, Cornelia Meisenberg, Andrew Lamb, Theo Roumeliotis, Samuel Jouny, Clémence Astier, Asha Konde, Geneviève Almouzni, Jyoti Choudhary, Jean-Charles Soria, Jessica Downs, Christopher J. Lord, Sophie Postel-Vinay. Gustave Roussy, Villejuif, France, The Francis Crick Institute, London, United Kingdom, Institute of Cancer Research, London, United Kingdom, Sage Bionetworks, Seattle, WA, Institute of Cancer Research, London, United Kingdom, Institute of Cancer Research, London, United Kingdom, Institut Curie, Paris, France, Université Paris-Sud/Université Paris-Saclay, Le Kremlin-Bicêtre, France, Gustave Roussy Cancer Campus and U981 INSERM, ATIP-Avenir group, Villejuif, FranceDisclosures R.M. Chabanon: None. D. Morel: None. L. Colmet-Daage: None. T. Eychenne: None. N. Dorvault: None. I. Bajrami: None. M. Garrido: None. S. Hopkins: ; Fishawack Group of Companies. C. Meisenberg: None. A. Lamb: None. T. Roumeliotis: None. S. Jouny: None. C. Astier: None. A. Konde: None. G. Almouzni: None. J. Choudhary: None. J. Soria: ; Medimmune/AstraZeneca. ; Astex. ; Gritstone. ; Clovis. ; GSK. ; GamaMabs. ; Lilly. ; MSD. ; Mission Therapeutics. ; Merus. ; Pfizer. ; PharmaMar. ; Pierre Fabre. ; Roche/Genentech. ; Sanofi. ; Servier. ; Symphogen. ; Takeda. J. Downs: None. C.J. Lord: ; AstraZeneca. ; Merck KGaA. ; Artios. ; Tango. ; Sun Pharma. ; GLG. ; Vertex. ; Ono Pharma. ; Third Rock Ventures. S. Postel-Vinay: ; Merck KGaA. ; Principal investigator of clinical trials for Gustave Roussy.; Boehringer Ingelheim. ; Principal investigator of clinical trials for Gustave Roussy.; Roche. ; Principal investigator of clinical trials for Gustave Roussy. Benefited from reimbursement for attending symposia.; AstraZeneca. ; Principal investigator of clinical trials for Gustave Roussy.; Clovis. ; Principal investigator of clinical trials for Gustave Roussy.; Bristol-Myers Squibb. ; Principal investigator of clinical trials for Gustave Roussy.; Agios. ; Principal investigator of clinical trials for Gustave Roussy.; GSK.AbstractAim: Polybromo-1 (PBRM1), a specific subunit of the pBAF chromatin remodeling complex, is frequently inactivated in cancer. For example, 40% of clear cell Renal Cell Carcinoma (ccRCC) and 15% of cholangiocarcinoma present deleterious PBRM1 mutations. There is currently no precision medicine-based therapeutic approach that targets PBRM1 defects. To identify novel, targeted therapeutic strategies for PBRM1-defective cancers, we carried out high-throughput functional genomics and drug screenings followed by in vitro and in vivo validation studies.
Methods: High-throughput siRNA-drug sensitization and drug sensitivity screens evaluating > 150 cancer-relevant small molecules in dose-response were performed in Pbrm1 siRNA-transfected mouse embryonic stem cells (mES) and isogenic PBRM1-KO or -WT HAP1 cells, respectively. After identification of PBRM1-selective small molecules, revalidation was carried out in a series of in-house-generated isogenic models of PBRM1 deficiency – including 786-O (ccRCC), A498 (ccRCC), U2OS (osteosarcoma) and H1299 (non-small cell lung cancer) human cancer cell lines – and non-isogenic ccRCC models, using multiple clinical compounds. Mechanistic dissection was performed using immunofluorescence, RT-qPCR, western blotting, DNA fiber assay, transcriptomics, proteomics and DRIP-sequencing to evaluate markers of DNA damage response (DDR), replication stress and cell-autonomous innate immune signaling. Preclinical data were integrated with TCGA tumor data.
Results: Parallel high-throughput drug screens independently identified PARP inhibitors (PARPi) as being synthetic lethal with PBRM1 defects – a cell type-independent effect which was exacerbated by ATR inhibitors (ATRi) and which we revalidated in vitro in isogenic and non-isogenic systems and in vivo in a xenograft model. PBRM1 defects were associated with increased replication fork stress (higher γH2AX and RPA foci levels, decreased replication fork speed and increased ATM checkpoint activation), R-loop accumulation and enhanced genomic instability in vitro; these effects were exacerbated upon PARPi exposure. In patient tumor samples, we also found that PBRM1-mutant cancers possessed a higher mutational load. Finally, we found that ATRi selectively activated the cGAS/STING cytosolic DNA sensing pathway in PBRM1-deficient cells, resulting in increased expression of type I interferon genes.
Conclusion: PBRM1-defective cancer cells present increased replication fork stress, R-loop formation, genome instability and are selectively sensitive to PARPi and ATRi through a synthetic lethal mechanism that is cell type-independent. Our data provide the pre-clinical rationale for assessing PARPi as a monotherapy or in combination with ATRi or immune-modulating agents in molecularly-selected patients with PBRM1-defective cancers.
1057 – Targeting MTHFD2 using first-in-class inhibitors kills haematological and solid cancer through thymineless-induced replication stress
Presenter/AuthorsThomas Helleday. University of Sheffield, Sheffield, United KingdomDisclosures T. Helleday: None.AbstractSummary
Thymidine synthesis pathways are upregulated pathways in cancer. Since the 1940s, targeting nucleotide and folate metabolism to induce thymineless death has remained first-line anti-cancer treatment. Recent discoveries that showing cancer cells have rewired networks and exploit unique enzymes for proliferation, have renewed interest in metabolic pathways. The cancer-specific expression of MTHFD2 has gained wide-spread attention and here we describe an emerging role for MTHFD2 in the DNA damage response (DDR). The folate metabolism enzyme MTHFD2 is one of the most consistently overexpressed metabolic enzymes in cancer and an emerging anticancer target. We show a novel role for MTHFD2 being essential for DNA replication and genomic stability in cancer cells. We describe first-in-class nanomolar MTHFD2 inhibitors (MTHFD2i), with protein co-crystal structures demonstrating binding in the active site of MTHFD2 and engaging with the target in cells and tumours. We show MTHFD2i reduce replication fork speed and induce replication stress, followed by S phase arrest, apoptosis and killing of a range of haematological and solid cancer cells in vitro and in vivo, with a therapeutic window spanning up to four orders of magnitude compared to non-transformed cells. Mechanistically, MTHFD2i prevent thymidine production leading to mis-incorporation of uracil into DNA and replication stress. As MTHFD2 expression is cancer specific there is a potential of MTHFD2i to synergize with other treatments. Here, we show MTHFD2i synergize with dUTPase inhibitors as well as other DDR inhibitors and demonstrate the mechanism of action. These results demonstrate a new link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically.
Keywords
MTHFD2, one-carbon metabolism, folate metabolism, DNA replication, replication stress, synthetic lethal, thymineless death, small-molecule inhibitor, DNA damage response
1060 – Genetic and pharmacologic inhibition of Skp2, an E3 ubiquitin ligase and RB1-target, has antitumor activity in RB1-deficient human and mouse small cell lung cancer (SCLC)
Presenter/Authors
Hongling Zhao, Vineeth Sukrithan, Niloy Iqbal, Cari Nicholas, Yingjiao Xue, Joseph Locker, Juntao Zou, Liang Zhu, Edward L. Schwartz. Albert Einstein College of Medicine, Bronx, NY, Albert Einstein College of Medicine, Bronx, NY, Albert Einstein College of Medicine, Bronx, NY, University of Pittsburgh Medical Center, Pittsburgh, PA, Albert Einstein College of Medicine, Bronx, NY
Disclosures
H. Zhao: None. V. Sukrithan: None. N. Iqbal: None. C. Nicholas: None. Y. Xue: None. J. Locker: None. J. Zou: None. L. Zhu: None. E.L. Schwartz: None.
Abstract
The identification of driver mutations and their corresponding targeted drugs has led to significant improvements in the treatment of non-small cell lung cancer (NSCLC) and other solid tumors; however, similar advances have not been made in the treatment of small cell lung cancer (SCLC). Due to their aggressive growth, frequent metastases, and resistance to chemotherapy, the five-year overall survival of SCLC is less than 5%. While SCLC tumors can be sensitive to first-line therapy of cisplatin and etoposide, most patients relapse, often in less than 3 months after initial therapy. Dozens of drugs have been tested clinically in SCLC, including more than 40 agents that have failed in phase III trials.
The near uniform bi-allelic inactivation of the tumor suppressor gene RB1 is a defining feature of SCLC. RB1 is mutated in highly aggressive tumors, including SCLC, where its functional loss, along with that of TP53, is both required and sufficient for tumorigenesis. While it is known that RB1 mutant cells fail to arrest at G1/S in response to checkpoint signals, this information has not led to effective strategies to treat RB1-deficient tumors, and it has been challenging to develop targeted drugs for tumors that are driven by the loss of gene function.
Our group previously identified Skp2, a substrate recruiting subunit of the SCF-Skp2 E3 ubiquitin ligase, as an early repression target of pRb whose knockout blocked tumorigenesis in Rb1-deficient prostate and pituitary tumors. Here we used genetic mouse models to demonstrate that deletion of Skp2 completely blocked the formation of SCLC in Rb1/p53-knockout mice (RP mice). Skp2 KO caused an increased accumulation of the Skp2-degradation target p27, a cyclin-dependent kinase inhibitor, and we confirmed this was the mechanism of protection in the RP-Skp2 KO mice by using the knock-in of a mutant p27 that was unable to bind to Skp2. Building on the observed synthetic lethality between Rb1 and Skp2, we found that small molecules that bind to and/or inhibit Skp2 induced apoptosis and inhibited SCLC cell growth. In a panel of SCLC cell lines, growth inhibition by a Skp2 inhibitor was not correlated with sensitivity/resistance to etoposide. Targeting Skp2 also had in vivo antitumor activity in mouse tumors and human patient-derived xenograft models of SCLC. Using the genetic and pharmacologic approaches, antitumor activity was seen in vivo in established SCLC primary lung tumors, in liver metastases, and in chemotherapy-resistant tumors. The identification and validation of an actionable target downstream of RB1 could have a broad impact on treatment of SCLC and other advanced tumors with mutant RB1, for which there are currently no targeted therapies available.
Core member and chair of the faculty, Broad Institute of MIT and Harvard; director, Klarman Cell Observatory, Broad Institute of MIT and Harvard; professor of biology, MIT; investigator, Howard Hughes Medical Institute; founding co-chair, Human Cell Atlas.
millions of genome variants, tens of thousands of disease-associated genes, thousands of cell types and an almost unimaginable number of ways they can combine, we had to approximate a best starting point—choose one target, guess the cell, simplify the experiment.
In 2020, advances in polygenic risk scores, in understanding the cell and modules of action of genes through genome-wide association studies (GWAS), and in predicting the impact of combinations of interventions.
we need algorithms to make better computational predictions of experiments we have never performed in the lab or in clinical trials.
Human Cell Atlas and the International Common Disease Alliance—and in new experimental platforms: data platforms and algorithms. But we also need a broader ecosystem of partnerships in medicine that engages interaction between clinical experts and mathematicians, computer scientists and engineers
Feng Zhang, PhD
investigator, Howard Hughes Medical Institute; core member, Broad Institute of MIT and Harvard; James and Patricia Poitras Professor of Neuroscience, McGovern Institute for Brain Research, MIT.
fundamental shift in medicine away from treating symptoms of disease and toward treating disease at its genetic roots.
Gene therapy with clinical feasibility, improved delivery methods and the development of robust molecular technologies for gene editing in human cells, affordable genome sequencing has accelerated our ability to identify the genetic causes of disease.
1,000 clinical trials testing gene therapies are ongoing, and the pace of clinical development is likely to accelerate.
refine molecular technologies for gene editing, to push our understanding of gene function in health and disease forward, and to engage with all members of society
Elizabeth Jaffee, PhD
Dana and Albert “Cubby” Broccoli Professor of Oncology, Johns Hopkins School of Medicine; deputy director, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.
a single blood test could inform individuals of the diseases they are at risk of (diabetes, cancer, heart disease, etc.) and that safe interventions will be available.
developing cancer vaccines. Vaccines targeting the causative agents of cervical and hepatocellular cancers have already proven to be effective. With these technologies and the wealth of data that will become available as precision medicine becomes more routine, new discoveries identifying the earliest genetic and inflammatory changes occurring within a cell as it transitions into a pre-cancer can be expected. With these discoveries, the opportunities to develop vaccine approaches preventing cancers development will grow.
shape how the culture of research will develop over the next 25 years, a culture that cares more about what is achieved than how it is achieved.
building a creative, inclusive and open research culture will unleash greater discoveries with greater impact.
John Nkengasong, PhD
Director, Africa Centres for Disease Control and Prevention.
To meet its health challenges by 2050, the continent will have to be innovative in order to leapfrog toward solutions in public health.
Precision medicine will need to take center stage in a new public health order— whereby a more precise and targeted approach to screening, diagnosis, treatment and, potentially, cure is based on each patient’s unique genetic and biologic make-up.
Eric Topol, MD
Executive vice-president, Scripps Research Institute; founder and director, Scripps Research Translational Institute.
In 2045, a planetary health infrastructure based on deep, longitudinal, multimodal human data, ideally collected from and accessible to as many as possible of the 9+ billion people projected to then inhabit the Earth.
enhanced capabilities to perform functions that are not feasible now.
AI machines’ ability to ingest and process biomedical text at scale—such as the corpus of the up-to-date medical literature—will be used routinely by physicians and patients.
the concept of a learning health system will be redefined by AI.
Linda Partridge, PhD
Professor, Max Planck Institute for Biology of Ageing.
Geroprotective drugs, which target the underlying molecular mechanisms of ageing, are coming over the scientific and clinical horizons, and may help to prevent the most intractable age-related disease, dementia.
Trevor Mundel, MD
President of Global Health, Bill & Melinda Gates Foundation.
finding new ways to share clinical data that are as open as possible and as closed as necessary.
moving beyond drug donations toward a new era of corporate social responsibility that encourages biotechnology and pharmaceutical companies to offer their best minds and their most promising platforms.
working with governments and multilateral organizations much earlier in the product life cycle to finance the introduction of new interventions and to ensure the sustainable development of the health systems that will deliver them.
deliver on the promise of global health equity.
Josep Tabernero, MD, PhD
Vall d’Hebron Institute of Oncology (VHIO); president, European Society for Medical Oncology (2018–2019).
genomic-driven analysis will continue to broaden the impact of personalized medicine in healthcare globally.
Precision medicine will continue to deliver its new paradigm in cancer care and reach more patients.
Immunotherapy will deliver on its promise to dismantle cancer’s armory across tumor types.
AI will help guide the development of individually matched
genetic patient screenings
the promise of liquid biopsy policing of disease?
Pardis Sabeti, PhD
Professor, Harvard University & Harvard T.H. Chan School of Public Health and Broad Institute of MIT and Harvard; investigator, Howard Hughes Medical Institute.
the development and integration of tools into an early-warning system embedded into healthcare systems around the world could revolutionize infectious disease detection and response.
But this will only happen with a commitment from the global community.
Els Toreele, PhD
Executive director, Médecins Sans Frontières Access Campaign
we need a paradigm shift such that medicines are no longer lucrative market commodities but are global public health goods—available to all those who need them.
This will require members of the scientific community to go beyond their role as researchers and actively engage in R&D policy reform mandating health research in the public interest and ensuring that the results of their work benefit many more people.
The global research community can lead the way toward public-interest driven health innovation, by undertaking collaborative open science and piloting not-for-profit R&D strategies that positively impact people’s lives globally.
2012pharmaceutical
Amandeep Kaur
Aashir Awan, Phd
Abhisar Anand
Adina Hazan
Alan F. Kaul, PharmD., MS, MBA, FCCP
alexcrystal6
anamikasarkar
apreconasia
aptubman
Arav Gandhi
aviralvatsa
David Orchard-Webb, PhD
danutdaagmailcom
Demet Sag, Ph.D., CRA, GCP
Dror Nir
dsmolyar
Ethan Coomber
evelinacohn
FrasonKalapurackal
Gail S Thornton
Irina Robu
jayzmit48
jdpmd
jshertok
kellyperlman
Ed Kislauskis
larryhbern
Madison Davis
marzankhan
megbaker58
ofermar2020
Dr. Pati
pkandala
ritusaxena
Rick Mandahl
sjwilliamspa
Srinivas Sriram
stuartlpbi
Dr. Sudipta Saha
tildabarliya
zraviv06
zs22