Genetic approaches to improve the characterization of anti-cancer drugs
97% of drug-indication pairs that are tested in clinical trials in oncology never advance to receive FDA approval. While lack of efficacy and dose-limiting toxicities are the most common causes of trial failure, the reason(s) why so many new drugs encounter these problems is not well understood. Using CRISPR-Cas9 mutagenesis, we are investigating a set of cancer drugs and drug targets in various stages of clinical testing. We show that—contrary to previous reports obtained predominantly with RNA interference and small-molecule inhibitors—the proteins ostensibly targeted by these drugs are nonessential for cancer cell proliferation. Moreover, the efficacy of each drug that we tested was unaffected by the loss of its putative target, indicating that these compounds kill cells via off-target effects. By applying a genetic target-deconvolution strategy, we found that the mischaracterized anticancer agent OTS964 is actually a potent inhibitor of the cyclin-dependent kinase CDK11 and that multiple cancer types are addicted to CDK11 expression. We suggest that stringent genetic validation of the mechanism of action of cancer drugs in the preclinical setting may decrease the number of therapies tested in human patients that fail to provide any clinical benefit. Additionally, we are investigating the role of CDK11 in cancer cell mitosis, in order to uncover whether a therapeutic window exists for inhibiting this kinase as an anti-cancer strategy.
10:00 am – 11:00 am Thursday, January 16, 2020
Harvard Medical School 210 Longwood Avenue Warren Alpert Building 563 Boston, MA 02115
Hosted by Kenichi Shimada, Ph.D.
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Director, Mayo Clinic Kogod Center on Aging, Rochester, MN, USA
Aging, Chronic Disease, and Senolytic Agents
Fundamental aging processes
including cellular senescence appear to make a “root cause” contribution to
multiple chronic diseases, geriatric syndromes, and loss of physiological
resilience. Interventions targeting aging processes such as cellular senescence
hold the potential to enhance healthspan by delaying, preventing, or
alleviating age-related diseases and conditions as a group, instead of
one-at-a-time, the “geroscience hypothesis.” Senescent cells accumulate in many
tissues with aging and at sites of etiology of numerous chronic diseases.
Senescent cells are resistant to apoptosis. They can release a range of factors
that are pro-apoptotic, pro-inflammatory, cause stem cell dysfunction, disrupt
tissues, and spread senescence to normal cells, the senescence-associated
secretory phenotype (SASP). Transplanting small numbers of senescent cells
around the knees of young mice caused osteoarthritis. Transplanting small
numbers of senescent cells into the abdomen of young mice, so that only
1/10,000 cells in the recipients are transplanted senescent cells, is
sufficient to cause frailty, accelerated onset of age-related chronic diseases,
and early mortality.
We developed senolytic agents ‒ drugs that selectively clear senescent cells by
inhibiting the pro-survival Senescent Cell Anti-apoptotic Pathways (SCAPs) that
prevent these cells from being cleared by apoptosis caused by their own SASP.
Intermittent administration of senolytic agents reduced frailty and
neuromuscular dysfunction in progeroid mice, enhanced cardiac function in old
mice, alleviated Alzheimer-like changes in Tau+ mice, alleviated
bleomycin-induced pulmonary fibrosis, reduced age-, high fat diet-, and shear
stress-related vascular dysfunction, restored hepatic function and reduced
liver fat and fibrosis in diet-induced liver steatosis, alleviated dysfunction
caused by radiation in mice, and restored bone mass and strength by reducing
resorption without impeding bone formation in age-induced osteoporosis.
Senolytics prevented the frailty, accelerated chronic disease onset, and early
death caused by transplanting senescent cells into younger mice. In old mice,
senolytics improved physical function, delayed age-related diseases, and
extended remaining lifespan by 36%. Thus, senolytics hold promise for delaying,
preventing, or treating multiple age- and chronic disease-related disorders if
they are safe and effective in humans. Frameworks will be considered for
proof-of-concept and later stage trials of senolytics for targeting age-related
chronic diseases, geriatric syndromes, and resilience to stressors.
10:00 am – 11:00 am Thursday, December 19, 2019
Harvard Medical School 200 Longwood Avenue Warren Alpert Bldg, Room 563 Boston, MA 02115
Hosted by Kenichi Shimada, Ph.D.
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The Harvard-MIT Center for Regulatory Science is hosting industry-academic-FDA meetings in the Spring of 2017 to identify areas of regulatory science where a private-public partnership can make significant progress toward addressing a need in therapeutic development or evaluation.
This all-day day symposium will gather together the Boston-area community in regulatory science. The program will feature faculty speakers from multiple institutions across the full spectrum of regulatory science activities and will include active, moderated discussion to identify where the Center should focus in the coming year.
The FDA defines regulatory science as “the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of all FDA-regulated products.” Within this guidance regulatory science will require many elements of translational medicine including innovation in measurement, trials focused on evidence generation and analysis of policies and their impact. This all-hands meeting will promote dialogue among Center members and build connections to other individuals in the broader research community. A summary paper will capture the major findings of the meeting and our agreed priority areas for 2017.
9:00 Registration and light breakfast
9:15 Welcome and introduction
9:30 Session 1 – The science of evaluation Chair Peter Sorger
Regulatory Incentives for Pharmaceutical Innovation: the FDA’s Breakthrough Therapy Designation
Ariel Stern, HBS
Precision Medicine in the Non-Oncology World
Scott Kennedy, Novartis
How Does the 21st Century Cures Act Change the FDA Drug and Device Approval Paradigm?
Aaron Kesselhiem, BWH
Rationale for and development of disease-specific platform trials
Brian Alexander, DFCI
Pharmacoepidemiology on the Front Line: Addressing Current Issues in Drug Effectiveness, Safety, and Affordability
Jerry Avorn, BWH
12:45 Special Lunch Session: Perspectives on partnering to advance regulatory science Chair Bruce Chabner
12:45-1:15 Break and pick up buffet lunch – Ballroom 2
1:15-1:30 Regulatory Science at FDA
York Tomita, FDA
1:30 -1:45 The role of academic centers in regulatory science
Elazer Edelman, MIT
2:00Session 2 – Applied computation to streamline drug development Chair Aaron Kesselheim
Model Aided Drug Invention: Systems approaches de-risking and accelerating R&D in pharma and biotech
John Burke, Applied BioMath
The impact of patient-to-patient variability on combination cancer therapies
Adam Palmer, HMS
3:25 Session 3 – Measuring safety and mitigating toxicities Chair Brian Alexander
Innovation in Drug Safety through Collaboration: Industry Perspective
Jay Mettetal, AstraZeneca
Micro-Nanofluidic real time quality monitoring for biologics
Jay Han, MIT
Unraveling the efficacy and toxicity of Immune Checkpoint Inhibitors in combination therapy
Gerald Feldman, FDA
Integrating Multi-Omic Techniques to Predict and Classify Toxicity in vitro
Susanne Ramm, HMS, BWH
Identifying and predicting poisons in food products
Tony Sinskey, MIT
6:00 Drinks reception
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