Archive for the ‘Uncategorized’ Category


Jason Sheltzer, PhD

Cold Spring Harbor Laboratory, NY

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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James Kirkland, MD, PhD

Noaber Foundation Professor of Aging Research

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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Discovery and Validation of Biomarkers 2017

A workshop on the development and use of biomarkers, regulation, and therapeutic innovation

Hosted by Harvard Medical School, Harvard Business School, and the Kennedy School of Government

April 3, 2017

Batten Hall Room 302, Harvard Business School


08:30-08:35 Introductory Remarks

      Aaron Kesselheim, M.D., J.D., Director of the Program On Regulation, Therapeutics, And Law
      Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School


08:35-09:20 Three Perspectives on Biomarkers’ Use in Approving New Drugs

  • Development
    • Vishal Vaidya, Ph.D., Director, Biomarker Analytics Global Lead at Pfizer
  • Government
    • Christopher Leptak, M.D., Ph.D., Director, Office of New Drug’s Regulatory Science Program, Food and Drug Administration
  • Clinical care
    • Jerry Avorn, M.D., Professor of Medicine, Harvard Medical School

Group Discussion

Coffee Break

10:00-10:45 Biomarker Discovery and Validation in 2017

  • Biomarkers and Discovery in Oncology
    • Bruce Chabner, M.D., former head, National Cancer Institute)
  • Ethical Challenges in Biomarker-driven Research
    • Spencer Hey, Ph.D., Program on Regulation, Therapeutics, And Law and Harvard Medical School Center for Bioethics
  • Discovering Biomarker Diagnostics
    • David Litwack, Ph.D., Policy Advisor of the Office of In Vitro Diagnostics and Radiological Health at the FDA Center for Devices and Radiological Health

10:45-11:45 Group Discussion

Break for Lunch

12:15-12:45 How Can Government/Clinicians/Academia/Industry Work Together to Overcome the Challenges with Biomarker Discovery and Use in Patient Care?

  • Incentives for Biomarker Discovery and Development
    • Ariel Stern, Ph.D., Assistant Professor of Business Administration in the Technology and Operations Management Unit at Harvard Business School
    • Amitabh Chandra, Ph.D., Malcolm Wiener Professor of Public Policy, Director of Health Policy Research at the Harvard Kennedy School of Government
  • Biomarkers and Cardiovascular Disease
    • Elliott Antman, M.D., Professor of Medicine, Harvard Medical School, President, American Heart Association
  • Biomarkers and Infectious Diseases
    • John Powers, M.D., Professor of Clinical Medicine, George Washington University School of Medicine

12:45-2:00 Group Discussion

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Harvard-MIT Regulatory Science Symposium

Harvard-MIT Center for Regulatory Science Annual Symposium

March 7, 2017

American Academy of Arts and Sciences | 136 Irving St. Cambridge MA


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

1:45-2:00 Break


2:00 Session 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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