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Emerging Strategies to Overcome Heterogeneous Resistance Mechanisms

October 28–31, 2021

Chaired By

 Joan Brugge, PhD of Harvard Medical School
 Kris C. Wood, PhD of Duke University

Meeting Description

Drug resistance limits the depth and duration of clinical responses to most anticancer therapies, including targeted therapies. This fact has motivated intense efforts in recent years to define the mechanisms of resistance to commonly used anticancer drugs based on the hope that by doing so, it will be possible to design new therapies that block these mechanisms and thereby circumvent resistance. In fact, the 2013 Forbeck Forum on Resistance Mechanisms, led by Joan Brugge, Ph.D. and Jeff Engelman, M.D., Ph.D., explored precisely this topic. Unfortunately, we now know that many diverse resistance mechanisms can exist for each drug, and these mechanisms often co-occur within individual patients. As a result, efforts to improve therapeutic responses by blocking individual resistance mechanisms have largely failed, while efforts to block combinations of resistance mechanisms have been limited by toxicities.

In light of this challenge, emerging studies in the field are seeking to identify creative and fundamentally new strategies to circumvent resistance. These strategies include identifying common downstream signaling nodes shared by many or all major resistance mechanisms; profiling resistant cells to identify “collateral sensitivities” – vulnerabilities caused by evolutionary trade-offs made by cancer cells along the path to resistance; defining drug combinations with non-overlapping resistance landscapes, and exploring the possibility of individually targeting discrete subclones. Already these studies have yielded compelling results. However, they have largely been performed in isolation from one another. Now is, therefore, an opportune time to gather experts in the field working on the problem of heterogeneous resistance to discuss and critically examine these emerging strategies with the goal of identifying key areas for focus and collaboration.

Meeting Summary

Drug resistance limits the depth and duration of clinical responses to most anticancer therapies, including targeted therapies. This fact has motivated intense efforts in recent years to define the mechanisms of resistance to commonly used anticancer drugs based on the hope that by doing so, it will be possible to design new therapies that block these mechanisms and thereby circumvent resistance. In fact, the 2013 Forbeck Forum on Resistance Mechanisms, led by Joan Brugge, Ph.D. and Jeff Engelman, M.D., Ph.D. from Harvard Medical School, explored precisely this topic. Unfortunately, we now know that many diverse resistance mechanisms can exist for each drug, and these mechanisms often co-occur within individual patients. As a result, efforts to improve therapeutic responses by blocking individual resistance mechanisms have largely failed, while efforts to block combinations of resistance mechanisms have been limited by toxicities.

In light of this challenge, emerging studies in the field are seeking to identify creative and fundamentally new strategies to more fully understand, and eventually circumvent, resistance evolution. At this meeting, held October 28-31 in Denver, CO, participants discussed cutting-edge insights and findings central to these areas. For example, in one area, investigators described high resolution studies defining the genetic heterogeneity and clonal evolutionary patterns observed in cancer patients with advanced disease. In another set of presentations, we learned about new tumor models that more accurately reflect the biological states of tumors in vivo, including those progressing on therapy. A third set of talks touched on ways in which principles of anti-tumor immunity can be advanced to make more patients responsive to powerful immunotherapies. In a fourth area, investigators described creative new approaches aimed at delaying, circumventing, or reversing resistance to high priority therapeutics. Finally, the meeting concluded with a series of bedside-to-bench discussions focusing on cutting-edge strategies to understand how tumor cells adapt to therapy, work which is already leading to pioneering new clinical trial approaches.

This Forbeck Forum provided a unique opportunity for investigators from around the world who are working on the above concepts largely in isolation to gather, discuss, and critically examine emerging concepts within the field of resistance evolution. The meeting generated tremendous enthusiasm from its attendees, who concluded the meeting with discussions of new governing concepts in the field, potential collaborative projects, ideas for sharing the concepts described in the meeting with the general scientific community through publications, and aspirations for a relatively near term follow up meeting.

Forum Participants

Saurav Bandyopadhyay, PhD
University of California, San Francisco

Alberto Bardelli, PhD
University of Torino

Trever Bivona, MD, PhD
University of California, San Francisco

Joan Brugge, PhD
Harvard Medical School

Kirsten Bryant, PhD
University of North Carolina, Chapel Hill
 Forbeck Scholar

Christina Curtis, PhD, MSc
Stanford University

Cihangir Duy, PhD
Weill Cornell Medicine
 Forbeck Scholar

Christine Lovly, MD, PhD
Vanderbilt University

Ira Mellman, PhD
Genetech

Gordon Mills, MD, PhD
Oregon Health and Science University

Nick Navin, PhD
MD Anderson

Kornelia Polyak, MD, PhD
Dana Farber Cancer Institute

Sydney Shaffer, MD, PhD
University of Pennsylvania

Charles Swanton, MBPhD, FRCP, FMedSci
The Francis Crick Institute

Peter Winter, PhD
Massachusetts Institute of Technology
 Forbeck Scholar

Kris Cameron Wood, PhD
Duke University