TARGETING DNA DAMAGE RESPONSE: At the Forefront of Emerging Concepts and Strategies

Activity Details
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  • Cost: Free
  • Release: Jul 6, 2017
  • Expires: Jul 6, 2018
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Needs Statement

DNA damage response (DDR) plays a key role in maintaining genomic integrity of the cell, and is involved in a host of other important physiologic processes.1 Its disruption, with consequent genomic instability, is one of the hallmarks of cancer. Targeting the aberrant DDR in cancer cells further limits their already compromised capacity for DNA repair and causes even greater genomic instability, stress, and, ultimately, cell death. Recently, this concept of “synthetic lethality” has been clinically validated with the approval of the poly ADP-ribose polymerase (PARP) inhibitors for the treatment of patients with BRCA mutation-positive ovarian cancer.2-4

With numerous DDR inhibitors currently in pre-clinical and clinical development, careful consideration of their mechanisms of action is necessary to maximize their therapeutic potential. For example, DDR-targeting drug combinations have the potential to provide broader and more effective response than DDR-targeting monotherapy. Moreover, combinations of DDR inhibitors and immunotherapy have the potential to broaden and deepen patient responses, and the clinical trials investigating the combination of a PARP inhibitor with immunotherapy are now in progress. Ultimately, in order to maximize the rational clinical development and clinical utility of DDR inhibitors, incorporation of translational studies and a closer collaboration between scientists and clinicians will be paramount.2,4

1Matt S, Hofmann TG. Cell Mol Life Sci. 2016;73:2829-2850. 2O’Connor MJ. Mol Cell. 2015;60:547-560. 3Pearl LH, et al. Nat Rev Cancer. 2015;15:166-180. 4Brown JS, et al. Cancer Discov. 2017;7:20-37.

Target Audience

This activity is designed to meet the educational needs of medical and research oncologists.

Objectives

At the conclusion of this activity, participants will be able to:

1. Describe the main signaling pathways, molecular players, and mechanisms guiding the DNA damage response (DDR) and its role in tumor suppression and tumorigenesis.

2. Appraise the rationale for combining DDR-targeting therapies and cancer immunotherapy, including immune checkpoint blockade.

3. Compare the current and emerging data on safety and efficacy of PARP inhibitors in patients with ovarian, breast, prostate, or pancreatic cancer.

4. Assess the current and emerging data on safety and efficacy of agents targeting ATR-, WEE1-, or ATM-mediated DDR in various types of solid tumors.

Faculty Disclosure

In accordance with the Food and Drug Administration, the speakers have disclosed that there is the potential for discussions concerning off-label uses of a commercial product/device during this educational activity.

Any person who may contribute to the content of this continuing education activity must disclose relevant relationships (and any known relationships of their spouse/partner) with commercial interests whose products or services are discussed in educational presentations. A commercial interest is defined as any entity producing, marketing, re-selling, or distributing healthcare goods or services consumed by, or used on, patients. Relevant relationships include receiving from a commercial interest research grants, consultant fees, travel, other benefits, or having a self-managed equity interest in a company.

Disclosure of a relationship is not intended to suggest or condone any bias in any presentation but is made to provide participants with information that might be of potential importance to their evaluation of a presentation.

Planners:

Joan B. Fowler, PharmD, BCPP has no relevant financial relationships to disclose in relation to the content of this activity.

Vanessa Carranza, PharmD has no relevant financial relationships to disclose in relation to the content of this activity.

Authors/Presenters:

Johann S. de Bono, MB ChB, FRCP, MSc, PhD, FMedSci: Dr. de Bono has disclosed that he is a consultant for AstraZeneca, Bayer, Genmab, GlaxoSmithKline, Genentech, Merck, and Sanofi; he receives grant/research support from Astex, AstraZeneca, GlaxoSmithKline, Genentech, Merck, and Sanofi.

James M. Ford, MD: Dr. Ford has no relevant financial relationships to disclose in relation to the content of this activity.

Christopher Lord, DPhil: Dr. Lord has disclosed that he is a consultant for Pango Therapeutics, Sun Pharma, and Vertex; he is also a member of the speakers’ bureau for AstraZeneca.

Ursula Matulonis, MD: Dr. Matulonis has disclosed that she is a consultant for AstraZeneca, Cerulean, Clovis, Genentech, and Immunogen.

Peer Reviewer:

Susan M. Domchek, MD, has disclosed that her institution (University of Pennsylvania) receives grant/research support from Abbvie, AstraZeneca, Clovis, and Pharmamar.