Cellular responses to DNA damage: new molecular insights and new opportunities for cancer therapy


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Steve Jackson
University of Cambridge, UK

Abstract

Work in my laboratory aims to decipher the mechanisms by which human cells detect, signal the presence of and repair DNA damage, particularly DNA double-strand breaks. To begin my talk, I will provide a broad overview of the DNA-damage response (DDR). I will then give examples of how our recent work has identified new DDR proteins and determined how these and already known DDR proteins work at the cellular, biochemical and molecular levels. Next, I will explain how KuDOS Pharmaceuticals Ltd, the company I founded in 1997, has developed DDR inhibitors for use as stand-alone agents and to enhance the efficacy of existing DNA-damaging anti-cancer treatments. KuDOS was acquired in 2006 by AstraZeneca and the most advanced of its drugs are now being evaluated in over 20 clinical trials. Currently, the most exciting of these drugs is olaparib, which inhibits the DDR protein PARP. Olaparib is generally well tolerated by patients but displays striking cytotoxic activity – by the mechanism of “synthetic lethality” – towards breast and ovarian cancers caused by BRCA1 or BRCA2 mutations. In addition to discussing the potential for olaparib and other PARP-targeting drugs, I will explain how new, emerging knowledge of DDR processes is providing additional avenues for developing anti-cancer agents that work by synthetic lethality-based mechanisms or enhance the clinical efficacy of radiotherapy and existing chemotherapies.