Developing novel therapeutic strategies to target DNA damage response

Timothy Yap, MBBS, PhD, MRCP, PgDip, University of Texas MD Anderson Cancer Center, Houston, TX, discusses the development of novel therapeutic strategies to target DNA damage response (DDR). DDR orchestrates a complex network of mechanisms that detect and repair damage to DNA, including DNA double-strand breaks and replication stress. DDR defects can promote uncontrolled cancer growth and enable cancer cells to invade and escape apoptosis. Novel therapies are being developed to target DDR by building on the success of first-generation PARP inhibitors. It is essential to develop new therapeutic strategies because not all patients with BRCA1 or BRCA2 associated cancers respond to current therapies, and drug resistance can occur. Modern cancer genome sequencing and CRISPR technologies have facilitated the development of new treatments, including AZD505, a next-generation PARP1 select inhibitor with greater efficiency than first-generation PARP inhibitors. Going forward, the main priorities for DDR inhibitor development include optimising the pharmacology of new therapies, achieving a greater therapy index for patients and developing multiple rational DDR inhibitor combination strategies. This interview took place at the American Association for Cancer Research Annual Meeting in New Orleans, LA.