This book discusses the latest developments in Poly (ADP-ribose) polymerase (PARP) inhibitor drug development. It focuses on the translational and clinical development of the latest drugs, as well as the evidence for regulatory approval of PARP inhibitors in multiple different molecular subtypes and tumor indications. The most-up-to-date information on basic scientific research on DNA repair pathways and the DNA Damage Response (DDR) is also covered. Every chapter contains insight into the preclinical, translational along with clinical aspects of a specific DDR inhibitor with key and expert opinion points reinforcing the most important concepts detailed to enable the reader to develop a deep understanding of the topic.
Targeting the DNA Damage Response for Cancer Therapy comprehensively reviews the application of PARP and other DDR inhibitors across oncology disciplines. Therefore, it is a valuable resource for all medical professionals and researchers who use or who are researching the use of these inhibitors on a day-to-day basis.
Evolution of the development of PARP inhibitors.- Exploiting cancer
synthetic lethality in cancer Lessons learnt from PARP inhibitors.-
Mechanisms of PARP inhibitor resistance.- Development of homologous
recombination functional assays for targeting the DDR.- Clinical application
of Poly(ADP Ribose) Polymerase (PARP) inhibitors in ovarian cancer.- Clinical
use of PARP inhibitors in BRCA mutant and non-BRCA mutant breast cancer.-
Development of PARP inhibitors in targeting castration-resistant prostate
cancer.- Strategies for the management of patients with pancreatic cancer
with PARP inhibitors.- Combining poly (ADP-ribose) polymerase (PARP)
inhibitors with chemotherapeutic agents: Promise and challenges.- Rational
combinations of PARP inhibitors with HRD-inducing molecularly targeted
agents.- Combining PARP inhibition and immunotherapy in BRCA-associated
cancers.- Mitotic MTH1 inhibitors in treatment of cancer.- Targeting ATR in
cancer medicine.- Targeting polymerase Theta (POLq) for cancer therapy.-
Targeting DNA-PK.- WRN is a promising synthetic lethal target for cancers
with microsatellite instability (MSI).
Dr. Timothy A. Yap is a Medical Oncology Physician-Scientist and tenured Professor based at the University of Texas MD Anderson Cancer Center. He is a Professor in the Department for Investigational Cancer Therapeutics (Phase I Program), and the Department of Thoracic/Head and Neck Medical Oncology. Dr. Yap is Vice President and Head of Clinical Development in the Therapeutics Discovery Division, a drug discovery biopharmaceutical division where drug discovery and clinical translation are seamlessly integrated. He is also the Associate Director of Translational Research in the Institute for Personalized Cancer Therapy, which is an integrated research and clinical trials program aimed at implementing personalized cancer therapy and improving patient outcomes. Dr. Yaps main research focuses on the first-in-human and combinatorial development of molecularly targeted agents and immunotherapies, and their acceleration through clinical studies using novel predictive and pharmacodynamic biomarkers. His main interests include the targeting of the DNA damage response (DDR) with novel therapeutics through clinical trials and translational studies. These including targets such as ATR, PARP1, WEE1, POLQ, USP1, PARG, CHK1, ATM and DNA-PK inhibitors, next generation CDK4 and CDK2-selective inhibitors, WRN inhibitors, SMARCA2 inhibitors, YAP/TEAD inhibitors, as well as the development of novel immunotherapeutics. Prior to his current position, Dr. Yap was a Consultant Medical Oncologist at The Royal Marsden Hospital in London, UK and National Institute for Health Research BRC Clinician Scientist at The Institute of Cancer Research, London, UK. Dr. Shapiro currently serves as Senior Vice President, Developmental Therapeutics, at the Dana-Farber Cancer Institute (DFCI). In this role, he co-leads the Developmental Therapeutics Program for theDana-Farber/Harvard Cancer Center (DF/HCC) as well as the Cancer Centers activities in the NCI-Cancer Therapy Evaluation Program (NCI-CTEP) Experimental Therapeutics Clinical Trials Network (ETCTN). He additionally serves as the Clinical Director for the DFCI Center for DNA Damage and Repair, where he has developed multiple predictive and pharmacodynamic biomarkers for DNA repair inhibitor agents, including those targeting PARP, the ATR-CHK1-WEE1 axis, and polymerase theta. Dr. Shapiro practices within the DFCI Center for Cancer Therapeutic Innovation, where he develops and leads multiple early phase trials focused primarily on cell cycle and DNA repair inhibitor therapeutics and provides mentorship to early career investigators. He has made proof-of-mechanism studies a mission of his program and has worked closely with basic and translational scientists at his institution and elsewhere to establish robust preclinical rationale for many trials. He also leads a complimentary laboratory effort where he studies resistance to these agents and their interaction with the immune microenvironment to inform the development of rational combinations.
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