Developing rational drug combination strategies for PARP inhibitors (ASCO 2012) - May 16, 2012 - Presentation time: Monday June 4, 8:00 AM to 12:00 PM; Promising combinations of PARP inhibitors with temozolomide, CHK1 inhibitors, ATM inhibitors and other agents found
Preclinical-other • Oncology
|
|
2012 American Society of Clinical Oncology Annual Meeting, Jun 1-5, 2012, Chicago, IL
|
|
Abstract No: 3050
Background: The recent clinical development of Poly (ADP-ribose) polymerase (PARP) inhibitors has provided formal proof-of-concept that synthetic lethal approaches can be used to treat cancer. The promise of PARP inhibitors in BRCA mutant tumours is apparent but questions regarding their wider clinical use remain. To date, a number of clinical trials have been designed using PARP inhibitors as single agents as well as in combination with current standards of care. However, there is a paucity of pre-clinical information about PARP inhibitor/drug combinations and empirical clinical trials of standard of care plus PARP inhibitors may not represent the most effective approach to dissect this. We aim to identify effective drug combination strategies that could be used clinically in selected patient groups. Methods: Using a combination of high and medium throughput techniques and established methodologies for determining synergy, additivity and antagonism, we have characterised the effects of combining PARP inhibitors with a diverse panel of over 3,000 compounds in a range of tumour cell models including isogenic matched cell line pairs to determine the impact of genetic background on drug combination efficacy. We have integrated this data with functional profiling data to identify genetic backgrounds where these combinations may be most effective. Results: Results to date suggest promising combinations of PARP inhibitors with temozolomide, CHK1 inhibitors, ATM inhibitors and other agents. Some of these combinations show specificity for genetic backgrounds such as PTEN mutations. Conclusions: Screening of drug libraries has identified promising PARP inhibitor drug combinations and demonstrates how some drug combinations show specificity in particular genetic backgrounds. This raises the possibility of widening the therapeutic index in patients with these genetic backgrounds and treating a wider group of patients with PARP inhibitors.
|