The Elephant and the Blind Men: Making Sense of PARP Inhibitors in Homologous Recombination Deficient Tumor Cells (technical) Ovarian Cancer and Us OVARIAN CANCER and US Ovarian Cancer and Us

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Wednesday, September 11, 2013

The Elephant and the Blind Men: Making Sense of PARP Inhibitors in Homologous Recombination Deficient Tumor Cells (technical)



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Introduction

Poly(ADP-ribose) polymerase (PARP) inhibitors are currently undergoing extensive testing as potential anticancer agents (113). These drugs were initially developed as modulating agents that could enhance the cytotoxicity of DNA damaging treatments such as ionizing radiation and temozolomide (1, 12, 14). Interest in these agents was heightened by the demonstration that BRCA1- and BRCA2- (BRCA1/2-) mutant cancer cells are selectively killed by single-agent PARP inhibitor treatment (15, 16). Consistent with these preclinical observations, the PARP inhibitor olaparib has exhibited substantial single-agent activity in BRCA1/2-mutant breast and ovarian cancer (1721). Nonetheless, fewer than 50% of patients with BRCA1/2-mutant cancers respond to these drugs, raising important questions about identifying patients most likely to derive benefit from PARP inhibition (22, 23). With this in mind, extensive efforts have been directed at further refining the mechanism of cytotoxicity of PARP inhibitors and elucidating mechanisms of resistance...........

.....In high-grade serous ovarian cancer, for example, BRCA1 and BRCA2 mutations are found in roughly 15% of cases, with mutations in another dozen or more HR genes found in an additional 10–15% of cases (8789). While some of these mutations are familial, as many as half appear to be sporadic (89, 90). These mutations and the resulting genomic instability are a hallmark of high-grade serous ovarian cancer (90). Likewise, mutations in BRCA1, BRCA2, PALB2, and other components with the HR pathway are common in familial and certain subtypes of sporadic breast cancer, particularly triple negative breast cancer (9193). PTEN is deleted or silenced in over 50% of endometrial cancers and a substantial fraction of glioblastomas and prostate cancers (9497).........

The Elephant and the Blind Men

Like the blind men examining the elephant, each of these models emphasizes a different aspect of PARP1 biology. Just as none of the blind men in the parable could provide a complete description of the elephant, we believe that the present models explain certain facets of PARP inhibitor-induced lethality but also leave some questions unanswered.......

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