C125

Introduction: Poly(ADP-ribose) polymerase (PARP1) is a critical enzyme of cell proliferation and DNA repair. Inhibition of PARP1 leads to apoptosis in BRCA1and BRCA2 deficient tumor cells and can facilitate the response to alkylating agents. Several PARP inhibitors are in clinical trials. We investigated PARP1 gene expression in major human primary cancers and corresponding morphologically normal tissues in order to direct clinical trial efforts toward cancers that over-express the PARP-1 enzyme.
 Experimental design: We used the Gene Logic BioExpress® System database to analyze PARP1 expression in human ovarian, breast, uterine, lung and prostate tumor samples in comparison to normal counterpart tissues. Gene expression was assessed on Affymetrix HU133AB microarrays and over-expression was defined by using a 95% upper confidence limit (UCL) calculated from the normal sample distribution for each tissue type. Samples from cancer subtypes were individually tested relative to the UCL and results tallied. In addition, PARP1 correlation with other genes was investigated across these sample sets.
 Results: The expression of PARP1 was above the 95% UCL of the corresponding normal tissue distribution in 75% of all ovarian cancers (n=64;nl=88), 66% of infiltrating ductal breast cancers (n=169;nl=68), 25% of uterine cancers (n=50;nl=23) and 75% of lung cancers (n=85;nl=122). In contrast prostate cancer (n=57;nl=57) demonstrated minimal PARP1 overexpression. Correlation analysis identified genes that are co-regulated with PARP1 that are involved in DNA repair, cell cycle and cell metabolism pathways.
 Conclusions: If PARP1 gene over-expression defines increased responsiveness to PARP1 inhibition, then these results imply that a substantial fraction of patients with cancer of the breast, ovary, uterus and lung would be rational candidates for therapy with a PARP inhibitor. These observations have been incorporated into the design of the clinical development of BSI-201, a novel PARP inhibitor.

AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics-- Oct 22-26, 2007; San Francisco, CA