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Can the PARP Inhibitors be tested with the Functional Profiling Platform?
Poly ADP ribose polymerase (PARP) is a nuclear enzyme associated with response to DNA damage. Following single strand DNA breaks, the enzyme attaches a backbone of ADP and ribose that serves to initiate DNA repair. Certain classes of chemotherapeutics, specifically alkylating agents, can induce injury that results in extensive poly ADP ribosylation resulting in the exhaustion of intercellular pools of NAD and ATP ultimately leading to cell death.
Although PARP inhibitors have recently entered the clinical cancer literature mostly relating to the treatment of BRCA+ and triple negative patients, neither PARP nor PARP inhibitors are new to the cancer researcher community, according to Dr. Robert Nagourney, medical director at Rational Therapeutics, one of the pioneers of the functional profiling technique.
His group first became interested following a 1988 study by Distelhorst from Case Western Reserve (Distelhorst CW, Blood 1988 Oct;72(4):1305-09) that described a mechanism of cell death that correlated with their work in childhood leukemia. Previously, investigators at Scripps Clinic had described PARP’s role in response to 2CDA (Seto, S., et al. J Clin. Invest. 1985 Feb;75(2):377-83). His group has studied small molecule inhibitors of PARP for many years, and more recently, they have expanded these investigations to include BSI201 (iniparib) and AZD2281 (olaparib). Both of which are undergoing clinical investigations. Nagourney will be reporting their findings with these PARP inhibitors at the 2011 ASCO meeting (Nagourney, R., et al Proceedings Amer Soc Clin Oncol. 2011).
PARP inhibitors are easily studied and provide interesting signals in the tissue studied. They have seen activity in BRCA+ patients and some triple negative breast cancers. They have also identified synergy with other classes of drugs. The compounds are a welcome addition to the cancer therapy armamentarium and continue to be actively studied in the cell-based functional profiling platform.
Of interest is the recent failure of the iniparib plus Carboplatin & gemcitabine Phase III trial to meet progression-free and overall survival goals in triple negative breast cancer patients (Zacks Investment Research on January 31, 2011). This failure may reflect the need to apply predictive methodologies to select candidates for these drugs, similar to Nagourney's successful work with other classes of compounds.
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