PARP INHIBITORS AS A THERAPY FOR HUMAN CANCER

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                Following the reports demonstrating that BRCA-deficient cells have increased sensitivity to PARP inhibitors, there has been a great deal of interest in testing

PARP inhibitors in patients with known BRCA-deficient cancers.  In this population, PARP inhibitors represent an opportunity to directly target tumor cells with therapy while sparing normal tissues, thus avoiding the systemic toxicities observed with standard chemotherapy and radiation therapy.  Although many efforts have been made to specifically test these agents in this cohort of patients, theoretically, any tumor with HR-deficiency, such as those with defects in RAD51, RAD54, DSS1, RPA1, NBS1, FANCD2, FANCA, or FANCC, should demonstrate increased sensitivity to PARP inhibition (40).  Loss of cell cycle checkpoint control may also be predictive of sensitivity to PARP inhibition.  Experiments in cells with disrupted ATM activity show sensitivity to PARP inhibition (40-43).  In addition, mantle cell lymphoma cell lines deficient in both ATM and p53, which are involved in checkpoint control, showed greater sensitivity to the PARP inhibitor olaparib than cell lines which are deficient in ATM activity alone, highlighting the importance of initiating checkpoint arrest in order to facilitate HR repair (44).   PTEN knockout cells also have increased chromosomal instability due to roles in controlling the expression of RAD51 and as well as cell cycle checkpoint function (45, 46).  In both in vitro and in vivo preclinical models, PTEN-deficient tumors were found be more sensitive to PARP inhibitor exposure compared to PTEN-functional tumors (47).  Given the potential for a number of tumors to be sensitive to PARP inhibitors beyond those with BRCA1/2 germline mutations, identifying sporadic tumors with HR-defects has increased in importance; this phenotype referred to as “BRCAness” in the literature (48).  Konstantinopoulos and colleagues have reported on preliminary efforts to design a gene expression profile to identify HR-deficient tumors (49).  Further efforts like this will be critical for the full clinical potential of PARP inhibitors to be realized.

               Given that PARP-deficient tumors have demonstrated increased sensitivity to chemotherapy agents and radiation, PARP inhibitors are also being evaluated as potential chemotherapy and radiation sensitizers.  Preclinical models have shown that PARP inhibitors increase the cytotoxic effects of alkylating agents, topoisomerase inhibitors, platinum agents and γ-radiation in a number of tumor types (50-53).  Based on these results, a number of clinical trials have been initiated assessing the safety and activity PARP inhibitors in combination with chemotherapy or radiation independent of any “BRCAness” phenotype.