Patients with BRCA-associated breast cancers may respond differently to monotherapy with platinum drugs versus poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Importantly, side effects with platinum drugs are often severe. Carboplatin and cisplatin, both platinum drugs, have different toxicity profiles and efficiencies. Combination treatments with a PARPi and a platinum drug may be able to achieve greater efficiency while limiting toxicity, increasing the therapeutic index. To date there is limited cytoxicity data on PARPi/cisplatin versus PARPi/carboplatin combination therapy, the mechanism of action of PARPi/platinum combination and the role of BRCA1 or BRCA2 in chemosensitivity. I compared the efficacy of ABT-888 (PARPi), cisplatin, or carboplatin single agent treatments to those in combinations using Brca/BRCA isogenic models and evaluated the mechanism of the combination treatments.
In vitro, each single or combination treatment killed or inhibited proliferation of Brca/BRCA-deficient cells more efficiently than the Brca/BRCA-proficient cells. An enhanced effect was observed principally for ABT-888/carboplatin rather than for ABT-888/cisplatin. In vivo, after ABT-888/carboplatin treatment, Brca2-deficient xenografts have a lower tumor volume and mitotic count than prior to treatment. In vitro, ABT-888/carboplatin enhanced apoptosis in the Brca1/BRCA1-deficient models compared to the proficient counterparts. For the isogenic Brca2/BRCA2 pairs, no enhanced apoptosis was observed. Moreover, greater PARP activity in Brca/BRCA-deficient cells versus Brca/BRCA-proficient cells correlated with increased chemosensitivity.
Our data suggest that ABT-888 and carboplatin combination treatment will be more successful than monotherapy in addressing many BRCA-associated cancers. Despite this initial work, more study on personalized medicine is required to improve therapeutic outcomes. Along those lines, a phase II clinical trial (NCI #8264) comparing ABT-888 (a PARPi)/carboplatin versus ABT-888 alone is currently ongoing to test those principles.
|Commitee:||Ann, David K., Negritto, Maria C., Stark, Jeremy M., Weitzel, Jeffrey N.|
|School:||City of Hope's Irell & Manella Graduate School of Biomedical Sciences|
|Department:||Graduate School of Biological Sciences|
|School Location:||United States -- California|
|Source:||DAI-B 74/04(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Pharmacy sciences, Oncology|
|Keywords:||BRCA1 and BRCA2, Cancer biology, Dna repair, PARP inhibitors, Personalized medicine, Platinum drugs, Poly(adp-ribose)polymerase (parp), Targeted therapy, Translational research|
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