Abstract 4428: Pre-clinical studies of the therpaeutic effect of a PARP inhibitor combined with radiotherapy for breast cancer treatment.

Abstract

Abstract Introduction: Triple negative breast cancer (TNBC) is an aggressive disease associated with a high risk of distant recurrence and poor overall survival and, as for other BC sub-types, loco-regional treatment relies on surgery and radiotherapy (RT). Small molecules inhibitors of poly(ADP-ribose) polymerases (PARP) can potentially be exploited to sensitise breast tumour cells either when used in combination with chemo- and radiotherapy or in certain genetic backgrounds. In order to test this hypothesis, pre-clinical studies of the therapeutic effects of the combination of a PARP inhibitor and RT in human breast cancer xenograft models have been initiated using two TNBC models. Experimental design: Two human TNBC models, HBCx-17 and HBCx-12A xenografts were subcutaneously transplanted into the flanks of nude mice. The PARP inhibitor, 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (PARPi), suspended in 0.5% methylcellulose was administered by tube feeding at 100 mg/kg for 3 or 28 days. After tumors reached a calculated average volume of 125 mm3 (HBCx-12A) or 300 mm3 (HBCx-17), the animals were randomized into 8 treatment groups (10 mice/group): (1, 2) methylcellulose alone for 3 or 28 days, (3,4) methylcellulose for 3 or 28 days with 3 days radiotherapy, (5, 6) PARPi alone for 3 or 28 days, (7) PARPi combined with RT for 3 days and (8) PARPi for 3 days, then PARPi combined with 3 days RT followed by 22 days of PARPi. To mimic the clinical application of RT, the tumors were locally irradiated with X-Rays (200 kV, mean energy 80 keV) with a fractionated (3.25 Gy per fraction) schedule. Preliminary Results: In both TNBC models, individual group comparisons showed that after 28 days of treatment with PARPi alone tumour growth was markedly slowed, an effect that has persisted to day 60. Treatment with RT alone or RT combined with PARPi also resulted in significant growth inhibition over the same period. Animals are being followed to assess tumour regrowth and determine the long-term outcome of these treatment protocols. Conclusion: Our preclinical results show the susceptibility of TNBCs to the PARP inhibitor alone or combined with RT. However whether the response seen when the PARP inhibitor was combined with RT is due exclusively to impaired DNA damage responses or whether tumor re-oxygenation via the vasoactive effects of the PARP inhibitors contributes remains to be fully determined in further preclinical and clinical studies. Acknowledgments: This project is in-part financially supported by Institut Curie's (IC) CEST program. V.P. was supported by an IC translational studentship (MD-Master2 science) and T.Z. by IC's International Postodoctoral fellowship program and the Fondation PGG. Citation Format: Frederic Pouzoulet, Victor Pernin, Christophe Roulin, Hélène Alcade, Franck Assayag, Frédérique Mégnin-Chanet, Laurence Vaslin-Lepetit, Sophie Heinrich, Florence Mahuteau-Betzer, Aurélie Thuleau, Tomasz Zaremba, Vincent Favaudon, Elisabetta Marangoni, Youlia Kirova, Alain Fourquet, Janet Hall, Didier Decaudin. Pre-clinical studies of the therpaeutic effect of a PARP inhibitor combined with radiotherapy for breast cancer treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4428. doi:10.1158/1538-7445.AM2013-4428