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Abstract
Metastasis to distant organs is the major cause of mortality in breast cancer patients. Median overall survival remains poor (5 year survival 26.1%) despite recent advances in new targeted biological therapy. Radiolabeled antibody offers an effective approach to deliver cytotoxic radiation doses to eliminate micrometastatic tumors. Alpha particle emitters are promising against small micrometastases because of their high potency and specificity (high linear energy transfer, LET>80 keV/µm, particle range ∼ 80 μm). Alpha particles typically cause DNA double strand breaks (DSBs) when they traverse the cell nucleus. Our experience with alpha particle emitter labeled antibody showed that it significantly prolonged survival in a mouse model of metastatic breast cancer with eventual recurrence at estimated micromet dose of 4.4 Gy. Understanding cellular repair of alpha radiation induced DNA DSBs could help us rationally design more effective strategy by inhibiting components of the DNA DSB repair pathways to sensitize cancer cells to alpha radiation. Under this hypothesis, we evaluated the role of DNA dependent protein kinase catalytic subunit (DNA-PKcs) inhibition on targeted alpha-emitter therapy. Inhibition, with small molecule inhibitor NU7441, of this key enzyme in the non-homologous end joining (NHEJ) pathway sensitizes triple negative breast cancer cells to alpha particle emitter 213Bi labeled anti-EGFR antibody. Immuno-fluorescent staining of γH2AX foci confirms a reduction in the DNA DSB repair rate in these cells. Using a cell-line deficient in the homologous recombination (HR) pathway (BRCA-1 deficient), we also have preliminary evidence suggesting that HR deficiency reduces the incremental effect of NHEJ inhibition but the combination increases overall cell kill. This data suggest inhibiting components of DNA double strand repair pathways is an effective approach to enhance the efficacy of alpha particle emitter labeled monoclonal antibody.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5081. doi:10.1158/1538-7445.AM2011-5081