BRCA1-Associated Protein BRCC36: A Novel Target for Breast Cancer Therapy
Annual rept. 15 Sep 2007-14 Sep 2008
FOX CHASE CANCER CENTER PHILADELPHIA PA
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Since tumor cells in general are genomically unstable and have defects in DNA damage responses, it has been proposed that targeting DNA repair pathways may lead to a therapeutic index in tumor cells over normal cells. Previous studies have demonstrated that BRCC36 is over-expressed in the vast majority of invasive breast cancers and that depletion of BRCC36 sensitizes breast cancer cells to IR via the BRCA1 DNA repair pathway. Therefore, we hypothesize that abrogation of BRCC36 will sensitize breast tumors to the DNA-damage based therapies. To test this hypothesis, we will utilize an antibody anti-HER2-protamine based siRNA delivery system to selectively deplete BRCC36 in breast tumor xenografts. This cancer cell-specific or smart therapeutic approach should improve the targeting of breast tumor cells while reducing non-specific toxicity. The proposed studies will clearly establish BRCC36 as a novel therapeutic target to enhance the efficacy of radiation and chemotherapy which elicit DNA damage. As the antibody is currently being developed for ImmunoPET imaging trials in breast cancer patients, clinical translation of successful preclinical results of our antibody-PsiRNA conjugates could be rapidly achieved.
- Medicine and Medical Research