PARP inhibitors have been used in the clinical treatment for tumors with BRCA1 or BRCA2 mutations. The major function of PARP inhibitors is to suppress PARP1 and PARP2 mediated poly(ADP-ribosyl)ation, a unique posttranslational modification, mainly induced in DNA damage. Suppression of PARylation by PARP inhibitors abolishes early recruitment of DNA damage response factors and impairs DNA damage repair. Because PARylation is a very transient posttranslational modification, normal cells have other repair mechanism to compensate for the loss of PARylation-dependent DNA damage response. However, a set of tumor cells harbor genetic mutations, such as BRCA1/2 mutations, which have already led to impaired DSB repair. With additional PARP inhibitor treatment to abolish PARylation-dependent DNA damage response, these tumor cells will undergo apoptosis. Thus, PARP inhibitor treatment selectively kills tumor cells with DNA damage repair defects, such as BRCA tumors. However, recent clinical trials suggest that only a set of BRCA tumors respond effectively to the PARP inhibitor treatment. Moreover, accumulated evidence indicates that PARP inhibitor treatment is able to suppress the growth of other types of tumor besides BRCA tumors. Thus, to extend the therapeutic potential of PARP inhibitors in cancer treatment, we explored biomarkers for the PARP inhibitor treatment. Interestingly, we found that NADP+, an NAD+ derivative, can suppress the activity of PARPs both in vitro and in vivo. Thus, we hypothesize that NADP+ is an endogenous PARP inhibitor, and the high level of NADP+ in tumor cells is able to sensitize tumor cells for DNA damaging related cancer therapy, including chemotherapy and radiation therapy. In this application, we plan to examine 1) the role of NADP+ in poly(ADP-ribosyl)ation-dependent DNA damage repair; 2) the molecular mechanism that regulates the cellular level of NADP+; 3) the role of NADP+ in sensitizing tumor cells to DNA damaging-associated cancer therapy. Taken together, the proposed study will not only reveal novel molecular mechanism in DNA damage repair, but also identify novel therapeutic approach for cancer treatment.
Although PARP inhibitors have been approved by FDA for the treatment of BRCA tumors, recent clinical studies suggest that not all the BRCA tumors respond well to PARP inhibitors, and other regulators may mediate cellular sensitivity to PARP inhibitors. In our preliminary studies, we found that NADP+ is a novel endogenous PARP inhibitor. In this proposal, we plan to examine the mechanism by which NADP+ participates in DNA damage repair, and if NADP+ can serve as a biomarker and a sensitizer for cancer therapy including chemotherapy and radiation therapy.
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