Radioresistance markedly impairs the efficacy of tumor radiotherapy and involves anti-apoptotic signal transduction pathways that prevent radiation-induced cell death. The inhibitors of apoptosis proteins (IAP) are important intrinsic cellular inhibitors of apoptosis, highly expressed in prostate and lung cancer cells, and play an important role in resistance to apoptosis induced by chemo/radiotherapy. Through computational structure-based 3D-database searching and rational design, a series of small molecule inhibitors of IAP have been discovered that showed promising therapeutic activity and specificity to overcome apoptosis-resistance in vitro in cancer cells with high levels of IAP.
The specific aim of this Phase I STTR project is to investigate radiosensitization potential of the small molecule IAP inhibitors in vitro and especially in vivo in nude mouse xenograft models of human cancers of prostate and lung. The proposed studies will test the hypothesis that inhibition of anti-apoptotic activity of IAP by small molecule IAP inhibitors will overcome radioresistance and restore sensitivity of cancer cells to ionizing irradiation. The success of this Phase I STTR project will pave the way to Phase II STTR, aiming to develop the most potent small molecule inhibitor of IAP as a novel, molecular targeted approach for radiosensitizing human cancers with high levels of IAP, and as an entirely new class of anticancer therapy.
