Radiosensitization by modulating inhibitors of apoptosis

描述（由申请方提供）：放射抗性显著损害肿瘤放疗的疗效，并涉及防止辐射诱导的细胞死亡的抗凋亡信号转导途径。 凋亡抑制蛋白（inhibitors of apoptosis proteins，IAP）是细胞内重要的凋亡抑制因子，在前列腺癌和肺癌细胞中高表达，在抗化疗/放疗诱导的细胞凋亡中起重要作用。 通过基于计算结构的3D数据库搜索和合理设计，已经发现了一系列IAP的小分子抑制剂，其在具有高水平IAP的癌细胞中显示出有希望的治疗活性和特异性，以克服体外肿瘤耐药性。 该I期STTR项目的具体目的是研究小分子IAP抑制剂在体外，特别是在人前列腺癌和肺癌的裸鼠异种移植模型中的体内放射增敏潜力。 所提出的研究将检验以下假设：通过小分子IAP抑制剂抑制IAP的抗凋亡活性将克服辐射抗性并恢复癌细胞对电离辐射的敏感性。 该I期STTR项目的成功将为II期STTR铺平道路，旨在开发最有效的IAP小分子抑制剂，作为一种新型的分子靶向方法，用于对具有高水平IAP的人类癌症进行放射增敏，并作为一种全新的抗癌疗法。

DESCRIPTION (provided by applicant): 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.