Death Receptor-mediated Apoptosis and Therapy Strategies in Ovarian Cancer

描述（由申请人提供）：我们的研究团队开发了一种新型抗dr5单克隆抗体（TRA-8），可触发多种肿瘤细胞系（包括卵巢癌）的细胞凋亡和细胞毒性。联合化疗药物（阿霉素、紫杉醇、卡铂、喜普达等）可显著增强TRA-8介导的小鼠异种移植模型的细胞毒性和体内抗肿瘤作用。与我们的行业合作伙伴（Sankyo Co., Ltd）合作，已经生成了TRA-8的人性化结构（CS-1008）。该建议的中心假设是，来自患者的卵巢癌肿瘤细胞的DR5表达水平升高，抗DR5介导的细胞凋亡增强，从而导致TRA-8作为单一药物或与化疗联合使用时的抗肿瘤效果。DR5死亡结构域周围的关键凋亡调节蛋白决定了肿瘤细胞对TRA-8介导的凋亡的易感性，这可能被用作选择可能受益于huTRA-8治疗的患者的生物标志物。这些凋亡调节蛋白可能作为化疗的靶点，进一步增强TRA-8的疗效。目的1：研究tra -8在原发性卵巢癌组织中诱导的细胞毒性及其与凋亡相关蛋白表达的关系。目的2：确定DR5/ ddx3相关clAP1与TRA-8介导的卵巢癌细胞系和患者卵巢癌组织凋亡易感性的相关性，作为预测肿瘤细胞对TRA-8反应的推定生物标志物。目的3：确定DDX3的调节如何影响TRA-8介导的细胞凋亡，以及增强TRA-8介导的细胞凋亡的化疗药物如何在体外和体内影响人卵巢癌细胞系中DR5/DDX3蛋白复合物。目的4：开展huTRA-8 （CS-1008）联合化疗治疗II期和IV期卵巢癌患者的I/II期方案。本试验将把TRA-8和药物细胞毒性测定（组织切片技术）、凋亡蛋白谱和DR5/DDX3复合物分析与临床疗效联系起来，并提供合理的治疗疗效估计。

DESCRIPTION (provided by applicant): Our investigative team has developed a novel anti-DR5 monoclonal antibody (TRA-8) which triggers apoptosis and cytotoxicity to a variety of tumor cell lines including ovarian cancer. The TRA-8 mediated cytotoxicity and in vivo anti-tumor efficacy in murine xenograft models is markedly enhanced in combination with chemotherapy drugs (Adriamycin, Taxol, Carboplatin, Camptostar, etc.). In collaboration with our industry partner (Sankyo Co., Ltd.), a humanized construct of TRA-8 has been generated (CS-1008). The central hypothesis of this proposal is that ovarian cancer tumor cells from patients express elevated levels of DR5 expression and enhanced anti-DR5 mediated apoptosis resulting in TRA-8 mediated anti-tumor efficacy as a single agent or in combination with chemotherapy. The key apoptosis regulatory proteins around the death domain of DR5 determine the susceptibility of tumor cells to TRA-8 mediated apoptosis which may be used as a biomarker for selection of patients likely to benefit from huTRA-8 therapy. These apoptosis regulatory proteins may serve as targets of chemotherapy for further enhancement of TRA-8 efficacy. There are four Specific Aims: Aim 1: To determine TRA-8-induced cytotoxicity and its correlation with expression of apoptosis-associated proteins in primary ovarian carcinoma tissues. Aim 2: To determine the correlation of the DR5/DDX3-associated clAP1 with the susceptibility to TRA-8-mediated apoptosis of ovarian cancer cell lines and patient ovarian cancer tissues as a putative biomarker for predicting tumor cell response to TRA-8. Aim 3: To determine how modulation of DDX3 affects TRA-8 mediated apoptosis and how chemotherapeutic agents which enhance TRA-8-mediated apoptosis affect the DR5/DDX3 protein complex in human ovarian cancer cell lines both in vitro and in vivo. Aim 4: To carry out a phase I/II protocol of huTRA-8 (CS-1008) plus combination chemotherapy in Stage Illc and IV ovarian cancer patients. This trial will correlate TRA-8 and drug cytotoxicity assays (tissue slice technique), apoptotic protein profile and DR5/DDX3 complex analysis with clinical efficacy as well as provide a reasonable estimate of therapeutic efficacy.