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），它可引发包括卵巢癌在内的多种肿瘤细胞系的细胞凋亡和细胞毒性。 TRA-8在小鼠异种移植模型中介导的细胞毒性和体内抗肿瘤功效与化疗药物（阿霉素、紫杉醇、卡铂、Camptostar等）联合显着增强。我们与行业合作伙伴（Sankyo Co., Ltd.）合作，生成了 TRA-8 的人源化构建体 (CS-1008)。该提议的中心假设是来自患者的卵巢癌肿瘤细胞表达升高的 DR5 表达水平并增强抗 DR5 介导的细胞凋亡，从而导致 TRA-8 作为单一药物或与化疗组合介导的抗肿瘤功效。 DR5 死亡结构域周围的关键凋亡调节蛋白决定肿瘤细胞对 TRA-8 介导的细胞凋亡的敏感性，这可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以作为化疗的靶点，进一步增强TRA-8的疗效。有四个具体目标： 目标 1：确定 TRA-8 诱导的细胞毒性及其与原发性卵巢癌组织中凋亡相关蛋白表达的相关性。目标 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的易感性之间的相关性，作为预测肿瘤细胞对 TRA-8 反应的假定生物标志物。目标 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的 DR5/DDX3 蛋白复合物。目标 4：在 IIIc 期和 IV 期卵巢癌患者中实施 huTRA-8 (CS-1008) 联合化疗的 I/II 期方案。该试验将 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相关联，并提供治疗效果的合理估计。

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.