Death Receptor-mediated Apoptosis and Therapy Strategies in Ovarian Cancer

描述(申请人提供)：我们的研究团队开发了一种新型的抗DR5单抗(TRA-8)，它可以触发包括卵巢癌在内的各种肿瘤细胞的凋亡和细胞毒作用。联合化疗药物(阿霉素、紫杉醇、卡铂、喜树碱等)，TRA-8介导的细胞毒作用和体内抗肿瘤效应显著增强。与我们的行业合作伙伴(三共株式会社)合作，已经生成了TRA-8的人性化构造(CS-1008)。这一建议的中心假设是，患者卵巢癌细胞表达高水平的DR5，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联合应用而发挥抗肿瘤作用。DR5死亡结构域周围的关键凋亡调控蛋白决定了肿瘤细胞对TRA-8介导的细胞凋亡的易感性，可作为选择可能受益于huTRA-8治疗的患者的生物标志物。这些凋亡调节蛋白可能成为进一步增强TRA-8疗效的化疗靶点。目的1：探讨TRA-8对卵巢癌组织的细胞毒作用及其与凋亡相关蛋白表达的关系。目的：探讨卵巢癌细胞株和卵巢癌组织中DR5/DDX3相关clAP1基因与TRA-8诱导的细胞凋亡易感性之间的关系，作为预测肿瘤细胞对TRA-8反应的生物标志物。目的：研究DDX3在体外和体内对人卵巢癌细胞株DR5/DDX3蛋白复合体的影响，以及DDX3对TRA-8介导的卵巢癌细胞凋亡的影响。目的：对卵巢癌患者实施huTRA-8(CS-1008)加联合化疗的I/II期方案。这项试验将TRA-8和药物细胞毒性分析(组织切片技术)、凋亡蛋白图谱和DR5/DDX3复合体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.