Combination Of Autophagy Selective Therapeutics (COAST) in Serous Ovarian Cancer

摘要 尽管卵巢癌是一种相对罕见的癌症，但它仍是导致女性癌症死亡的第五大原因 (ACS)。复杂的遗传学和缺乏针对性的改变导致了目前铂类药物的治疗方案。 和紫杉烷类药物进行外科手术清理。浆液性卵巢癌的靶向治疗没有变化 发生在过去的40年里，唯一的和最近的PARP抑制剂例外。的研究范式 寻找一种有希望的癌基因作为单一药物辅助治疗的靶点，在临床试验中未能通过每一项测试。 这种情况需要改变。我们之前已经证实，5种药物与自噬药物联合治疗是非 对患者来源的异种移植铂耐药卵巢癌小鼠的毒性和诱导完全缓解 模特们。然而，一项合乎伦理的人体试验需要对这种组合进行改进，才能令人信服地表明 在保持安全的同时，最低限度地需要哪种组合才能达到完全的疗效。我们建议进行这方面的研究 OVCAR3裸鼠模型和混合背景B6D2F1小鼠模型的联合疗效 为了安全起见。体内荧光将跟踪肿瘤的进展。1例复发患者的异种细胞移植 将测试PARP抑制后的疾病。安全标准将包括老鼠体重、食物消耗量、 所有器官的H&E病理、血液生化和血细胞计数。这些将作为最后的鼠标 卵巢癌人体试验前的模型数据。为了进一步确定自噬靶向的好处 药物适用于其他含有自噬缺陷的癌症，如三阴性乳腺癌和 P53突变的子宫内膜癌，这些实体瘤的皮下异种移植将额外进行测试。

Abstract Despite being a relatively rare form of cancer, ovarian cancer is the 5th leading cause of cancer deaths in women (ACS). The complex genetics and lack of targetable alterations yield a current treatment regimen of platinum and taxane agents with surgical debulking. No changes in targeted therapy for serous ovarian cancer have occurred in the last 40 years, with the lone and recent exception of PARP inhibitors. The research paradigm of finding a promising oncogene to target with single-drug adjuvant therapy has failed every test in clinical trials. This needs to change. We previously established that 5-drug combination therapy with autophagy drugs is non- toxic and induces complete remission in patient-derived-xenograft platinum-resistant ovarian cancer mouse models. However, an ethical human trial would require a refinement of this combination to convincingly show which combination is minimally required for full efficacy while remaining safe. We propose to study such combinations in an OVCAR3 nude mouse model for efficacy, and a mixed-background B6D2F1 mouse model for safety. In vivo fluorescence will track tumor progression. A xenograft of cells from a patient with recurrent disease following PARP inhibition will be tested. Safety criteria will include mouse weight, food consumption, H&E pathology on all organs, blood biochemistry, and blood cell counts. These will serve as the final mouse model data prior to human trials in ovarian cancer. To further ascertain if the benefits of autophagy-targeting drugs are amenable to other cancers containing autophagy deficiency, such as triple negative breast cancer and p53 mutant endometrial cancer, subcutaneous xenografts of these solid tumors will additionally be tested.