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

摘要 尽管是一种相对罕见的癌症，但卵巢癌是女性癌症死亡的第五大原因 （ACS）。复杂的遗传学和缺乏靶向改变产生了目前的铂治疗方案 以及紫杉烷类药物与外科减瘤的联合应用。浆液性卵巢癌的靶向治疗没有变化， 发生在过去的40年里，唯一的和最近的例外是PARP抑制剂。的研究范式 在临床试验中，寻找一种有希望的癌基因来靶向单一药物辅助治疗失败了。 这种情况需要改变。我们先前已经确定，5种药物联合治疗与自噬药物是非- 在患者来源的异种移植铂耐药卵巢癌小鼠中毒性并诱导完全缓解 模型然而，一个符合伦理的人体试验需要对这种组合进行改进，以令人信服地表明， 该组合对于完全功效的要求最低，同时保持安全。我们建议研究这种 在OVCAR 3裸鼠模型中进行组合的功效，以及在混合背景B6 D2 F1小鼠模型中进行组合的功效。 为了安全体内荧光将跟踪肿瘤进展。从一个复发性乳腺癌患者身上移植的细胞 将测试PARP抑制后的疾病。安全性标准将包括小鼠体重、食物消耗， 所有器官的H&E病理学、血液生化和血细胞计数。这些将作为最后一只老鼠 在卵巢癌人体试验之前的模型数据。为了进一步确定自噬靶向的益处 药物适用于含有自噬缺陷的其他癌症，如三阴性乳腺癌， p53突变子宫内膜癌，这些实体瘤的皮下异种移植物将另外进行测试。

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.