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

自噬选择性治疗 (COAST) 组合治疗浆液性卵巢癌

基本信息

批准号：
10530691
负责人：
Joe R Delaney
金额：
$ 7.55万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10530691
关键词：
Adjuvant Chemotherapy Aneuploidy Antidiabetic Drugs Antineoplastic Agents Apoptotic Autophagocytosis Biochemistry Bioluminescence Blood Blood Cell Count Body Weight decreased Cancer Etiology Cell Death Cell Line Cells Cessation of life Chloroquine Clinical Protocols Clinical Trials Combination Drug Therapy Combined Modality Therapy Complex Costs and Benefits Dasatinib Data Diagnosis Disease Disease remission Dose Doxorubicin Hydrochloride Liposome Drug Combinations Drug Prescriptions Drug Targeting Drug usage Eating Endometrial Carcinoma Ethics Euthanasia FDA approved Frustration Genes Genetic Genetic Predisposition to Disease Genomics Goals HIV Histology Hodgkin Disease Human Hydroxychloroquine In complete remission Individual Label Luciferases Malaria Malignant Neoplasms Malignant neoplasm of ovary Measurement Measures Metformin Molecular Mus Nelfinavir Nude Mice Oncogenes Oncology Operative Surgical Procedures Organ PARP inhibition Pathology Patients Persons Pharmaceutical Preparations Phase I/II Trial Photosensitivity Plasma Platinum Poly(ADP-ribose) Polymerase Inhibitor Pregnancy Progression-Free Survivals Proteins Quality Control Recommendation Recurrence Recurrent disease Recycling Regimen Research Resistance Risk Safety Serous Sirolimus Solid Neoplasm TP53 gene Testing Therapeutic Toxic effect Treatment Protocols Tumor Debulking Weight White Blood Cell Count procedure Woman Work Xenograft procedure base bevacizumab cancer cell cell killing chemotherapy cohort data modeling drug mechanism efficacy evaluation experimental study follow-up food consumption gastrointestinal imager improved in vivo in vivo evaluation in vivo fluorescence individual patient intraperitoneal mouse model mutant novel therapeutics patient derived xenograft model phase III trial pre-clinical pregnant prevent protein aggregation side effect subcutaneous success targeted treatment taxane triple-negative invasive breast carcinoma tumor tumor growth tumor progression

项目摘要

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.

抽象的尽管卵巢癌是一种相对罕见的癌症，但它是女性癌症死亡的第五大原因（美国化学协会）。复杂的遗传学和缺乏针对性的改变产生了目前的铂治疗方案和紫杉烷类药物通过手术减灭。浆液性卵巢癌的靶向治疗没有变化近 40 年来，PARP 抑制剂是唯一的例外。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标，但在临床试验中的每一项测试都失败了。这需要改变。我们之前确定，使用自噬药物的 5 种药物联合疗法是非毒性并诱导患者来源的异种移植铂耐药卵巢癌小鼠完全缓解模型。然而，符合道德的人体试验需要对这种组合进行改进，以令人信服地证明哪种组合是在保持安全的同时充分发挥功效所需的最低限度。我们建议研究这样的在 OVCAR3 裸鼠模型和混合背景 B6D2F1 小鼠模型中进行组合以提高疗效为了安全。体内荧光将追踪肿瘤进展。来自复发性癌症患者的细胞异种移植将测试 PARP 抑制后的疾病。安全标准包括小鼠体重、食物消耗、所有器官、血液生化和血细胞计数的 H&E 病理学。这些将作为最终的鼠标卵巢癌人体试验之前的模型数据。进一步确定自噬靶向是否有好处药物适用于其他含有自噬缺陷的癌症，例如三阴性乳腺癌和 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。