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：
10357996
负责人：
Joe R Delaney
金额：
$ 7.54万
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/10357996
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 Data 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 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 Pregnancy Progression-Free Survivals Proteins Quality Control 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 experimental study follow-up food consumption gastrointestinal imager in vivo in vivo evaluation in vivo fluorescence individual patient inhibitor 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.

抽象的尽管癌症是一种相对罕见的癌症，但卵巢癌是女性癌症死亡的第五个主要原因（ACS）。复杂的遗传学和缺乏目标改变产生了铂的当前治疗方案和手术延伸的紫杉烷剂。针对性治疗的浆液卵巢癌没有变化发生在过去的40年中，唯一的和最近的PARP抑制剂除外。研究范式在临床试验中，发现有希望的致癌基因可以通过单药辅助治疗靶向。这需要改变。我们以前确定使用自噬药物的5药物联合疗法是非 - 有毒和诱导患者衍生的 - Xenograpt铂抗卵巢癌小鼠完全缓解型号。但是，道德的人类试验将需要对这种组合进行完善，以令人信服地表明在保持安全的同时，最少需要哪种组合。我们建议研究 OVCAR3裸鼠模型的组合，以及混合背景B6D2F1鼠标模型为了安全。体内荧光将跟踪肿瘤进展。来自复发的患者的细胞异种移植将测试PARP抑制后的疾病。安全标准将包括老鼠体重，食物消耗，所有器官，血液生物化学和血细胞计数的H＆E病理学。这些将用作最终鼠标在卵巢癌进行人体试验之前进行模型数据。进一步确定靶向自噬的好处药物适合其他含有自噬缺陷的癌症，例如三重阴性乳腺癌和 p53突变体子宫内膜癌，这些实体瘤的皮下异种移植物将进一步测试。