Validation of, and therapeutic evaluation in ovarian cancer GEM models

卵巢癌 GEM 模型的验证和治疗评估

• 批准号: 9344072
• 负责人: SHYAM SHARAN
• 金额: $ 49.52万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9344072
• 关键词: Aftercare; BRCA1 gene; BRCA2 gene; Biological Markers; Cells; Cisplatin; Collaborations; Combined Modality Therapy; Cooperative Research and Development Agreement; Data; Development; Dose; Environment; Epithelium; FDA approved; Genetically Engineered Mouse; Histologic; Human; Immune; Implant; KDR gene; Libraries; Malignant neoplasm of ovary; Modeling; Molecular Profiling; Mus; Patients; Pharmaceutical Preparations; Preventive therapy; Publishing; Pump; Resistance; Route; Sampling; Serous; Serum; System; The Cancer Genome Atlas; Therapeutic Intervention; Treatment Protocols; Validation; clinically relevant; drug efficacy; efficacy testing; genomic aberrations; inhibitor/antagonist; killings; novel therapeutics; protein biomarkers; response; standard of care; therapeutic evaluation; tumor; tumor progression

We verified that the SEOC GDA models respond to cisplatin or olaparib similarly to patients. olaparib is efficacious only for BRCA deficient tumors and cisplatin is optimally effective in these tumors. The combination of these two drugs for BRCA deficient tumors is no more efficacious than cisplatin alone. We have evaluated consolidated therapy for BRCA1-deficient GDA tumors in which mice are treated with cisplatin to de-bulk tumors followed by treatment with an FDA-approved drug shown in drug library screens to be effective at killing both human and mouse SEOC derived cells in 2-D culture. With standard routes of introduction, the compound was not more effective than the vehicle control. We are now evaluating the efficacy of this drug when delivered by implanted continuous dosing pumps. Studies for all other objectives are currently in progress. We have also entered in a CRADA-supported collaboration with a Big Pharma company to assess the biomarker environment and conduct efficacy studies with combined treatment regimen of a PARP inhibitor, a VEGFR inhibitor, and an immune checkpoint inhibitor. These efficacy tests will be performed in both BRCA-proficient and BRCA-deficient models.

我们验证了 SEOC GDA 模型对顺铂或奥拉帕尼的反应与患者相似。奥拉帕尼仅对 BRCA 缺陷肿瘤有效，顺铂对这些肿瘤最有效。这两种药物联合治疗 BRCA 缺陷肿瘤并不比单独使用顺铂更有效。我们评估了针对 BRCA1 缺陷型 GDA 肿瘤的综合疗法，其中使用顺铂治疗小鼠以缩小肿瘤，然后使用 FDA 批准的药物进行治疗，药物库筛选显示该药物可有效杀死人类和小鼠 SEOC 衍生细胞。二维文化。通过标准的引入途径，该化合物并不比载体对照更有效。我们现在正在评估这种药物通过植入式连续剂量泵输送时的功效。所有其他目标的研究目前正在进行中。我们还与一家大型制药公司进行了 CRADA 支持的合作，以评估生物标志物环境，并利用 PARP 抑制剂、VEGFR 抑制剂和免疫检查点抑制剂的联合治疗方案进行疗效研究。这些功效测试将在 BRCA 充足和 BRCA 缺陷模型中进行。