Development of next-generation cancer functional diagnostics

描述(申请人提供)：大多数接受分子导向疗法治疗的癌症患者都有短暂或不完全的反应。虽然打破对肿瘤抗原耐受性的新型免疫疗法的反应是有希望的，但只有少数患者对这种疗法有反应。因此，需要在靶向小分子之间以及免疫疗法和小分子抑制剂之间进行联合治疗，但目前尚不清楚如何优先测试这些组合，特别是在一些靶向抑制剂可以拮抗免疫系统效应器功能的情况下。众所周知，已建立的癌细胞株在预测患者反应方面的能力有限，而且不能在自己的模型上与免疫系统进行非自治的相互作用。我们已经验证了一种患者肿瘤的体外培养系统，该系统在活检后的几天内捕捉到与分子分析互补的功能信息。重要的是，该系统评估了肿瘤和间质人群中的非自主效应，包括肿瘤浸润性淋巴细胞(TIL)。在这里，我们建议使用这项技术在患者样本中发现治疗黑色素瘤的靶向药物的新组合，并模拟小分子和免疫治疗之间的相互作用对肿瘤细胞抗原表达和TIL效应功能的影响。最后，我们将探讨该技术作为一种预测BRAF突变黑色素瘤对BRAF抑制剂反应的诊断方法的临床有效性。因此，我们提出以下具体目标：

DESCRIPTION (provided by applicant): Most cancer patients treated with molecular-directed therapies have short-lived or incomplete responses. While responses to novel immunotherapies breaking tolerance to tumor antigens are promising, only a minority of patients respond to this therapies. Therefore, combination therapies will be required, both among targeted small molecules and between immunotherapies and small molecule inhibitors, but it is not clear how to prioritize testing these combinations, particularly as some targeted inhibitors can antagonize immune system effector functions. Established cancer cell lines are known to be limited in their ability to predict patient responses and cannot on their own model non- autonomous interactions with the immune system. We have validated an ex vivo culture system of patient tumors within days from biopsy that captures functional information complimentary to molecular analysis. Importantly, this system evaluates non- autonomous effects in both tumor and stromal populations, including tumor-infiltrating lymphocytes (TILs). Here, we propose use this technology to discover novel combinations of targeted agents for melanoma therapy in patient samples and to model interactions between small molecules and immunotherapy on tumor cell antigen expression and TIL effector functions. Lastly, we will explore the clinical validity of thi technology as a diagnostic assay to predict response of BRAF-mutant melanoma to BRAF inhibitors. Therefore, we propose the following specific aims: