Development of next-generation cancer functional diagnostics

下一代癌症功能诊断的开发

基本信息

批准号：
8492572
负责人：
DAVID E FISHER
金额：
$ 22.71万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-27 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8492572
关键词：
Alleles Antibodies Antigens Apoptosis Asses BRAF gene Biological Assay Biological Markers Biopsy Biopsy Specimen Cancer Patient Cancer cell line Cell Culture Techniques Cell Death Cells Clinical Collection Combined Modality Therapy Data Development Diagnostic Drug Combinations Enhancers Evaluation Gene Frequency General Hospitals Genomics Heterogeneity Image Analysis Immune Immune system Immunologics Immunotherapy Individual Institutional Review Boards Interferons Interleukin-2 Lead Libraries Life Lymphocyte Function MEKs Malignant Neoplasms Massachusetts Measures Methods Microscopy Minority Modality Modeling Molecular Molecular Analysis Molecular Profiling Mus Nuclear Oncogenes Patients Pharmaceutical Preparations Population Population Heterogeneity Protocols documentation Sampling Signal Pathway Somatic Mutation Stromal Cells Stromal Neoplasm System Technology Testing Therapeutic Tumor Antigens Tumor-Infiltrating Lymphocytes anticancer research base cancer cell cytokine deep sequencing drug discovery experience improved in vivo inhibitor/antagonist killings kinase inhibitor melanocyte melanoma molecular marker mutant neoplastic cell next generation novel public health relevance response screening small molecule therapeutic target tool treatment center tumor

项目摘要

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:

描述（由申请人提供）：大多数接受分子定向疗法治疗的癌症患者的反应短暂或不完全。虽然打破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，无论是靶向小分子之间还是免疫疗法与小分子抑制剂之间都需要联合治疗，但尚不清楚如何优先测试这些组合，特别是因为一些靶向抑制剂可以拮抗免疫系统效应器功能。众所周知，已建立的癌细胞系预测患者反应的能力有限，并且不能建立与免疫系统非自主相互作用的模型。我们在活检后几天内验证了患者肿瘤的离体培养系统，该系统捕获了与分子分析互补的功能信息。重要的是，该系统评估肿瘤和基质群体的非自主效应，包括肿瘤浸润淋巴细胞（TIL）。在这里，我们建议使用这项技术来发现用于患者样本中黑色素瘤治疗的新型靶向药物组合，并模拟小分子和免疫疗法之间对肿瘤细胞抗原表达和 TIL 效应器功能的相互作用。最后，我们将探讨该技术作为预测 BRAF 突变黑色素瘤对 BRAF 抑制剂反应的诊断测定的临床有效性。因此，我们提出以下具体目标：