Molecular Mechanisms in Gastrointestinal Stromal Tumor

胃肠道间质瘤的分子机制

基本信息

批准号：
9547053
负责人：
Ronald P Dematteo
金额：
$ 40.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9547053
关键词：
Aftercare Binding Biology Biopsy Specimen Cell Line Cell Survival Clinical Trials Cytotoxic T-Lymphocyte-Associated Protein 4 Data Dependence Effectiveness Environment Estrogen Receptor alpha Gastrointestinal Stromal Tumors Genetic Transcription Genetically Engineered Mouse Gleevec Goals Human Imatinib Imatinib mesylate Immune Immune response Immune system Immunity Immunologics Immunotherapy Interferon Type II Knock-in Mouse Lead Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Messenger RNA Molecular Molecular Models Mus Mutation Oncoproteins Operative Surgical Procedures Outcome Patient-Focused Outcomes Patients Phase I Clinical Trials Platelet-Derived Growth Factor alpha Receptor Protein Tyrosine Kinase Proteins Residual Tumors Resistance Resistance development Signal Pathway Signal Transduction Solid Specimen Stable Disease T-Lymphocyte Tamoxifen Testing Tryptophan 2,3 Dioxygenase Tumor Cell Line Tumor Immunity Tumor Weights Tyrosine Kinase Inhibitor antitumor effect base beta catenin chemotherapy improved molecular modeling molecular targeted therapies mouse model neoplastic cell novel novel strategies partial response pre-clinical promoter public health relevance sarcoma small molecule inhibitor targeted treatment therapeutic target transcription factor transcriptome treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Targeted molecular therapy is a landmark advance in the treatment of solid cancers. Gastrointestinal stromal tumor (GIST), the most common human sarcoma, has been a model for molecular therapy because it is driven primarily by either a Kit or Pdgfrα mutation, and the small molecule inhibitor imatinib mesylate is effective against both associated oncoproteins. Previously, we have shown that part of the anti-tumor efficacy of imatinib depends on altering the intratumoral immune response to promote T cell immunity. Our goal is to optimize the use of immune therapy with molecular therapy to achieve better oncologic outcomes. Current therapy of advanced GIST relies entirely on tyrosine kinase inhibitors, since conventional chemotherapy is ineffective. While imatinib is efficacious, its effects are usually short-lived as acquired resistance develops, usually due to an additional mutation in Kit. Furthermore, some patients with GIST have primary resistance to imatinib, as their tumor never responds to treatment. Therefore, novel treatments are needed. We have discovered that the transcription factors estrogen receptor alpha and beta-catenin are critical to tumor cell survival in mouse and human GIST. In this proposal, we will investigate estrogen receptor alpha and beta-catenin inhibition in imatinib-sensitive and imatinib-resistant GIST and combine it with immunotherapy to increase anti-tumor efficacy. We will utilize three genetically engineered mouse models of GIST, two of which contain imatinib-resistant Kit mutations. We will perform correlative immunologic studies on freshly procured human GIST surgical specimens. We expect that the results will advance our understanding of the biology of GIST and lead to novel clinical trials combining immune and molecular therapy. While we are focused on GIST, our findings will have relevance to other cancers treated with targeted therapy.

描述（由适用提供）：靶向分子疗法是治疗固体癌症的里程碑式增长。胃肠道肿瘤（GIST）是最常见的人类肉瘤，它一直是分子疗法的模型，因为它是由试剂盒或PDGFRα突变驱动的，并且小分子抑制剂伊替尼甲酯有效抗两种相关的癌蛋白。以前，我们已经表明，伊马替尼的抗肿瘤有效性的一部分取决于改变肿瘤内免疫响应以促进T细胞免疫异化。我们的目标是优化伊马替尼与分子疗法的使用，以获得更好的肿瘤结局。由于常规化学疗法无效，因此晚期GAIS的当前治疗完全依赖于酪氨酸激酶抑制剂。尽管伊马替尼是有效的，但其效果通常是由于试剂盒中的额外突变而成为获得的耐药性发展。此外，某些GIST患者对伊马替尼具有主要抵抗力，因为他们的肿瘤从未对治疗做出反应。因此，需要新颖的治疗方法。我们已经发现，雌激素受体α和β-catenin的转录因子对于小鼠和人类观点中的肿瘤细胞存活至关重要。在此提案中，我们将研究伊马替尼敏感和抗伊马替尼的抗雌激素受体α和β-catenin抑制作用，并将其与免疫疗法相结合以提高抗肿瘤效率。我们将利用三种一般设计的要点的鼠标模型，其中两个包含抗伊马替尼的套件突变。我们将对新鲜购买的人类GIST手术标本进行相关免疫学研究。我们预计结果将提高我们对要点生物学的理解，并导致新的临床试验结合了免疫和分子疗法。尽管我们专注于要点，但我们的发现将与其他接受有针对性疗法治疗的癌症有关。