Molecular Mechanisms in Gastrointestinal Stromal Tumor

胃肠道间质瘤的分子机制

• 批准号: 9753726
• 负责人: Ronald P Dematteo
• 金额: $ 39.04万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/9753726
• 关键词: Aftercare; Binding; Biology; Biopsy Specimen; CTLA4 gene; Cell Line; Cell Survival; Clinical Trials; 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; 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; SLEB2 gene; 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; alpha catenin; anti-PD-1; 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

 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（由申请人提供）：靶向分子治疗是实体癌治疗的一个里程碑式的进展。胃肠道间质瘤（GIST）是最常见的人类肉瘤，已成为分子治疗的模型，因为它主要由Kit或Pdgfrα突变驱动，并且小分子抑制剂甲磺酸伊马替尼对两种相关癌蛋白都有效。以前，我们已经证明伊马替尼的部分抗肿瘤疗效取决于改变肿瘤内免疫应答以促进T细胞免疫。我们的目标是优化免疫治疗与分子治疗的使用，以实现更好的肿瘤学结果。目前晚期GIST的治疗完全依赖于酪氨酸激酶抑制剂，因为常规化疗无效。虽然伊马替尼是有效的，但其效果通常是短暂的，因为获得性耐药性的发展，通常是由于Kit中的额外突变。此外，一些GIST患者对伊马替尼有原发性耐药，因为他们的肿瘤从未对治疗有反应。因此，需要新的治疗方法。我们发现转录因子雌激素受体α和β-连环蛋白对小鼠和人GIST中的肿瘤细胞存活至关重要。在这个提议中，我们将研究伊马替尼敏感和伊马替尼耐药GIST中的雌激素受体α和β-连环蛋白抑制，并将其与免疫治疗结合联合收割机以增加抗肿瘤疗效。我们将利用三种GIST的基因工程小鼠模型，其中两种含有伊马替尼耐药Kit突变。我们将对新鲜获得的人GIST手术标本进行相关的免疫学研究。我们希望这些结果将促进我们对GIST生物学的理解，并导致结合免疫和分子治疗的新型临床试验。虽然我们专注于GIST，但我们的发现将与靶向治疗的其他癌症相关。