Exploiting vulnerabilities in GIST using novel combination therapies

使用新型联合疗法利用 GIST 的弱点

• 批准号: 10165655
• 负责人: Lori Rink
• 金额: $ 42.78万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165655
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Animals; Apoptosis; Apoptotic; BAX gene; BCL1 Oncogene; BCL2 gene; Bad protein; Bax protein; Binding; Biological Assay; Brain; Cell Death; Cell Line; Cells; Clinical; Combined Modality Therapy; Critical Pathways; Data; Disease; Drug Combinations; Drug resistance; Equilibrium; Evaluation; Family; Gastrointestinal Stromal Tumors; Gene Expression; Genes; Goals; Imatinib mesylate; Lead; Link; MCL1 gene; Malignant Neoplasms; Measures; Mitochondria; Modality; Molecular; Molecular Target; Oncogenic; Outcome; PDGFRA gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases; Recurrence; Refractory; Resistance; Role; Route; Sampling; Testing; Time; Translations; Tumor Cell Line; Tumor Suppressor Genes; Tyrosine Kinase Inhibitor; Up-Regulation; Validation; Xenograft Model; Xenograft procedure; cell type; cohort; cytotoxicity; deep sequencing; design; disorder control; efficacy evaluation; experience; experimental study; improved; in vivo; inhibitor/antagonist; insight; knock-down; member; neoplastic cell; neuron loss; neuronal pentraxin; novel; novel therapeutics; overexpression; patient derived xenograft model; pre-clinical; preclinical study; prevent; receptor; response; standard of care; synergism; targeted agent; targeted treatment; therapeutic target; transcriptome sequencing; tumor; tumor xenograft

Gastrointestinal stromal tumor (GIST) treated with targeted therapies such as imatinib mesylate (IM), sunitinib, and regorafenib, generally escape disease control and progress over time. The current standard of care for advanced inoperable GIST involves the sequential application of these inhibitors that target the activated forms of the KIT or PDGFRA receptors found in GIST. We hypothesized that inhibiting additional molecular targets in combination with IM may provide more substantial disease control. Recent studies have implicated the PI3- kinase/AKT pathway in survival of IM-resistant GIST cell lines and tumors. We therefore challenged IM- sensitive GIST xenografts with a novel combination of IM and an AKT inhibitor to test if the combination enhanced disease stabilization afforded by front-line IM therapy. In these preliminary studies, the combination therapy provided significantly improved efficacy as compared to treatment with monotherapy alone, as measured by tumor response and animal survival. These results provide justification for additional pre-clinical studies challenging various GIST xenografts modeling both intrinsic and acquired IM resistance, as described in this proposal. To explore the molecular aspects of tumor response to this novel combination, we carried out RNAseq studies on these xenografts, in the hope of identifying additional therapeutic targets for GIST. This analysis was fruitful, identifying two genes, brain expressed, X-linked 1 (BEX1) and neuronal pentraxin I (NPTX1), whose expression was significantly up-regulated only in combination-treated tumors. BEX1 and NPTX1 have been implicated as tumor-suppressor genes in various cancers, and with the induction of apoptotic pathways in diverse cell types. Specifically, BEX1 acts as a BCL-2 antagonist, inducing apoptosis by binding BCL-2 and suppressing the formation of anti-apoptotic BCL-2/BAX heterodimers, while NPTX1 expression has been linked to enhanced mitochondrial translocation of pro-apoptotic BAD and BAX proteins and enhanced neuronal cell death. We hypothesize that this combination results in induction of these two genes that influence tumor cell fate by shifting the pro/anti-apoptotic balance towards cell death via the BCL-2, BAD/BAX pathways, and may provide additional avenues to approach GIST treatment. This proposal seeks to functionally test this central hypothesis, as well as to evaluate targeting members of these pathways in both IM- sensitive and –resistant GIST xenograft models. The proposed studies are designed to provide support for potential application of these novel therapeutic modalities in the clinical setting.

胃肠道间质瘤（GIST）采用靶向疗法治疗，例如甲磺酸伊马替尼（IM）、舒尼替尼、 和瑞戈非尼，通常会逃脱疾病控制并随着时间的推移而进展。目前的护理标准 晚期无法手术的胃肠道间质瘤涉及连续应用这些针对激活形式的抑制剂 GIST 中发现的 KIT 或 PDGFRA 受体。我们假设抑制其他分子靶标 与 IM 联合使用可以提供更实质性的疾病控制。最近的研究表明 PI3- 激酶/AKT 通路在 IM 抗性 GIST 细胞系和肿瘤的存活中的作用。因此我们挑战 IM- 敏感 GIST 异种移植物与 IM 和 AKT 抑制剂的新型组合，以测试该组合是否有效 一线 IM 治疗可增强疾病稳定性。在这些初步研究中，结合 与单独使用单一疗法相比，该疗法的疗效显着提高， 通过肿瘤反应和动物存活来衡量。这些结果为额外的临床前研究提供了理由 研究挑战各种胃肠道间质瘤异种移植模型的内在和获得性 IM 耐药性，如上所述 在此提案中。为了探索肿瘤对这种新型组合反应的分子方面，我们进行了 对这些异种移植物进行 RNAseq 研究，希望能够确定 GIST 的其他治疗靶点。这 分析卓有成效，确定了大脑表达的两个基因：X 连锁 1 (BEX1) 和神经元正五聚蛋白 I (NPTX1)，其表达仅在联合治疗的肿瘤中显着上调。 BEX1 和 NPTX1 已被认为是多种癌症中的肿瘤抑制基因，并可诱导 不同细胞类型中的凋亡途径。具体来说，BEX1 作为 BCL-2 拮抗剂，通过诱导细胞凋亡 结合 BCL-2 并抑制抗凋亡 BCL-2/BAX 异二聚体的形成，而 NPTX1 表达与促凋亡 BAD 和 BAX 蛋白的线粒体易位增强有关 并增强神经细胞死亡。我们假设这种组合会导致这两种现象的产生 通过 BCL-2 将促凋亡/抗凋亡平衡转向细胞死亡来影响肿瘤细胞命运的基因， BAD/BAX 途径，可能为 GIST 治疗提供其他途径。该提案旨在 功能测试这个中心假设，以及评估这些途径的靶向成员 IM 敏感且耐药的 GIST 异种移植模型。拟议的研究旨在提供支持 这些新颖的治疗方式在临床环境中的潜在应用。