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: 9494539
• 负责人: Lori Rink
• 金额: $ 41.86万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9494539
• 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; Malignant Neoplasms; Measures; Mitochondria; Modality; Modeling; 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; experience; experimental study; improved; in vivo; inhibitor/antagonist; insight; knock-down; member; neoplastic cell; neuron loss; neuronal pentraxin; novel; novel therapeutics; overexpression; 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.

胃肠道肿瘤（GIST）用靶向疗法（例如伊马替尼）（IM），Sunitinib治疗的胃肠道肿瘤（GIST） 和雷莫非尼（Regorafenib），通常会逃避疾病控制和随着时间的流逝。当前的护理标准 先进的无法手术的要点涉及针对激活形式的这些抑制剂的顺序应用 在GIST中发现的套件或PDGFRA受体。我们假设抑制其他分子靶标 与IM结合使用可能提供更实质性的疾病控制。最近的研究实施了PI3- 激酶/AKT途径在不耐离的GIST细胞系和肿瘤存活中。因此，我们挑战了 具有IM和AKT抑制剂的新型组合，以测试该组合是否合并 一线IM治疗提供的疾病稳定增强。在这些初步研究中，组合 与单独的单一疗法治疗相比，治疗可显着提高效率 通过肿瘤反应和动物生存测量。这些结果为额外的临床前提供了理由 如所述 在此提案中。为了探索肿瘤对这种新型组合的反应的分子方面，我们进行了 RNASEQ对这些异种移植物进行了研究，以期鉴定出GIST的其他治疗靶标。这 分析是富有成果的，鉴定了两个基因，大脑表达，X连锁1（BEX​​1）和神经元素pentraxin I （NPTX1），其表达仅在组合处理的肿瘤中显着上调。 bex1和 NPTX1已暗示为各种癌症中的肿瘤抑制基因，并诱导 潜水细胞类型的凋亡途径。具体而言，BEX1充当Bcl-2拮抗剂，通过 结合Bcl-2并抑制抗凋亡Bcl-2/Bax异二聚体的形成，而NPTX1 表达已与促凋亡坏和Bax蛋白的线粒体易位有关 并增强神经元细胞死亡。我们假设这种组合导致了这两个 通过将pro/抗凋亡平衡转移到细胞死亡的基因，通过Bcl-2， 不良/BAX途径，可能会提供其他途径来进行GIST治疗。该提议试图 在功能上检验此中心假设，并评估这两个途径的目标成员 非常敏感和抗性的特里斯特征模型。拟议的研究旨在为 这些新型热模式在临床环境中的潜在应用。