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: 9384277
• 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/9384277
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Alpha Cell; 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; 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.

用甲磺酸伊马替尼（IM）、舒尼替尼等靶向疗法治疗胃肠道间质瘤（GIST）， 和瑞戈非尼，通常逃避疾病控制并随时间进展。的当前标准治疗 晚期不能手术的GIST涉及这些针对活化形式的抑制剂的顺序应用 GIST中发现的KIT或PDGFRA受体。我们假设，抑制额外的分子靶点， 与IM组合可提供更实质性的疾病控制。最近的研究表明，PI 3- 激酶/AKT通路在IM抗性GIST细胞系和肿瘤存活中的作用。因此，我们提出了挑战- 用IM和AKT抑制剂的新组合来测试该组合是否 通过一线IM治疗增强疾病稳定性。在这些初步研究中， 与单独的单一疗法治疗相比， 通过肿瘤反应和动物存活来测量。这些结果为额外的临床前研究提供了依据。 挑战各种GIST异种移植物的研究，如所述， 在这个提议中。为了探索肿瘤对这种新组合的反应的分子方面，我们进行了 RNAseq研究这些异种移植物，希望确定GIST的其他治疗靶点。这 分析是富有成效的，确定了两个基因，脑表达，X连锁1（BEX 1）和神经元五聚体蛋白I （NPTX 1），其表达仅在联合治疗的肿瘤中显著上调。BEX 1和 NPTX 1在多种癌症中被认为是肿瘤抑制基因，并且与诱导肿瘤细胞凋亡有关。 不同细胞类型的凋亡途径。具体而言，BEX 1作为BCL-2拮抗剂，通过以下途径诱导细胞凋亡： 结合BCL-2并抑制抗凋亡BCL-2/BAX异二聚体的形成，而NPTX 1 表达与促凋亡BAD和BAX蛋白的线粒体易位增强有关 和增强的神经元细胞死亡。我们假设，这种组合导致诱导这两个 通过BCL-2将促/抗凋亡平衡向细胞死亡方向转移而影响肿瘤细胞命运的基因， BAD/BAX通路，并可能提供额外的途径来接近GIST治疗。这项建议旨在 在功能上测试这一中心假设，以及评估这些途径的靶向成员， IM-敏感性和-抗性GIST异种移植物模型。拟议的研究旨在为以下方面提供支持： 这些新的治疗方式在临床环境中的潜在应用。