Targeting Oncogenic Pathways in Genetically Complex Sarcomas

靶向遗传复杂肉瘤的致癌途径

• 批准号: 10016098
• 负责人: SAMUEL SINGER
• 金额: $ 42.08万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016098
• 关键词: Affect; Apoptosis; CDK4 gene; Cell Line; Cells; Clinical Trials; Collaborations; Combined Modality Therapy; Complex; DNA copy number; Data; Dedifferentiated Liposarcomas; Development; Disease; Drug Kinetics; Drug Targeting; Drug resistance; ETV1 gene; Effectiveness; FRAP1 gene; Feedback; Genetic Translation; Genomics; Genotype; Goals; Growth; Human; Individual; Integrins; Knowledge; Lead; Letters; MAP Kinase Gene; MDM2 gene; MEK inhibition; MEKs; Malignant Fibrous Histiocytoma; Measures; Messenger RNA; Methods; Modeling; Molecular; Myxoid Malignant Fibrous Histiocytoma; NTRK1 gene; Neoplasm Metastasis; Oncogenic; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacologic Substance; Phase; Preclinical Testing; Primary Neoplasm; Prognostic Marker; Proteins; RNA Helicase; Ribosomes; Role; Sampling; Signal Pathway; Signal Transduction; Soft tissue sarcoma; Testing; Therapeutic; Tissue Sample; Toxic effect; Translating; Translational Regulation; Translations; Up-Regulation; Work; Xenograft Model; Xenograft procedure; clinical practice; clinical translation; common treatment; drug development; effective therapy; improved; improved outcome; in vitro activity; in vivo; inhibitor/antagonist; knock-down; mTOR Inhibitor; mTOR inhibition; nanomolar; new therapeutic target; novel therapeutics; overexpression; precision oncology; prevent; prognostic value; response; sarcoma; targeted treatment; therapy resistant; transcriptome; treatment strategy; tumor; tumor growth; tumorigenesis

RP-3: Targeting oncogenic pathways in genetically complex sarcomas ABSTRACT Our overall goal is to find effective targeted therapies for two of the most common and aggressive types of genetically complex sarcomas: myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS). The development of new targeted therapies is urgent and vital for improving outcomes of these patients. However, the complexity of alterations in these sarcomas has made it difficult to find the true drivers of oncogenesis. We found that high expression of ITGA10 (integrin-α10) in MFS and UPS drives sarcomagenesis by activating RAC/PAK and PI3K/mTOR signaling, and that 85% of MFS and UPS harbor alterations that can activate the PI3K/mTOR signaling cascade. Signaling in this cascade stimulates protein translation, and our preliminary results suggest that MFS and UPS, as well as dedifferentiated liposarcoma (DDLS), rely on oncogenic translation enabled by the RNA helicase eIF4A. We therefore hypothesize that most MFS/UPS will be dependent on PI3K/mTOR signaling and eIF4A for growth and survival. First, we plan to define the role of the PI3K/mTOR and MAPK pathway activation in sarcomagenesis and identify molecular alterations that associate with outcome. Second, we plan to determine the efficacy of mTOR, PI3K, and MEK inhibitors in MFS/UPS cell lines, xenografts and PDX models. In preliminary data the PI3K/mTOR inhibitors alone led to feedback upregulation of the MAPK pathway, which could cause adaptive resistance to therapy. Therefore, we will test combining each of the PI3K and mTOR inhibitors with a MEK inhibitor, to test whether the combination blocks the adaptive response and leads to synergistic suppression of MFS/UPS. Third, we will determine the efficacy and mechanism of action of a new eIF4A inhibitor, CR31B, in MFS, UPS, and DDLS cell lines and xenografts. To discover which mRNAs require eIF4A for their translation in these cell lines, we will perform ribosome footprinting on CR31B-treated cells. We expect that mTOR, PI3K, and eIF4A inhibitors will be effective therapy in the majority of MFS and UPS. Clarification of the roles of the PI3K/mTOR and oncogenic translation pathways will elucidate mechanisms of tumorigenesis and metastasis, identify new drug targets, identify effective combination therapies, and enable precision oncology. We expect that at least one of the treatment strategies investigated in this proposal will lead to clinical trials for patients with MFS and UPS.

RP-3：针对遗传复杂肉瘤中的致癌途径 抽象的 我们的总体目标是为两种最常见和最具侵袭性的类型找到有效的靶向疗法 遗传复杂肉瘤：粘液纤维肉瘤（MFS）和未分化多形性肉瘤 （UPS）。开发新的靶向疗法对于改善这些疾病的结果是紧迫且至关重要的 患者。然而，这些肉瘤改变的​​复杂性使得很难找到真正的肉瘤 肿瘤发生的驱动因素。我们发现 ITGA10（整合素-α10）在 MFS 和 UPS 驱动器中高表达 通过激活 RAC/PAK 和 PI3K/mTOR 信号传导来促进肉瘤发生，并且 85% 的 MFS 和 UPS 港口改变可以激活 PI3K/mTOR 信号级联。该级联中的信号传递 刺激蛋白质翻译，我们的初步结果表明 MFS 和 UPS 以及 去分化脂肪肉瘤 (DDLS) 依赖于 RNA 解旋酶 eIF4A 实现的致癌翻译。 因此，我们假设大多数 MFS/UPS 将依赖于 PI3K/mTOR 信号传导和 eIF4A 为了成长和生存。首先，我们计划定义 PI3K/mTOR 和 MAPK 通路的作用 肉瘤发生中的激活并识别与结果相关的分子改变。第二，我们 计划确定 mTOR、PI3K 和 MEK 抑制剂在 MFS/UPS 细胞系、异种移植物中的功效 和 PDX 模型。初步数据显示，PI3K/mTOR 抑制剂单独导致反馈上调 MAPK 通路，可能会导致对治疗的适应性抵抗。因此，我们将测试组合 将 PI3K 和 mTOR 抑制剂与 MEK 抑制剂结合使用，以测试该组合是否会阻断 自适应响应并导致 MFS/UPS 的协同抑制。第三，我们将确定 新型 eIF4A 抑制剂 CR31B 在 MFS、UPS 和 DDLS 细胞系中的功效和作用机制 异种移植物。为了发现哪些 mRNA 在这些细胞系中需要 eIF4A 进行翻译，我们将 对 CR31B 处理的细胞进行核糖体足迹分析。我们预计 mTOR、PI3K 和 eIF4A 抑制剂 将是大多数 MFS 和 UPS 的有效治疗方法。阐明 PI3K/mTOR 的作用 致癌翻译途径将阐明肿瘤发生和转移的机制，识别 新的药物靶点，确定有效的联合疗法，并实现精准肿瘤学。我们期望 该提案中研究的至少一种治疗策略将导致临床试验 患有 MFS 和 UPS 的患者。