Targeting Oncogenic Pathways in Genetically Complex Sarcomas

靶向遗传复杂肉瘤的致癌途径

• 批准号: 10932623
• 负责人: SAMUEL SINGER
• 金额: $ 27.56万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10932623
• 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; G-Quartets; Genomics; Genotype; Goals; Growth; Human; Individual; Institution; Integrins; Knowledge; 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; PIK3CG gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacologic Substance; Phase; Preclinical Testing; Primary Neoplasm; Prognostic Marker; Proliferating; Proteins; RNA Helicase; Ribosomes; Role; Sampling; Signal Pathway; Signal Transduction; 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; efficacy evaluation; improved; improved outcome; in vitro activity; in vivo; inhibitor; inhibitor therapy; knock-down; mRNA Translation; mTOR Inhibitor; mTOR inhibition; nanomolar; new therapeutic target; novel therapeutics; overexpression; patient derived xenograft model; precision oncology; prevent; 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：靶向一般复杂的肉瘤中的致癌途径 抽象的 我们的总体目标是为两种最常见和激进类型找到有效的靶向疗法 一般复杂的肉瘤：粘纤维肉瘤（MFS）和未分化的多形性肉瘤 （UPS）。新靶向疗法的发展对于改善这些结果至关重要 患者。但是，这些肉瘤的改动的复杂性使得很难找到真实 肿瘤发生的驱动因素。我们发现MFS和UPS驱动器中ITGA10（整合素-α10）的高表达 通过激活RAC/PAK和PI3K/MTOR信号传导以及85％的MFS和UPS来激活肌瘤作用 可以激活PI3K/MTOR信号级联的港口改变。在此级联 刺激蛋白质翻译，我们的初步结果表明MFS和UPS以及 去分化的脂肪肉瘤（DDLS）依赖于由RNA解旋酶EIF4A启用的致癌翻译。 因此，我们假设大多数MF/UPS都取决于PI3K/MTOR信号和EIF4A 用于生长和生存。首先，我们计划定义PI3K/MTOR和MAPK途径的作用 肉瘤发生的激活并鉴定与结果相关的分子改变。第二，我们 计划确定MFS/UPS细胞系中MTOR，PI3K和MEK抑制剂的效率，异种移植物 和PDX型号。在初步数据中，PI3K/MTOR抑制剂仅导致反馈上调 MAPK途径，可能会引起对治疗的自适应性。因此，我们将测试组合 每个具有MEK抑制剂的PI3K和MTOR抑制剂，以测试组合是否阻止 自适应反应并导致对MFS/UPS的协同抑制。第三，我们将确定 新的EIF4A抑制剂CR31B，MFS，UPS和DDLS细胞系的功效和作用机理，以及 异种移植物。为了发现哪些mRNA需要EIF4A在这些细胞系中进行翻译，我们将 在CR31B处理的细胞上进行核糖体足迹。我们希望MTOR，PI3K和EIF4A抑制剂 在大多数MFS和UPS中将是有效的疗法。澄清PI3K/mTOR的角色 和致癌的翻译途径将阐明肿瘤发生和转移的机制，鉴定 新药物靶标，确定有效的组合疗法并实现精确肿瘤学。我们期望 该提案中至少研究的一种治疗策略将导致临床试验 MFS和UPS的患者。