Targeting Oncogenic Pathways in Genetically Complex Sarcomas

RP-3：靶向基因复杂肉瘤的致癌途径 摘要 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 基因复杂的肉瘤：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和至关重要的。 病人。然而，这些肉瘤变化的复杂性使人们很难找到真正的 肿瘤发生的驱动因素。我们发现整合素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信号通路发生肉瘤，85%的MFS和UPS 可以激活PI3K/mTOR信号级联的港口改变。此级联中的信令 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信令和eIF4A 为了成长和生存。首先，我们计划确定PI3K/mTOR和MAPK通路的作用 在肉瘤发生中的激活，并确定与结果相关的分子变化。第二，我们 计划确定mTOR、PI3K和MEK抑制剂在MFS/UPS细胞系、异种移植瘤中的疗效 和PDX型号。在初步数据中，PI3K/mTOR抑制剂单独导致反馈上调 MAPK通路，这可能导致适应性抵抗治疗。因此，我们将测试组合 每种PI3K和mTOR抑制剂与一种MEK抑制剂一起使用，以测试组合是否阻止 适应性反应，导致对MFS/UPS的协同抑制。第三，我们将确定 新型eIF4A抑制剂CR31B对MFS、UPS和DDLS细胞株的疗效和作用机制 异种移植物。为了发现哪些mRNAs需要eIF4A在这些细胞系中进行翻译，我们将 在CR31B处理的细胞上执行核糖体足迹。我们预计mTOR、PI3K和eIF4A抑制剂 将是治疗大多数MFS和UPS的有效方法。澄清PI3K/mTOR的作用 而癌基因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，并使精确肿瘤学成为可能。我们预计 本提案中调查的至少一种治疗策略将导致临床试验 MFS和UPS患者。

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.