Targeting Oncogenic Pathways in Genetically Complex Sarcomas

RP-3：在遗传复杂肉瘤中靶向致癌通路 摘要 我们的总体目标是为两种最常见和最具侵略性的类型找到有效的靶向治疗方法 遗传复杂肉瘤：粘液纤维肉瘤（MFS）和未分化多形性肉瘤 （UPS）。新的靶向治疗的发展是迫切和重要的，以改善这些结果， 患者然而，这些肉瘤的复杂变化使得很难找到真正的 肿瘤发生的驱动因素。我们发现ITGA 10（整合素-α10）在MFS和UPS驱动器中的高表达， 通过激活RAC/PAK和PI 3 K/mTOR信号传导，85%的MFS和UPS 具有可激活PI 3 K/mTOR信号级联的改变。在这个级联信号 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）依赖于由RNA解旋酶eIF 4A实现的致癌翻译。 因此，我们假设大多数MFS/UPS将依赖于PI 3 K/mTOR信号传导和eIF 4A。 for growth生长and survival生存.首先，我们计划确定PI 3 K/mTOR和MAPK通路的作用， 激活肉瘤发生，并确定与结果相关的分子改变。二是 计划确定mTOR、PI 3 K和MEK抑制剂在MFS/UPS细胞系、异种移植物 PDX模型在初步数据中，单独的PI 3 K/mTOR抑制剂导致PI 3 K/mTOR的反馈上调。 MAPK通路，这可能导致对治疗的适应性抵抗。因此，我们将测试组合 将PI 3 K和mTOR抑制剂中的每一种与MEK抑制剂组合，以测试组合是否阻断PI 3 K和mTOR抑制剂之间的相互作用。 适应性反应，并导致MFS/UPS的协同抑制。第三，我们将确定 新的eIF 4A抑制剂CR 31 B在MFS、UPS和DDLS细胞系中的疗效和作用机制， 异种移植为了发现在这些细胞系中哪些mRNA需要eIF 4A进行翻译，我们将 在CR 31 B处理的细胞上进行核糖体足迹分析。我们预期mTOR、PI 3 K和eIF 4A抑制剂 将是治疗大多数MFS和UPS的有效方法。阐明PI 3 K/mTOR的作用 和致癌翻译途径将阐明肿瘤发生和转移的机制， 新的药物靶点，确定有效的联合疗法，并实现精确的肿瘤学。我们预计 本提案中研究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.