"Exploring the potential of SYK inhibitors to sensitize ovarian cancer to the anti-tumor effects of paclitaxel"

项目4：摘要/摘要 这项建议的目的是提供关键的临床前和早期临床证据，以确定 脾酪氨酸激酶(SYK)是否是卵巢癌有希望的治疗靶点。我们有 先前比较了原发和复发/化疗后卵巢高级别浆液的蛋白质组 来自同一患者的癌组织(HGSC)。在复发性癌中优先表达的蛋白质中 HGSCs，一种非受体酪氨酸激酶，SYK，被优先研究，因为小分子抑制剂 包括福斯塔替尼在内的SYK可用于临床前试验和临床试验。我们能够验证 复发HGSC中SYK及其活性(自身)磷酸化形式的过度表达 紫杉醇治疗与单纯肿瘤治疗的比较。SYK抑制表现出协同的细胞毒作用 紫杉醇、多西紫杉醇和长春瑞滨，所有这些药物都针对微管网络。紫杉醇耐药 卵巢癌细胞表现出比卡铂耐药细胞更高水平的SYK表达。我们的 初步的磷蛋白质组学分析显示微管蛋白和几种微管相关蛋白为SYK 卵巢癌细胞中的底物。这些蛋白的磷酸化已被证明可以增加微管 动力学，一个拮抗紫杉醇稳定微管作用的过程。在小鼠肿瘤异种移植中 在模型中，R406(福斯塔替尼的活性形式)和紫杉醇联合显著抑制肿瘤 生长时没有明显的毒性迹象。我们的临床前研究支持一种新的假设，即SYK活性是 这是紫杉醇耐药所必需的，并且SYK抑制使HGSC对紫杉醇的细胞毒作用敏感。 因此，SYK抑制剂是治疗卵巢癌的一种很有前途的新策略。要检验以上几点， 根据假设，我们提出了以下具体目标： 目的1.福斯塔替尼联合紫杉醇治疗卵巢癌的I/Ib期临床试验。 目的2.鉴定在卵巢癌细胞中发现的优先的SYK底物。 目的3.在小鼠模型上评价以SYK为基础的联合治疗的疗效。

PROJECT 4: SUMMARY/ ABSTRACT The purpose of this proposal is to provide critical pre-clinical and early phase clinical evidence to determine whether the Spleen Tyrosine Kinase (SYK) is a promising therapeutic target in ovarian cancer. We have previously compared the proteomes of primary and recurrent/post-chemotherapy ovarian high-grade serous carcinoma (HGSC) tissues from the same patients. Among the preferentially expressed proteins in recurrent HGSCs, a non-receptor tyrosine kinase, SYK, was prioritized for study because small molecule inhibitors of SYK including fostamatinib are available for pre-clinical testing and clinical trials. We were able to validate overexpression of SYK and its active (auto)phosphorylated form in recurrent HGSC after carboplatin and paclitaxel treatment compared to treatment naive tumors. SYK inhibition exhibited a synergistic cytotoxic effect with paclitaxel, docetaxel, and vinorelbine, all of which target the microtubule network. Paclitaxel resistant ovarian cancer cells exhibit higher levels of SYK expression than their carboplatin-resistant counterparts. Our preliminary phosphoproteomic analysis revealed tubulins and several microtubule-associated proteins as SYK substrates in ovarian cancer cells. Phosphorylation of these proteins has been shown to increase microtubule dynamics, a process antagonizing the microtubule-stabilizing effect of paclitaxel. In a mouse tumor xenograft model, the combination of R406 (the active form of fostamatinib) and paclitaxel significantly suppressed tumor growth without overt signs of toxicity. Our pre-clinical studies support a novel hypothesis that SYK activity is required for paclitaxel resistance and that SYK inhibition sensitizes HGSC to the cytotoxic effect of paclitaxel. Therefore, SYK inhibitors represent a promising new strategy to treat ovarian cancer. To test the above hypotheses, we propose the following Specific Aims: Aim 1. Phase I/Ib clinical trial of combined Fostamatinib and paclitaxel in ovarian cancer. Aim 2. Characterize the prioritized SYK substrates discovered in ovarian cancer cells. Aim 3. Assess the efficacy of SYK-based combination therapy in mouse models..