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

项目4：总结/摘要 本提案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 先前比较了原发性和复发性/化疗后卵巢高级别浆液性卵巢癌的蛋白质组， 癌（HGSC）组织。在复发性乳腺癌中的优先表达蛋白中， HGSC，一种非受体酪氨酸激酶，SYK，被优先用于研究，因为小分子抑制剂， SYK包括fostamatinib可用于临床前测试和临床试验。我们能够验证 卡铂后复发性HGSC中SYK及其活性（自身）磷酸化形式的过表达， 紫杉醇治疗与未经治疗的肿瘤相比。SYK抑制表现出协同细胞毒效应 紫杉醇、多西他赛和长春瑞滨，所有这些都靶向微管网络。紫杉醇耐受性 卵巢癌细胞表现出比卡铂抗性对应物更高水平的SYK表达。我们 初步的磷酸化蛋白质组学分析显示微管蛋白和几种微管相关蛋白，如SYK 卵巢癌细胞中的底物。这些蛋白质的磷酸化已被证明可以增加微管 动力学，拮抗紫杉醇的微管稳定作用的过程。在小鼠肿瘤异种移植物中 在模型中，R406（福他替尼的活性形式）和紫杉醇的组合显著抑制肿瘤 没有明显毒性迹象的生长。我们的临床前研究支持一个新的假设，即SYK活性是 紫杉醇耐药所需的SYK抑制剂，并且SYK抑制剂使HGSC对紫杉醇的细胞毒性作用敏感。 因此，SYK抑制剂代表了治疗卵巢癌的有希望的新策略。为了测试上述内容， 根据这些假设，我们提出以下具体目标： 目标1.联合福他替尼和紫杉醇治疗卵巢癌的I/Ib期临床试验。 目标二。表征卵巢癌细胞中发现的优先SYK底物。 目标3。评估基于SYK的联合治疗在小鼠模型中的疗效。

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..