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

“探索 SYK 抑制剂使卵巢癌对紫杉醇抗肿瘤作用敏感的潜力”

基本信息

批准号：
10222607
负责人：
IE-MING SHIH
金额：
$ 25.61万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-18 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10222607
关键词：
Antibodies Basophils Biochemical Biological Assay Biological Markers Biological Process Blood Cancer Patient Carboplatin Carcinoma Chemoresistance Clinical Clinical Management Clinical Research Clinical Trials Combined Modality Therapy Correlative Study Dose Drug resistance Exhibits Future Generations Goals Hematologic Neoplasms Immunohistochemistry Immunoprecipitation Implant In Vitro Journals Malignant neoplasm of ovary Maximum Tolerated Dose Measurable Measures Methods Microtubule Stabilization Microtubule-Associated Proteins Microtubules Monitor Mus Oral Outcome Ovarian Paclitaxel Pathogenesis Patients Phase Phase 1/1b Clinical Trial Phosphorylated Peptide Phosphorylation Physiological Platinum Positioning Attribute Preclinical Testing Process Prodrugs Proteins Proteome Public Health Publishing Recurrence Recurrent disease Reporting Resistance Rheumatoid Arthritis Role SYK gene Serous Signal Transduction Site Testing Time Tissues Toxic effect Treatment outcome Tubulin Tumor Debulking Tumor Tissue Tyrosine Kinase Inhibitor Tyrosine Phosphorylation Vinorelbine Woman Xenograft Model antitumor effect base biomarker validation cancer cell cancer therapy chemotherapy clinical practice clinical translation clinically relevant cytotoxic docetaxel improved in vivo insight intraperitoneal mouse model neoplastic cell novel novel therapeutic intervention novel therapeutics overexpression patient derived xenograft model personalized approach phase I trial phosphoproteomics pre-clinical preclinical efficacy preclinical study predictive marker response small molecule small molecule inhibitor taxane therapeutic target tool translational study treatment comparison treatment response tumor tumor growth tumor xenograft

项目摘要

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..

项目 4：总结/摘要该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。我们有之前比较了原发性和复发性/化疗后卵巢高级浆液性卵巢癌的蛋白质组来自同一患者的癌（HGSC）组织。复发性肿瘤中优先表达的蛋白质之一 HGSCs 是一种非受体酪氨酸激酶 SYK，被优先研究，因为 HGSCs 的小分子抑制剂 SYK 包括 fostamatinib 可用于临床前测试和临床试验。我们能够验证卡铂治疗后复发性 HGSC 中 SYK 及其活性（自）磷酸化形式的过度表达紫杉醇治疗与治疗初治肿瘤的比较。 SYK 抑制表现出协同细胞毒作用紫杉醇、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为 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，拮抗紫杉醇微管稳定作用的过程。在小鼠肿瘤异种移植物中模型中，R406（福斯塔替尼的活性形式）和紫杉醇的组合显着抑制肿瘤生长无明显毒性迹象。我们的临床前研究支持一个新的假设，即 SYK 活性是紫杉醇耐药性所必需的，并且 SYK 抑制使 HGSC 对紫杉醇的细胞毒性作用敏感。因此，SYK抑制剂代表了一种有前景的治疗卵巢癌的新策略。测试以上内容假设，我们提出以下具体目标：目标 1. Fostamatinib 和紫杉醇联合治疗卵巢癌的 I/Ib 期临床试验。目标 2. 表征在卵巢癌细胞中发现的优先 SYK 底物。目标 3. 评估基于 SYK 的联合疗法在小鼠模型中的疗效。