权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

TARGETING SPLEEN TYROSINE KINASE IN CHEMORESISTANT OVARIAN CARCINOMA

靶向脾酪氨酸激酶治疗化疗耐药卵巢癌

基本信息

批准号：
8754936
负责人：
Tian-Li Wang
金额：
$ 21.14万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-08 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8754936
关键词：
Address Advanced Malignant Neoplasm Affect Amino Acids Biochemical Biological Assay Cancer Patient Carboplatin Carcinoma Cell Culture Techniques Cell physiology Cells Clinical Clinical Trials Development Diagnosis Disease model Disease remission Drug Targeting Drug resistance Evaluation Event Fluorescence Recovery After Photobleaching Foundations Future Goals Grant Hematopoietic Neoplasms Image Immune System Diseases In Vitro Laboratories Lead Life Link MAP4 Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mediating Methods Microtubule Polymerization Microtubule Stabilization Microtubule-Associated Proteins Microtubules Molecular Mus Operative Surgical Procedures Ovarian Ovarian Carcinoma Paclitaxel Pathway interactions Patients Phagocytosis Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Phosphorylation Play Primary Neoplasm Protein Kinase Protein Tyrosine Kinase Proteins Proteome Proteomics Reagent Recurrence Recurrent tumor Resistance Resistance development Rheumatoid Arthritis Role SKOV3 cells Sampling Serous Signal Transduction Solid Stable Isotope Labeling Staging Testing Therapeutic Tissues Toxic effect Treatment Protocols Tubulin Tyrosine Kinase Inhibitor Woman Xenograft Model anticancer research base cancer cell cancer type cell growth cell motility chemotherapy cofactor cytotoxic experience human SYK protein improved in vivo inhibitor/antagonist interest microtubule-associated protein 1B mouse model neoplastic cell novel outcome forecast ovarian neoplasm pre-clinical public health relevance research clinical testing research study response therapeutic target treatment response tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): The objective of this proposal is to address a critical issue in cancer research - the molecular basis of drug resistance. The ultimate goal is to improve treatment response and overall prognosis in patients diagnosed with advanced cancer. We will use ovarian high-grade serous carcinoma (HGSC) as the disease model because it is one of the most aggressive cancer types in women. The development of resistance to chemotherapeutic reagents in HGSC represents a major challenge to achieving long term remission. To accomplish this goal, we have employed a proteomic method to compare global proteomes between primary and recurrent/post-chemotherapy HGSC tissues from the same patients. Among the preferentially expressed proteins identified in recurrent HGSCs, a non-receptor tyrosine kinase, Spleen Tyrosine Kinase (SYK), is of great interest. SYK is a non-receptor protein tyrosine kinase that is involved in signaling events that mediate diverse cellular responses, including proliferation, cell movement, differentiation, and phagocytosis. Small compound inhibitors such as Fostamatinib (AstraZeneca) and R112 (Rigel) are available and have been used in late phase clinical trials for patients with rheumatoid arthritis, auto-immune diseases, and hematopoietic malignancy. In our preliminary studies, we were able to show that total SYK and p-SYK (the active form) levels increased in recurrent post-chemotherapy tumors as compared to corresponding primary tumors from the same HGSC patients. We found that SYK inhibition cooperated synergistically with paclitaxel to inhibit tumor cell growth in vitro. A combination of SYK inhibitor and paclitaxel had the greatest anti-tumor effect in a mouse tumor xenograft model. We have applied quantitative proteomic analysis, SILAC (stable isotope labeling by/with amino acids in cell culture), to identify potential SYK substrates and discovered microtubule-associated proteins (MAPs) and tubulins that may contribute to aberrant microtubule dynamics in paclitaxel-resistant cancer cells. Based on our preliminary results, we hypothesize that SYK activation phosphorylates MAPs and tubulin, resulting in increased microtubule dynamics and thus antagonizing the effects of paclitaxel. SYK inhibitors could decrease the phosphorylation in MAPs or tubulin, rendering chemoresistant cells susceptible to paclitaxel treatment. Thus, targeting SYK signaling may reverse paclitaxel resistance and potentiate paclitaxel effects in HGSCs. The concept of targeting SYK in chemoresistant cancers is novel and highly translational. If our preclinical results turn out to be promising, SYK inhibitrs would warrant further evaluation in clinical trials.

描述（由申请人提供）：该提案的目的是解决癌症研究中的一个关键问题——耐药性的分子基础。最终目标是改善晚期癌症患者的治疗反应和总体预后。我们将使用卵巢高级别浆液性癌（HGSC）作为疾病模型，因为它是女性中最具侵袭性的癌症类型之一。 HGSC 对化疗试剂耐药性的发展是实现长期缓解的重大挑战。为了实现这一目标，我们采用蛋白质组学方法来比较来自同一患者的原发性和复发/化疗后 HGSC 组织之间的整体蛋白质组。在复发性 HGSC 中优先表达的蛋白质中，一种非受体酪氨酸激酶——脾酪氨酸激酶 (SYK) 引起了人们的极大兴趣。 SYK 是一种非受体蛋白酪氨酸激酶，参与介导多种细胞信号传导事件反应，包括增殖、细胞运动、分化和吞噬作用。 Fostamatinib（阿斯利康）和 R112（Rigel）等小化合物抑制剂已上市，并已用于治疗类风湿关节炎、自身免疫性疾病和造血系统恶性肿瘤患者的后期临床试验。在我们的初步研究中，我们能够证明，与来自同一 HGSC 患者的相应原发肿瘤相比，化疗后复发肿瘤中的总 SYK 和 p-SYK（活性形式）水平有所增加。我们发现 SYK 抑制与紫杉醇协同作用，在体外抑制肿瘤细胞生长。 SYK抑制剂和紫杉醇的组合在小鼠肿瘤异种移植模型中具有最大的抗肿瘤效果。我们应用定量蛋白质组分析 SILAC（细胞培养物中氨基酸的稳定同位素标记）来鉴定潜在的 SYK 底物，并发现微管相关蛋白 (MAP) 和微管蛋白，它们可能导致紫杉醇耐药癌细胞中微管动力学异常。根据我们的初步结果，我们假设 SYK 激活会使 MAP 和微管蛋白磷酸化，导致微管动力学增加，从而拮抗紫杉醇的作用。 SYK 抑制剂可以降低 MAP 或微管蛋白的磷酸化，使化疗耐药细胞对紫杉醇治疗敏感。因此，靶向 SYK 信号传导可能会逆转紫杉醇耐药性并增强 HGSC 中紫杉醇的作用。在化疗耐药癌症中靶向 SYK 的概念是新颖且高度转化的。如果我们的临床前结果被证明是有希望的，那么 SYK 抑制剂将需要在临床试验中进行进一步评估。