TARGETING SPLEEN TYROSINE KINASE IN CHEMORESISTANT OVARIAN CARCINOMA

描述（由申请人提供）：本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整体预后。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略性的癌症类型之一。HGSC对化疗药物的耐药性的发展是实现长期缓解的主要挑战。为了实现这一目标，我们采用了一种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学。在复发性造血干细胞中发现的优先表达蛋白中，非受体酪氨酸激酶脾酪氨酸激酶（SYK）引起了极大的兴趣。SYK是一种非受体蛋白酪氨酸激酶，参与介导多种细胞的信号事件

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.