C-Src Kinase-Calmodulin Interaction: A Therapeutic Target For Pancreatic Cancer

描述（由申请人提供）：胰腺癌是影响美国人的最致命的恶性肿瘤之一，并且被认为在很大程度上是无法治愈的-根据美国癌症协会，一年生存率（所有阶段）为20%，而五年生存率仅为4%。这种低存活率是由于癌症扩散，在诊断时难以通过手术切除。根据美国癌症协会（American cancer Society）的数据，2012年，约有43920名美国人将被诊断出患有这种癌症，约有37390人将死于这种癌症。现有的化疗和靶向治疗效果并不令人满意。因此，迫切需要确定新的靶点来开发治疗这种致命癌症的疗法。这项拟议的R21研究工作将借鉴UAB研究人员最近的新发现。Yabing Chen和Jay McDonald)的研究表明，Fas以不依赖于Fas的方式通过ERK激活激活胰腺癌细胞，并参与酪氨酸蛋白激酶Src进入DISC（死亡诱导信号复合体）的募集。此外，他们发现钙调蛋白通过与c-Src-SH2结构域的直接相互作用激活Src是ERK激活和胰腺癌细胞存活的原因。基于这些研究，我们假设抑制c-Src-SH2结构域与细胞CaM相互作用的小分子化合物也会有效抑制胰腺癌细胞逃逸凋亡的信号通路。因此，这些化合物将表现出抗胰腺癌的活性。为了验证上述假设，在响应PA-11-297计划的R21应用中（胰腺癌的试点研究），我们已经确定酪氨酸激酶c-Src-SH2/钙调蛋白相互作用是胰腺癌的新治疗靶点。R21应用程序的具体目标是

DESCRIPTION (provided by applicant): Pancreatic cancer is one of the most lethal malignancies affecting Americans, and is considered largely incurable - according to the American Cancer Society, the one year survival rate (for all stages together) is 20% while the five-year survival rate is only 4%. This low survival rate is due to the difficulty in surgically removing the cancer at the time of diagnosis due to its spread. In 2012, about 43,920 Americans will be diagnosed with this cancer, and about 37,390 will die from it, according to the American Cancer Society. The existing chemotherapies and targeted therapies have not been satisfactory. Thus, there is a pressing and critical need to identify novel targets to develop therapies to treat this lethal cancer. This proposed R21 research effort will draw upon recent novel discovery by researchers at UAB (Drs. Yabing Chen and Jay McDonald) that showed that Fas activated the survival of pancreatic cancer cells through ERK activation in a FADD-independent manner, and involved the recruitment of tyrosine-protein kinase Src into the DISC (death-inducing signaling complex). Further, they showed that the activation of Src by calmodulin through its direct interaction with the c-Src-SH2 domain was responsible for the activation of ERK and pancreatic cancer cell survival. Based on these studies, we hypothesize that small molecule compounds that inhibit the interaction of the c-Src-SH2 domain with cellular CaM will also effectively inhibit the signaling pathway through which the pancreatic cancer cells escape apoptosis. Thus, these compounds will exhibit anti-pancreatic cancer activity. To test the above hypothesis, in this R21 application in response to PA-11-297 program (Pilot Studies in Pancreatic Cancer) we have identified the tyrosine kinase c-Src-SH2/calmodulin interaction as a novel therapeutic target for pancreatic cancer. The specific aim for the R21 application is to undertake structure-based identification of several small molecule compounds that specifically bind to the SH2 domain, inhibit the c-Src-SH2/calmodulin interaction, and exhibit anti-pancreatic activity in vitro. We will utilize molecular biology, high-field NMR spectroscopy, structure-based virtual screening of compound libraries, and functional assays using MiaPaCa-2 and BxPC-3 pancreatic cells to identify several promising small compounds with anti-pancreatic cancer activity. In future studies, some of these promising compounds will be further developed into leads and inhibitors with high anti-pancreatic cancer activity, low toxicity and favorable pharmacokinetic and pharmacodynamic profiles for testing in preclinical and clinical trials. Ultimately, the most successful inhibitors will play a significant role in the treatment of patient with pancreatic cancer.