Inhibitors in Src Signaling for Antitumor Therapy

描述（由申请人提供）：肿瘤细胞在肿瘤微环境中招募正常内皮细胞（ECs），这是肿瘤持续生长和扩散所必需的过程。许多致癌信号通路，包括Src癌蛋白，诱导血管生成因子的表达，如促进肿瘤血管生成的血管内皮生长因子（VEGF）。我们已经证明Src激酶通过激活肿瘤细胞中的Stat3信号来调节VEGF的表达。此外，Stat3是Src下游的主要信号通路之一，在包括黑色素瘤和肉瘤在内的许多人类肿瘤中经常被激活。我们认为Src和下游Stat3信号不仅对肿瘤细胞存活至关重要，而且对肿瘤微环境中血管生成因子的产生及其对内皮细胞的作用也至关重要。因此，最近有临床前景的药理学Src抑制剂的发展为测试新一代抗肿瘤和抗血管生成疗法奠定了基础。该建议的中心假设是Src激酶和下游Stat3信号的抑制剂会通过直接的肿瘤细胞凋亡和肿瘤血管生成的损害诱导肿瘤消退。我们将使用已经处于早期临床试验的新一代口服生物可利用的药理学Src抑制剂来解决这一假设。我们的重点将是黑色素瘤和肉瘤，因为我们已经证明了Src和下游Stat3信号在这些肿瘤细胞中的重要作用。此外，恶性黑色素瘤和肉瘤需要更有效的治疗方法。本文拟开展的研究将通过以下具体目的探讨新型药理学Src激酶抑制剂的分子作用机制：(1)确定Src激酶抑制剂对培养的人类黑色素瘤和肉瘤细胞系生长和存活的生物学效应；(2)评估Src信号抑制如何影响肿瘤细胞生成血管生成因子及其在肿瘤内皮细胞中的应答；(3)在人黑色素瘤和肉瘤动物模型中评估Src抑制剂对肿瘤消退和肿瘤血管系统的影响；(4)验证活化Src信号在人类黑色素瘤和肉瘤临床标本中的潜在相关性。总之，这些研究将为新一代Src激酶抑制剂的药理作用机制提供新的见解，从而为更有效的黑色素瘤和肉瘤的分子靶向治疗奠定基础。

DESCRIPTION (provided by applicant): Tumor cells recruit normal endothelial cells (ECs) in the tumor microenvironment, a process which is essential for continued growth and spread of tumors. Numerous oncogenic signaling pathways, including the Src oncoprotein, induce expression of angiogenic factors such as vascular endothelial growth factor (VEGF) that promote tumor angiogenesis. We have shown that the Src kinase regulates VEGF expression through activation of Stat3 signaling in tumor cells. Furthermore, Stat3 is one of the major signaling pathways downstream of Src that is frequently activated in many human tumors, including melanoma and sarcoma. We propose that Src and downstream Stat3 signaling are essential not only for tumor cell survival but also for production of angiogenic factors and their actions on ECs in the tumor microenvironment. Thus, the recent development of clinically-promising pharmacologic Src inhibitors sets the stage for testing a new generation of antitumor and antiangiogenesis therapeutics. The central hypothesis of this proposal is that inhibitors of Src kinase and downstream Stat3 signaling will induce tumor regression through both direct tumor cell apoptosis and impairment of tumor angiogenesis. We will address this hypothesis using a new generation of orally-bioavailable pharmacologic Src inhibitors that are already in early-phase clinical trials. Our focus will be on melanoma and sarcoma because we have shown the important role of Src and downstream Stat3 signaling in these tumor cells. Furthermore, there is a need for more effective therapies in malignant melanoma and sarcoma. The studies proposed here will investigate the molecular mechanisms of action of novel pharmacologic Src kinase inhibitors through the following specific aims: (1) determine the biological effects of Src kinase inhibitors on growth and survival of human melanoma and sarcoma cell lines in culture; (2) assess how inhibition of Src signaling effects production of angiogenesis factors by tumor cells and response to them in tumor ECs; (3) evaluate the effects of Src inhibitors on tumor regression and tumor vasculature in animal models of human melanoma and sarcoma; (4) validate the potential relevance of activated Src signaling in human melanoma and sarcoma clinical specimens. In sum, these studies will provide insights into the mechanism of action of a new generation of pharmacologic Src kinase inhibitors and thereby lay the foundation for more effective molecular-targeted therapy of melanoma and sarcoma.