Inhibiting VHL-positive kidney cancer

描述(由申请人提供)：VHL阳性肾细胞癌(RCC)患者的治疗选择非常少。事实上，这些患者最常被他们的肿瘤学家告知，实验性治疗是他们的最佳选择，因为他们没有生物学上合理的治疗方法。缺乏治疗VHL阳性肾细胞癌的治疗靶点是癌症治疗中一个严重的未得到满足的需求。我们最近在人类VHL阳性的肾细胞癌细胞和患者肿瘤中证明了致癌的Src激酶信号通路升高。此外，我们还发现，在体外和小鼠模型中，Src抑制剂达沙替尼都能抑制VHL阳性细胞的增殖。总之，我们的研究是VHL阳性肾癌分子靶向治疗的第一次突破。尽管单用达沙替尼确实减缓了细胞的增殖，但它在体外和体内都未能杀死VHL阳性的肾细胞癌。我们假设，达沙替尼单独抑制Src的反应是由于肾癌中存在的旁路通路超过了抑制单个靶点的治疗益处。与这种可能性一致的是，VHL阳性肾细胞癌中信号转导和转录激活因子-3(STAT3)和激活的Src同源磷酸酪氨酸磷酸酶(Shp2)水平升高。事实上，单靠达沙替尼未能阻止致癌的STAT3激活。我们进一步假设，STAT3和Shp2信号通路代表了VHL阳性肾癌治疗的新靶点。这是因为STAT3在激活负责生存和化疗耐药的基因方面发挥了关键作用，而Shp2在面对Src抑制时可以激活细胞转化的下游效应因子。为了解决这一假设，我们将进行以下工作：目标1：确定STAT3在推翻Src抑制中的作用；目标2：确定Shp2信号在VHL阳性肾癌发病机制中的作用和要求；以及目标3：寻找与达沙替尼协同作用的激酶抑制剂，以杀死VHL阳性肾癌细胞。我们将使用人类癌细胞株和肿瘤标本来建立抑制VHL阳性肾细胞癌生存和肿瘤特异性旁路通路的生物学基础，并利用这一洞察力为一种无法治愈的疾病提供新的药物组合和生物标记物。这项拟议的研究建立在我们已发表的工作的基础上，将全面确定转录因子、酪氨酸磷酸酶和激酶在调节对Src抑制剂的耐药性中的作用-最终有望提供更有效的治疗方法。重要的是，这不是治疗上的渐进进步，因为它从依赖单一疗法转向以证据为基础的联合疗法，从一开始就克服阻力，从而提供持续的临床反应。

DESCRIPTION (provided by applicant): Patients with VHL-positive renal cell carcinoma (RCC) have very few treatment options. Indeed, these patients are most often told by their oncologists that experimental treatments are their best option, since there are no biologically rational treatments for them. The lack of therapeutic targets to treat VHL-positive RCC is a critical unmet need in cancer treatment. We recently demonstrated in human VHL-positive RCC cancer cells and patient tumors that the oncogenic Src kinase signaling pathway was elevated. Moreover, we found that the Src inhibitor, dasatinib reduced the proliferation of VHL-positive cells both in vitro and in mouse models. Together, our studies represent the first breakthrough for the molecularly targeted treatment of VHL-positive RCC. While dasatinib alone did slow cell proliferation, however, it failed to kill VHL-positive RCC in vitro and in vivo. We hypothesize tha the response observed with Src inhibition by dasatinib alone resulted from bypass pathways present in kidney cancer that override the therapeutic benefit of inhibiting a single target. Consistent with this possibility, VHL-positive RCC contains elevated levels of Signal Transducer and Activator of Transcription-3 (STAT3) and activated Src homology phosphotyrosine phosphatase (Shp2). Indeed, dasatinib alone failed to block oncogenic STAT3 activation. We further hypothesize that the STAT3 and Shp2 signaling pathways represent new therapeutic targets for treatment of VHL-positive RCC. This is because STAT3 plays a pivotal role in activating genes responsible for survival and chemoresistance, and Shp2 can activate downstream effectors of cell transformation in the face of Src inhibition. To address this hypothesis we will pursue the following: Aim 1: Determine the role of STAT3 in overriding Src inhibition; Aim 2: Determine the role and requirement of Shp2 signaling in VHL-positive RCC pathogenesis; and Aim 3: Identify kinase inhibitors that work synergistically with dasatinib to kil VHL-positive RCC cells. We will use human cancer cell lines and tumor specimens to establish the biological rationale for inhibiting survival and tumor-specific bypass pathways in VHL-Positive RCC and leverage this insight into novel drug combinations and biomarkers for a disease that is incurable. This proposed research, which builds on our published work, will comprehensively determine the role of transcription factors, tyrosine phosphatases and kinases in mediating resistance to Src inhibitors-and ultimately is expected to deliver more effective therapies. Importantly, this is not an incremental advance in treatment since it shifts from a reliance on monotherapy to evidence-based combination therapies that override resistance from the get-go, and thereby deliver sustained clinical responses.