Inhibiting VHL-positive kidney cancer

抑制 VHL 阳性肾癌

基本信息

批准号：
9038327
负责人：
George Victor Thomas
金额：
$ 31.96万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9038327
关键词：
Address Agreement Apoptosis Biochemical Biological Biological Assay Biological Markers Bypass Cancer Patient Cancer cell line Cell Line Cell Proliferation Cell Survival Cells Clinical Clinical Trials Combined Modality Therapy Cytostatics DNA biosynthesis Dasatinib Disease Effector Cell Focal Adhesion Kinase 1 Genes Genetic Goals Growth Health Human Hypoxia Image Analysis Immunohistochemistry In Vitro Kidney Malignant Epithelial Cell Malignant Neoplasms Mediating Mediator of activation protein Metastatic Renal Cell Cancer Modeling Molecular Mus Mutation Oncogenic Oncologist Operative Surgical Procedures Outcome Pathogenesis Pathway interactions Patients Play Protein Kinase Protein Tyrosine Kinase Protein Tyrosine Phosphatase Publishing Quality of life Radiation Receptor Protein-Tyrosine Kinases Regimen Renal Cell Carcinoma Renal carcinoma Reporting Research Resistance Role SRC gene Science Signal Pathway Signal Transduction Specimen Stat3 protein Therapeutic Therapeutic Effect Translating Tumor Suppressor Genes Urogenital Cancer VHL protein Validation Vascular Endothelial Growth Factors Work Xenograft procedure angiogenesis base biomarker-driven cancer cell cancer therapy cell transformation chemotherapy clinically relevant cytotoxicity digital imaging effective therapy evidence base fitness histological studies improved in vivo inhibitor/antagonist insight killings kinase inhibitor molecular diagnostics mouse model neoplastic cell new therapeutic target novel drug combination novel therapeutics personalized medicine phosphoproteomics predictive signature protein tyrosine phosphatase 1B response small molecule inhibitor src-Family Kinases targeted treatment therapeutic target transcription factor translational medicine treatment response tumor

项目摘要

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.

描述（由申请人提供）：VHL阳性肾细胞癌（RCC）患者的治疗选择很少。确实，这些患者经常被肿瘤学家告知实验治疗是他们的最佳选择，因为对他们没有生物学上的理性治疗。缺乏治疗VHL阳性RCC的治疗靶标在癌症治疗中是一个至关重要的未满足需求。我们最近在人VHL阳性RCC癌细胞和患者肿瘤中证明了致癌SRC激酶信号传导途径的升高。此外，我们发现SRC抑制剂达沙替尼在体外和小鼠模型中都降低了VHL阳性细胞的增殖。总之，我们的研究代表了分子靶向VHL阳性RCC的第一个突破。然而，虽然单独的达沙替尼确实会减慢细胞的增殖，但它未能在体外和体内杀死VHL阳性的RCC。我们假设单独的达沙替尼对SRC抑制所观察到的反应是由肾脏癌中存在的旁路途径引起的，从而覆盖了抑制单个靶标的治疗益处。与这种可能性一致，VHL阳性RCC含有转录3（STAT3）的信号传感器和激活因子的水平升高和激活的SRC同源性磷酸酪氨酸磷酸酶（SHP2）。实际上，单独的达沙替尼未能阻止致癌性STAT3激活。我们进一步假设STAT3和SHP2信号通路代表了治疗VHL阳性RCC的新治疗靶标。这是因为STAT3在激活负责生存和化学抗性的基因中起关键作用，而SHP2可以在SRC抑制时激活细胞转化的下游效应因子。为了解决这一假设，我们将追求以下内容：目标1：确定STAT3在压倒SRC抑制中的作用； AIM 2：确定SHP2信号在VHL阳性RCC发病机理中的作用和需求；目标3：鉴定与dasatinib协同作用的激酶抑制剂可与KIL VHL阳性RCC细胞。我们将使用人类癌细胞系和肿瘤标本来建立生物学原理，以抑制VHL阳性RCC中的生存和肿瘤特异性旁路途径，并利用这种洞察力对新的药物组合和生物标志物，以造成无法治愈的疾病。这项拟议的研究基于我们发表的工作，将全面确定转录因子，酪氨酸磷酸酶和激酶在介导对SRC抑制剂的抗性中的作用，并最终有望提供更有效的疗法。重要的是，这不是治疗的增量进步，因为它从对单一疗法的依赖转变为基于证据的组合疗法，这些疗法超过了从一开始的耐药性，从而提供了持续的临床反应。