A Role for AMH Autocrine Signaling in NSCLC

AMH 自分泌信号在 NSCLC 中的作用

• 批准号: 8756117
• 负责人: ERICA A. GOLEMIS
• 金额: $ 19.11万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-07 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8756117
• 关键词: Antibodies; Autocrine Communication; Binding; Bioinformatics; Biological Markers; Biology; Cancer Patient; Cancer cell line; Cell Survival; Cells; Client; Clinical; Clinical Trials; Combined Modality Therapy; Data; Development; Diagnostic Neoplasm Staging; Dose-Limiting; Drug resistance; ERBB2 gene; Family; Generations; Goals; Grant; Growth; HSP 90 inhibition; Heat-Shock Proteins 90; Hormones; Human; In Vitro; KRAS2 gene; Laboratories; Libraries; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Molecular Chaperones; Monoclonal Antibodies; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Play; Progression-Free Survivals; Property; Proteins; Radiation therapy; Regulation; Reporting; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Small Interfering RNA; Staging; Stem cells; Supporting Cell; Survival Rate; TGFBR1 gene; Testing; Therapeutic; Tissue Microarray; Tissues; Toxic effect; Transforming Growth Factors; Tumor stage; Tumor-Derived; Up-Regulation; autocrine; base; cancer cell; cancer therapy; chemotherapy; effective therapy; improved; in vivo; inhibitor/antagonist; insight; killings; member; mutant; novel; outcome forecast; overexpression; pre-clinical; protein expression; public health relevance; receptor; research study; response; screening; therapeutic target; therapy resistant; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The goal of this application is to investigate the unexpected role we have recently identified for anti-M¿llerian hormone (AMH) in supporting the metastatic and drug resistance properties of aggressive lung cancer. Lung cancer kills approximately 160,000 people in the US annually, with a 5 year survival rate of ~16%. As a chaperone protein, heat shock protein 90 (HSP90) is essential to support the activity of many proteins involved in oncogenesis, and HSP90 overexpression in tumors correlates with worse outcomes. The clinically promising HSP90 inhibitor ganetespib is showing considerable promise in late stage clinical trials, including those for NSCLC, and has recently been granted Fast Track status for NSCLC. Our initial goal was to understand and further improve the activity of this and other HSP90 inhibitors. Following extensive screening of a targeted siRNA library, we identified AMH and its receptor AMHRII as significant regulators of resistance to ganetespib. AMH is a member of the transforming growth factor (TGF)-? ligand family, and AMHRII heterodimerizes with co-receptors also required by TGF-? and BMP, influencing common effector cascades. The role for TGF-? signaling in NSCLC proliferation, survival and metastasis is well established, but no prior study has ever identified a role for AMH and AMHRII in this context. Our preliminary data suggests a novel autocrine-signaling loop involving AMH and AMHIIR in multiple NSCLC cell lines, and also suggest a monoclonal antibody to AMHRII sensitizes cells to HSP90 inhibition. AMHRII stability was recently shown to be highly dependent on HSP90, while we have shown that there is significant expression of AMH and AMHRII in a subset of lung cancer cell lines as well as in many primary lung cancers. We hypothesize that previously undetected autocrine AMH signaling plays a critical role in supporting the TGF-? pathway in a subpopulation of lung cancers, that AMH/AMHRII inhibition may potentiate the efficacy of ganetespib and other therapies, and that AMH and AMHRII may be utilized as biomarkers for tumor aggressiveness. Our long-term goals are to better understand the role of AMH and AMHRII in therapeutic response to ganetespib and other agents, and use this information to improve the treatment of lung cancer patients. In this proposal, the first aim will use siRNA and overexpression experiments to probe the functional interactions of AMH with TGF-? signaling in lung cancer cells. The second aim will explore the in vitro and in vivo effects of inhibiting AMH and AMHRII for drug response, and use tissue microarrays of human lung cancer to gauge expression of AMH, AMHRII, HSP90 and related partners as predictors of tumor stage, grade, and prognosis.

描述(申请人提供)：本申请的目的是调查我们最近发现的抗Méllerian激素(AMH)在支持侵袭性肺癌的转移和耐药特性中的意外作用。在美国，每年约有16万人死于肺癌，5年生存率约为16%。热休克蛋白90(HSP90)是一种伴侣蛋白，对许多参与肿瘤发生的蛋白的活性起着至关重要的支持作用，而HSP90在肿瘤中的过度表达与不良预后密切相关。临床上有前景的HSP90抑制剂Ganetespib在包括NSCLC在内的晚期临床试验中显示出相当大的前景，最近获得了NSCLC的快速通道状态。我们最初的目标是了解并进一步提高这种和其他HSP90抑制剂的活性。经过对靶向siRNA文库的广泛筛选，我们确定AMH及其受体AMHRII是对Ganetespib的抗性的重要调节因子。AMH是转化生长因子(TGF)-？配体家族，AMHRII与共受体异源二聚，这也是转化生长因子-？和BMP，影响常见的效应器级联。转化生长因子-2的作用？信号在非小细胞肺癌的增殖、存活和转移中的作用已经得到了很好的证实，但先前的研究还没有确定AMH和AMHRII在这方面的作用。我们的初步数据表明，在多个非小细胞肺癌细胞系中存在一个涉及AMH和AMHIIR的新的自分泌信号环，也表明AMHRII的单抗使细胞对HSP90抑制敏感。AMHRII的稳定性最近被证明高度依赖于HSP90，而我们已经证明AMH和AMHRII在肺癌细胞亚群中以及在许多原发肺癌中都有显著表达。我们假设先前未检测到的自分泌AMH信号在支持转化生长因子？在肺癌的一个亚群中，AMH/AMHRII的抑制可能会增强加奈替比布和其他疗法的疗效，AMH和AMHRII可能被用作肿瘤侵袭性的生物标记物。我们的长期目标是更好地了解AMH和AMHRII在对Ganetespib和其他药物的治疗反应中的作用，并利用这些信息来改进肺癌患者的治疗。在这个方案中，第一个目的是利用siRNA和过表达实验来探索AMH与转化生长因子？肺癌细胞中的信号。第二个目的是探索抑制AMH和AMHRII对药物反应的体外和体内效应，并利用人类肺癌组织芯片检测AMH、AMHRII、HSP90和相关伙伴的表达，作为预测肿瘤分期、分级和预后的指标。