A Role for AMH Autocrine Signaling in NSCLC

描述（由申请人提供）：本申请的目的是研究我们最近发现的抗<s:1>勒氏杆菌激素（AMH）在支持侵袭性肺癌的转移和耐药特性中的意想不到的作用。美国每年约有16万人死于肺癌，5年生存率约为16%。作为一种伴侣蛋白，热休克蛋白90 （HSP90）对支持许多参与肿瘤发生的蛋白的活性至关重要，而HSP90在肿瘤中的过表达与较差的预后相关。临床前景良好的HSP90抑制剂ganetespib在晚期临床试验中显示出相当大的希望，包括用于非小细胞肺癌的临床试验，并且最近被授予非小细胞肺癌的快速通道状态。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。在对靶向siRNA文库进行广泛筛选后，我们确定AMH及其受体AMHRII是对ganetespib耐药的重要调节因子。AMH是转化生长因子(TGF)-β配体家族的成员，AMHRII与TGF-β和BMP所需的共受体异二聚体，影响常见效应级联反应。TGF-β信号在非小细胞肺癌的增殖、生存和转移中的作用已经得到了很好的证实，但此前没有研究发现AMH和AMHRII在这一背景下的作用。我们的初步数据表明，在多种NSCLC细胞系中存在一种涉及AMH和AMHIIR的新型自分泌信号环，并且AMHRII单克隆抗体使细胞对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在肺癌细胞系的一个亚群以及许多原发性肺癌中有显著的表达。我们假设以前未检测到的自分泌AMH信号在肺癌亚群中支持TGF-β通路中起关键作用，AMH/AMHRII抑制可能增强ganetespib和其他治疗的疗效，并且AMH和AMHRII可能被用作肿瘤侵袭性的生物标志物。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，并利用这些信息改善肺癌患者的治疗。在本课题中，第一个目标将通过siRNA和过表达实验来探索肺癌细胞中AMH与TGF-β信号的功能相互作用。第二个目的是探讨抑制AMH和AMHRII对药物反应的体内外影响，并利用人肺癌组织微阵列检测AMH、AMHRII、HSP90及其相关伙伴的表达，作为肿瘤分期、分级和预后的预测指标。

DESCRIPTION (provided by applicant): The goal of this application is to investigate the unexpected role we have recently identified for anti-Müllerian 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)-β ligand family, and AMHRII heterodimerizes with co-receptors also required by TGF-β and BMP, influencing common effector cascades. The role for TGF-β 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-β 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-β 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.