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（由应用程序提供）：本应用的目的是研究我们最近在支持侵袭性肺癌的转移性和耐药性特性方面确定了我们最近确定的抗M llerian Horsene（AMH）的意外作用。肺癌在美国每年约有160,000人死亡，5年生存率约为16％。作为伴侣蛋白，热休克蛋白90（HSP90）对于支持许多参与肿瘤发生的蛋白的活性至关重要，而肿瘤中HSP90的过表达与结果较差。临床上有希望的HSP90抑制剂Ganetespib在后期临床试验（包括NSCLC的临床试验）中表现出可观的承诺，并且最近已获得NSCLC的快速轨道状态。我们的最初目标是了解并进一步改善该HSP90抑制剂的活性。在广泛筛选靶向siRNA文库之后，我们将AMH及其受体AMHRII确定为对Ganetespib的耐药性的重要调节剂。 AMH是转化生长因子（TGF）的成员 - ？配体家族和Amhrii杂二聚体与TGF-也需要共二聚体？和BMP，会影响共同的效应级联。 TGF-的角色？在这种情况下，NSCLC增殖，生存和转移中的信号传导尚未确定AMH和AMHRII的作用。我们的初步数据表明，在多个NSCLC细胞系中涉及AMH和AMHIIR的新型自分泌信号回路，还提出了对AMHRII感官对HSP90抑制的单克隆抗体。最近显示，AMHRII稳定性高度依赖于Hsp90，而我们已经表明，AMH和AMHRII在肺癌细胞系的子集以及许多原发性肺癌中都有显着的表达。我们假设先前未被发现的自分泌AMH信号在支持TGF-中起着至关重要的作用。在肺癌亚群中的途径，AMH/AMHRII抑制作用可能有可能具有Casetespib和其他疗法的有效性，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Casetespib和其他药物的热反应中的作用，并使用此信息来改善肺癌患者的治疗。在此提案中，第一个目标将使用siRNA和过表达实验来探测AMH与TGF-的功能相互作用？肺癌细胞中的信号传导。第二个目的将探索抑制AMH和AMHRII对药物反应的体外和体内效应，并使用人类肺癌的组织微阵列来衡量AMH，AMHRII，HSP90及其相关伙伴的表达，作为肿瘤阶段，等级和预后的预测指标。