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（由申请人提供）：本申请的目的是调查我们最近发现的抗 M¿勒氏激素 (AMH) 支持侵袭性肺癌的转移性和耐药性，在美国每年导致大约 16 万人死亡，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质的活性至关重要，并且肿瘤中 HSP90 的过度表达与较差的结果相关。 ganetespib 在后期临床试验（包括非小细胞肺癌的临床试验）中显示出巨大的前景，并且最近已获得非小细胞肺癌的快速通道资格。我们最初的目标是在广泛筛选后了解并进一步提高该抑制剂和其他 HSP90 抑制剂的活性。通过靶向 siRNA 文库，我们确定 AMH 及其受体 AMHRII 是 ganetespib 抗性的重要调节因子，AMH 是转化生长因子 (TGF)-? 配体家族的成员。与 TGF-β 和 BMP 也需要的共受体形成异二聚体，影响常见的效应级联 TGF-β 信号传导在 NSCLC 增殖、存活和转移中的作用已得到充分证实，但之前尚未有研究确定 AMH 和 AMHRII 的作用。在这种情况下，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路，并且还表明了一种针对 AMHRII 的单克隆抗体。最近表明 AMHRII 的稳定性高度依赖于 HSP90，而我们已经证明 AMH 和 AMHRII 在肺癌细胞系亚群以及之前的许多原发性肺癌中都有显着表达。未检测到的自分泌 AMH 信号在支持肺癌亚群中的 TGF-β 通路中发挥着关键作用，AMH/AMHRII 抑制可能会增强ganetespib 和其他疗法，并且 AMH 和 AMHRII 可以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 ganetespib 和其他药物的治疗反应中的作用，并利用这些信息来改善肿瘤侵袭性。在该提案中，第一个目标将使用 siRNA 和过表达实验来探讨肺癌细胞中 AMH 与 TGF-β 信号传导的功能相互作用。抑制 AMH 和 AMHRII 对药物反应的影响，并使用人肺癌的组织微阵列来测量 AMH、AMHRII、HSP90 和相关伙伴的表达，作为肿瘤分期、分级和预后的预测因子。