Inhibition of Hedgehog Signaling in Gli-1+Adeno CA of the Esoph or GE junction

食管或胃食管交界处 Gli-1 腺 CA 中 Hedgehog 信号传导的抑制

• 批准号: 8583913
• 负责人: Jaffer A. Ajani
• 金额: $ 27.98万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583913
• 关键词: ATP-Binding Cassette Transporters; Adenocarcinoma Cell; Aftercare; Basal Cell Cancer; Beds; Biological Markers; Biological Preservation; Biopsy; Cancer Therapy Evaluation Program; Cell Line; Clinic; Clinical Trials; Colorectal Adenocarcinoma; Data; Diagnosis; Disease; Dose; Dose-Limiting; Down-Regulation; Drug resistance; Embryonic Development; Empiricism; Erinaceidae; Esophageal; Esophageal Adenocarcinoma; Exposure to; FDA approved; Future; Gene Expression; Genes; Growth; Human; In Vitro; In complete remission; Incidence; Injury; Investigation; Maintenance; Malignant Neoplasms; Mediating; Memorial Sloan-Kettering Cancer Center; Methods; MicroRNAs; Modeling; Molecular; Molecular Biology; Molecular Profiling; NF-kappa B; Nuclear; Oral; Outcome; Pancreatic Adenocarcinoma; Pathologic; Pathway interactions; Patients; Pharmacodynamics; Phase; Phase II Clinical Trials; Play; Population; Proteins; Radiation; Radio; Randomized; Reporting; Research; Resistance; Role; Safety; Sampling; Signal Pathway; Signal Transduction; Southwest Oncology Group; Specificity; Specimen; Testing; Toxic effect; Up-Regulation; Validation; Xenograft Model; arm; base; cancer cell; chemoradiation; cytotoxic; design; global health; hedgehog signal transduction; improved; in vivo; inhibitor/antagonist; neoplastic cell; novel strategies; overexpression; posters; pre-clinical; prospective; public health relevance; research study; response; small molecule; smoothened signaling pathway; therapy resistant; translational clinical trial; tumor; tumor xenograft

DESCRIPTION (provided by applicant): Esophageal adenocarcinoma (EAC) is a major global health burden and its incidence has risen considerably. The patient outcome is often very poor with the 5-year cure rate remaining <20%. Preoperative chemo radiation provides the strongest Level 1 evidence for treating localized EAC, however, this is an empiric approach with unpredictable outcomes. In summary, none of the current approaches to localized EAC are based on fundamental understanding of molecular biology. We have generated compelling data supporting the central role of hedgehog (Hh) pathway in conferring resistance to therapy. Our data document that in EAC cells, inhibition of Hh can overcome resistance to cytotoxics and radiation. We have also developed a validated 3- biomarker (sonic Hh, NF-kB, and Gli-1) signature for predicting pathologic complete response (pathCR) to chemoradiaiton in EAC patients. Thus Hh signaling and the NF-kB pathway appear very important in mediating resistance in EAC. In this Project we focus on Hh signaling. Our hypothesis is that inhibition of Hh signaling during chemoradiation in patients with localized nuclear Gli-1 expressing EAC would result in a e40% pathCR rate. GDC-0449 (a smo inhibitor of Hh pathway) down regulates nuclear Gli-1 in vitro and in vivo and has efficacy in vivo. GDC-0449 has antitumor activity but no dose-limiting toxicity (150, 270, and 540 mg). In this project, we propose an elaborate translational clinical trial and other non-clinical experiments to uncover molecular mechanisms of EAC resistance despite the inhibition of Hh signaling. We propose 3 Specific Aims as follows: Aim 1: To conduct a phase IB/II trial of GDC-0449 (NSC 747691) plus preoperative chemoradiation in enriched patients with localized nuclear Gli-1+ EAC. A: Conduct a phase IB trial to establish safety of GDC-0449 plus chemoradiation. B: Conduct a phase II trial to estimate the rate of pathCR and establish pharmacodynamic effects of GDC-0449 (compare with historical controls). C: Carry out a prospective validation of 3-biomarker pathCR-predicting signature. Aim 2: To identify the molecular pathways of GDC-0449 drug resistance in cell lines and patients in Aim 1. A: Determine the change in activation and expression status of proteins in cell signaling pathways after GDC-0449 treatment and identify key molecules of GDC-0449 resistance (Cell lines and patients). B: Determine the change of gene expression profiles after GDC-0449 treatment and establish biomarkers for GDC response and resistance. Aim 3: To identify the GDC-0449/chemoradiation resistance/response-related microRNA signature. A: To determine the microRNA profile changes in the EAC cell lines before or after biochemoradiation and find the resistance-related microRNA signature. B: To determine the microRNA profile changes in the chemo/radio resistant EAC patients' specimens before or after biochemoradiation and identify the GDC-0449-related microRNA signature of response/resistance.

描述（由申请人提供）：食管腺癌（EAC）是全球重大的健康负担，其发病率大大增加。患者的预后通常很差，而5年治疗率少于20％。术前化学辐射为治疗局部EAC提供了最强的1级证据，但是，这是一种经验性方法，具有无法预测的结果。总而言之，当前局部EAC的方法均基于对分子生物学的基本理解。我们已经产生了令人信服的数据，支持刺猬（HH）途径在赋予治疗的抗性中的核心作用。我们的数据文献是，在EAC细胞中，HH的抑制可以克服对细胞毒素和辐射的耐药性。我们还开发了经过验证的3-生物标志物（Sonic HH，NF-KB和GLI-1）的特征，以预测EAC患者对化学腺经的病理完全反应（PATHCR）。因此，HH信号传导和NF-KB途径似乎在介导EAC中的抗性中非常重要。在这个项目中，我们专注于HH信号。我们的假设是，在表达EAC的局部核GLI-1患者化学放疗过程中对HH信号传导的抑制作用将导致E40％路径率。 GDC-0449（HH途径的SMO抑制剂）降低了体外和体内核Gli-1的调节，并在体内具有功效。 GDC-0449具有抗肿瘤活性，但没有限制剂量的毒性（150、270和540 mg）。在这个项目中，我们提出了一项精致的翻译临床试验和其他非临床实验，以发现EAC抗性的分子机制，尽管抑制了HH信号传导。我们提出3个特定目的如下：目标1：在富含局部核GLI-1+ EAC的患者中，对GDC-0449（NSC 747691）以及术前化学放疗进行IB/II期试验。答：进行IB期试验以建立GDC-0449加化学放疗的安全性。 B：进行II期试验以估计路径速率并建立GDC-0449的药效学效应（与历史控制相比）。 C：对3个生物标记路径预测签名进行前瞻性验证。目标2：确定在AIM 1中的细胞系和患者中GDC-0449耐药性的分子途径。 B：确定GDC-0449处理后基因表达谱的变化，并为GDC反应和抗性建立生物标志物。目标3：确定GDC-0449/化学放射电阻/与响应相关的microRNA签名。答：确定生物化化之前或之后的MicroRNA轮廓在EAC细胞系中发生变化，并找到与抗性相关的MicroRNA特征。 B：确定生物化化化学抗化性EAC患者标本的microRNA曲线变化，并确定与GDC-0449相关的响应/抗性的MicroRNA签名。