Targeting the Oncogenic Transcription Factor c-myb in Adenoid Cystic Carcinomas

靶向腺样囊性癌中的致癌转录因子 c-myb

• 批准号: 8551646
• 负责人: Alan L. Ho
• 金额: $ 32.84万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8551646
• 关键词: Adenoid Cystic Carcinoma; Award; Biology; Biopsy; Cancer Therapy Evaluation Program; Cell Line; Clinical; Clinical Research; Clinical Trials; Collaborations; Cytogenetics; Detection; Development; Disease; Down-Regulation; Experimental Models; Fluorescent in Situ Hybridization; Future; Genetic; Goals; Histologic; Immunohistochemistry; K-Series Research Career Programs; Lead; Length; Letters; MYB gene; Malignant Neoplasms; Measures; Mediating; Memorial Sloan-Kettering Cancer Center; Metastatic/Recurrent; Modeling; Molecular; Multicenter Studies; Mutation; National Cancer Institute; Oncogenic; Outcome; PIK3CA gene; Pathologic; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Preclinical Testing; Predisposition; Progression-Free Survivals; Proto-Oncogene Proteins c-myb; Protocols documentation; Radiosurgery; Recurrent Malignant Neoplasm; Safety; Salivary; Salivary Glands; Staging; Testing; Therapeutic; Tissues; Translating; Tumor Markers; Tumor Tissue; Variant; Western Blotting; Work; Writing; activating transcription factor; base; cancer recurrence; clinical efficacy; design; effective therapy; experience; fusion gene; human NFIB protein; inhibitor/antagonist; novel; novel strategies; oncology; overexpression; patient population; phase 2 study; pre-clinical; programs; public health relevance; response; small molecule; standard care; therapeutic target; transcription factor; tumor; tumorigenesis

DESCRIPTION (provided by applicant): This is a new 3-year R01 application involving a Cancer Therapy Evaluation Program of the National Cancer Institute (NCI/CTEP) awarded phase II study of the Akt inhibitor MK-2206 in patients with progressive, recurrent/metastatic adenoid cystic carcinomas (R/M ACCs). This will be a national study conducted through the Alliance for Clinical Trials in Oncology cooperative group mechanism. ACC is one of the most common histologic subtypes of salivary cancers, and R/M ACC is an incurable disease with no standard treatments. New therapies are urgently needed for this patient population. The recent discovery of a unique t(6;9) translocation in a significant proportion of ACC tumors has provided a primary genetic driver of ACC tumorigenesis at which therapeutic strategies may now be directed. Specifically, the translocation involves the creation of a fusion gene (MYB-NFIB) that results in the marked overexpression of c-myb, an oncogenic transcription factor that activates a transcriptional program critical to the biology of several malignancies. While over 70% of all ACCs overexpress MYB, it is virtually undetectable in either normal salivary tissue or other salivary cancers. Without validated ACC experimental models with which to explore strategies for MYB targeting, we developed a cell line model expressing either full-length MYB or the MYB-NFIB fusion and discovered that Akt inhibition with the allosteric small molecule inhibitor MK-2206 (Merck) effectively downregulates c-myb levels. We hypothesized that this would be a novel strategy for clinically targeting c-myb in ACC. In collaboration with CTEP, we have developed a phase II clinical trial evaluating MK-2206 in patients with progressive, R/M ACC based upon this hypothesis. In this application, we propose to evaluate the clinical efficacy of MK-2206 in the treatment of ACC patients (Specific Aim #1), explore potential molecular and pathologic predictors of objective response to MK-2206 (Specific Aim #2), and analyze pre- and post-MK- 2206 treatment biopsies in order to test our preclinical hypothesis that MK-2206 inhibition of Akt in ACC tumors translates to clinical responses (Specific Aim #3). Such work will not only guide the development of future ACC studies, but will also validate c-myb overexpression as a marker of tumor susceptibility to Akt targeting strategies that can be applied to other cancers that overexpress MYB.

描述（由申请人提供）：这是一项新的 3 年 R01 申请，涉及美国国家癌症研究所 (NCI/CTEP) 的癌症治疗评估计划，授予 Akt 抑制剂 MK-2206 在进行性、复发性/转移性腺样囊性癌（R/M ACC）。这将是通过肿瘤临床试验联盟合作组机制进行的一项全国性研究。 ACC 是唾液腺癌最常见的组织学亚型之一，而 R/M ACC 是一种无法治愈的疾病，没有标准的治疗方法。该患者群体迫切需要新的疗法。最近在相当大比例的 ACC 肿瘤中发现了独特的 t(6;9) 易位，这提供了 ACC 肿瘤发生的主要遗传驱动因素，现在可以针对该驱动因素制定治疗策略。具体来说，易位涉及融合基因 (MYB-NFIB) 的产生，导致 c-myb 显着过度表达，c-myb 是一种致癌转录因子，可激活对多种恶性肿瘤生物学至关重要的转录程序。虽然超过 70% 的 ACC 过表达 MYB，但在正常唾液组织或其他唾液癌中几乎检测不到 MYB。由于没有经过验证的 ACC 实验模型来探索 MYB 靶向策略，我们开发了表达全长 MYB 或 MYB-NFIB 融合体的细胞系模型，并发现变构小分子抑制剂 MK-2206 (Merck) 可有效抑制 Akt下调 c-myb 水平。我们假设这将是临床上针对 ACC 中 c-myb 的一种新策略。基于这一假设，我们与 CTEP 合作开发了一项 II 期临床试验，评估 MK-2206 在进展性 R/M ACC 患者中的作用。在此应用中，我们建议评估 MK-2206 治疗 ACC 患者的临床疗效（具体目标 #1），探索 MK-2206 客观反应的潜在分子和病理预测因子（具体目标 #2），并分析MK-2206 治疗前和治疗后活检，以测试我们的临床前假设，即 ACC 肿瘤中 MK-2206 对 Akt 的抑制转化为临床反应（具体目标＃3）。此类工作不仅将指导未来 ACC 研究的发展，还将验证 c-myb 过表达作为肿瘤对 Akt 靶向策略敏感性的标志物，该策略可应用于其他过表达 MYB 的癌症。

项目成果

Phase II Study of Lenvatinib in Patients With Progressive, Recurrent or Metastatic Adenoid Cystic Carcinoma.

Lenvatinib 在进展性、复发性或转移性腺样囊性癌患者中的 II 期研究。

• 发表时间: 2019
• 作者: Tchekmedyian, Vatche;Sherman, Eric J;Dunn, Lara;Tran, Crystal;Baxi, Shrujal;Katabi, Nora;Antonescu, Cristina R;Ostrovnaya, Irina;Haque, Sofia S;Pfister, David G;Ho, Alan L
• 通讯作者: Ho, Alan L