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

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）的癌症治疗评估项目，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 ACCs）患者中的II期研究。这将是一项通过肿瘤临床试验联盟合作小组机制进行的全国性研究。ACC是唾液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。这一患者群体迫切需要新的治疗方法。最近在相当比例的ACC肿瘤中发现了一种独特的t（6;9）易位，这为ACC肿瘤发生提供了主要的遗传驱动因素，现在可以指导治疗策略。具体来说，易位涉及融合基因（MYB-NFIB）的产生，导致c-myb的显著过表达，c-myb是一种致癌转录因子，可激活对几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。在没有经过验证的ACC实验模型来探索MYB靶向策略的情况下，我们建立了表达全长MYB或MYB- nfib融合的细胞系模型，并发现变构小分子抑制剂MK-2206（默克）抑制Akt有效下调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合作开展了一项II期临床试验，评估MK-2206在进行性R/M型ACC患者中的作用。在本申请中，我们建议评估MK-2206治疗ACC患者的临床疗效（Specific Aim #1），探索MK-2206客观反应的潜在分子和病理预测因素（Specific Aim #2），并分析MK-2206治疗前后的活检，以验证我们的临床前假设，即MK-2206抑制ACC肿瘤中Akt转化为临床反应（Specific Aim #3）。这项工作不仅将指导未来ACC研究的发展，而且将验证c-myb过表达作为肿瘤对Akt靶向策略易感性的标志，可应用于其他MYB过表达的癌症。

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. PUBLIC HEALTH RELEVANCE: Adenoid cystic carcinomas are tumors that commonly arise from the salivary glands. Despite surgery and radiation, patients with this disease will commonly experience incurable cancer recurrences for which no effective therapies exist. The goals of this project are to develop a novel drug treatment for adenoid cystic carcinoma and to increase our understanding of this disease in order to facilitate future research efforts focused on discovering new therapies for these patients.