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R 01申请，涉及美国国家癌症研究所（NCI/CTEP）的癌症治疗评价项目，该项目授予Akt抑制剂MK-2206在进行性、复发性/转移性腺样囊性癌（R/MACs）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组机制进行的国家研究。ACC是涎腺癌中最常见的组织学亚型之一，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。最近发现的一个独特的t（6;9）易位在一个显着比例的ACC肿瘤提供了一个主要的遗传驱动程序ACC肿瘤的治疗策略，现在可以针对。具体而言，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腺癌中几乎检测不到。在没有经验证的ACC实验模型来探索MYB靶向策略的情况下，我们开发了表达全长MYB或MYB-NFIB融合体的细胞系模型，并发现用变构小分子抑制剂MK-2206（Merck）抑制Akt有效地下调c-myb水平。我们假设，这将是一个新的战略，在ACC临床靶向c-myb。在CTEP合作，我们已经开发了一个II期临床试验，评估MK-2206在进行性，R/M ACC患者基于这一假设。在本申请中，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客观缓解的潜在分子和病理学预测因素（具体目标#2），并分析MK- 2206治疗前后的活检，以检验我们的临床前假设，即MK- 2206治疗前后的活检，2206 ACC肿瘤中Akt的抑制转化为临床反应（具体目标#3）。这项工作不仅将指导未来ACC研究的发展，而且还将验证c-myb过表达作为肿瘤对Akt靶向策略敏感性的标志物，该策略可应用于过表达MYB的其他癌症。 公共卫生相关性：腺样囊性癌是一种常见于唾液腺的肿瘤。尽管有手术和放射治疗，患有这种疾病的患者通常会经历无法治愈的癌症复发，对此没有有效的治疗方法。该项目的目标是开发一种治疗腺样囊性癌的新药，并增加我们对这种疾病的了解，以促进未来的研究工作，重点是发现 新的治疗方法。

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.