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

描述(申请人提供)：这是一项新的为期3年的R01申请，涉及美国国家癌症研究所(NCI/CTEP)癌症治疗评估计划(NCI/CTEP)授予的Akt抑制剂MK-2206在进展性、复发性/转移性腺样囊性癌(R/M ACCs)患者中的第二阶段研究。这将是一项通过肿瘤学临床试验联盟合作小组机制进行的全国性研究。ACC是涎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。对于这一患者群体，迫切需要新的疗法。最近在相当大比例的ACC肿瘤中发现了一种独特的t(6；9)易位，这为ACC肿瘤的发生提供了一个主要的基因驱动因素，治疗策略现在可能被定向。具体地说，易位涉及创建融合基因(MYB-NFIB)，导致c-MYB的显著过表达，c-MYB是一种癌基因转录因子，激活对几种恶性肿瘤的生物学至关重要的转录程序。虽然超过70%的AC细胞过度表达MYB，但在正常唾液组织或其他唾液癌组织中几乎检测不到MYB。在没有有效的ACC实验模型来探索MYB靶向策略的情况下，我们建立了一个表达全长MYB或MYB-NFIB融合的细胞系模型，发现变构小分子抑制剂MK-2206(Merck)对Akt的抑制有效地下调了c-myb水平。我们假设这将是一种针对ACC中c-myb的临床靶向的新策略。根据这一假设，我们与CTEP合作，开发了一项II期临床试验，评估MK-2206在进行性R/M ACC患者中的应用。在这项应用中，我们建议评估MK-2206治疗ACC患者的临床疗效(特定目标#1)，探索对MK-2206客观反应(特定目标#2)的潜在分子和病理预测因素，并分析MK-2206治疗前和治疗后的活检组织，以验证我们的临床前假设，即MK-2206抑制ACC肿瘤中的Akt可转化为临床反应(特定目标#3)。这项工作不仅将指导未来ACC研究的发展，还将验证c-myb过度表达作为肿瘤对Akt靶向策略的易感性的标记，该策略可应用于其他过度表达myb的癌症。 公共卫生相关性：腺样囊性癌是通常发生在唾液腺的肿瘤。尽管进行了手术和放射治疗，但患有这种疾病的患者通常会经历无法治愈的癌症复发，而且没有有效的治疗方法。这个项目的目标是开发一种治疗腺样囊性癌的新药物，并增加我们对这种疾病的了解，以便促进未来专注于发现 针对这些患者的新疗法。

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.