Genome-Guided Therapeutic Vulnerabilities in Esophageal Cancer

项目3摘要 食道癌是一种常见病、致命性疾病，治疗方法不足。系统性治疗仍在继续 依靠经验性化疗，在姑息性环境下单独给予，并结合放射治疗 辅助性护理。我们关于癌症基因组的快速增长的知识和 无数靶向药物的开发创造了一个新的独特的机会来推动Rational， 生物标记物驱动的食道癌治疗。我们对食道癌的基因组研究 确定了两类主要的靶标：针对受体酪氨酸激酶的高重复扩增， 最常见的是EGFR和ERBB2(Her2)，以及放大的细胞周期调节器，Cyclin D1，Cyclin E1和 CDK6。尽管这些靶点以及现有的和正在出现的抑制物具有强大的基因组学基础，但我们缺乏 临床前数据，以指导开发战略，以开发这些目标。因此，我们建议 开发靶向受体酪氨酸基因改变的食道癌的策略 利用体内外基因组学特征的模型系统研究细胞周期调节因子和蛋白激酶 治疗剂的测试。我们将测试有关靶向肿瘤的方法的假设，这两种方法都是 有针对性的治疗和合理的组合。在整个提案中，我们将努力与其他方案相结合 本项目中的项目通过本项目授予和广泛使用核心资源并进行评估 针对食管鳞癌和食管腺癌的有针对性的策略。在……里面 目的1，我们建议通过评估细胞周期蛋白CDK2作为食道癌的治疗靶点。 在食道癌基因组模型中利用遗传学和药理学手段评估这一靶点 使它们更有可能依赖CDK2的病变，编码细胞周期蛋白D1和 细胞周期蛋白E1.在目标2中，我们评估了不同类别的小分子和抗体酪氨酸激酶抑制剂。 具有导致ERBB家族致癌活性的基因组改变的食道癌模型系统 EGFR和ERBB2的激活酶。此外，在目标2中，我们还测试了增强ERBB导向效应的能力 联合应用MAPK或PI3-K通路抑制剂治疗食道癌模型。 最后，在目标3中，我们评估了我们观察到的食道癌通常存在的现象。 基因组异常影响同一肿瘤中的细胞周期介体和ERBB家族激酶， 这表明联合使用这两组靶点的抑制剂可能对这些肿瘤有效。我们 因此建议刻画这些靶标在这些病毒基因组中共存的模式 癌症及其在大量组织样本中的共同表达。此外，我们还将利用 EGFR和Cyclin D1共扩增食道癌模型的系统评价 将抑制剂组合到这些途径的不同方法。这三个目标加在一起就是为了追求 使我们能够更快、更有效地开发新的治疗策略的具体假设 对于患有这些致命疾病的患者。

PROJECT 3 ABSTRACT Esophageal cancer is a common and deadly disease with inadequate therapies. Systemic therapy remains reliant upon empiric chemotherapy, given alone in the palliative setting and in conjunction with radiation for adjuvant care. The convergence of our rapidly expanding knowledge of the cancer genome and the development of a myriad of targeted agents has created a new and unique opportunity to advance rational, biomarker-driven therapies for esophageal cancer. Our genomic studies of esophageal cancers have identified two dominant classes of targets: highly recurrent amplifications targeting receptor tyrosine kinases, most frequently EGFR and ERBB2 (Her2), and amplified modulators of the cell cycle, Cyclin D1, Cyclin E1 and CDK6. Despite strong genomic rationale for these targets and the available and emerging inhibitors, we lack pre-clinical data to guide the development strategies to exploit these targets. Therefore, we propose to develop strategies to target esophageal cancers harboring targetable genomic alterations of receptor tyrosine kinases and of cell cycle mediators utilizing genomically-characterized model systems in in vitro and in vivo testing of therapeutic agents. We will tests hypotheses regarding means to target tumors, both with single targeted therapies and with rational combinations. Throughout this proposal, we integrate efforts with the other projects in this Project Grant and make extensive use of core resources through this Project and evaluate targeted strategies that for both esophageal squamous cell carcinoma and esophageal adenocarcinoma. In Aim 1, we propose to evaluate the cell cycle kinase CDK2 as a therapeutic target in esophageal carcinomas by evaluating this target using genetic and pharmacologic tools in esophageal cancer models with genomic lesions that make them more likely dependent upon CDK2, amplifications of genes encoding cyclin D1 and cyclin E1. In Aim 2, we evaluate distinct classes of small molecule and antibody tyrosine kinase inhibitors in esophageal cancer model systems with genomic alterations leading to oncogenic activation of ERBB family kinases EGFR and ERBB2. Furthermore, in Aim 2 we also test the ability to augment effects of ERBB-directed therapy in esophageal cancer models by combinations with inhibitors of either the MAPK or PI3-K pathway. Finally, in Aim 3 we evaluate the phenomena we have observed that esophageal cancers often harbor genomic aberrations impacting both cell cycle mediators and ERBB-family kinases in the same tumor, suggesting that combining inhibitors of these two sets of targets may be efficacious for these tumors. We therefore propose to characterize the patterns of co-occurrence of these targets in the genomes of these cancers and their co-expression in a large panel of tissue samples. Additionally, we will utilize the example of esophageal cancer models with co-amplification of both EGFR and Cyclin D1 to systematically evaluate distinct methods of combing inhibitors to these pathways. Together, these three aims are designed to pursue specific hypotheses that will allow us to much more rapidly develop new more effective therapeutic strategies for patients with these deadly diseases.