Epigenetic changes and phenotype-specific therapeutic strategies in breast cancer

描述（由申请人提供）： 乳腺癌是一种异质性疾病。 新疗法开发和测试的一个重大挑战是确定药物将靶向哪些肿瘤。对一类新型表观遗传途径小分子抑制剂的初步研究显示了对某些乳腺癌的治疗反应性。在这里，我们建议调查表观遗传学的变化，其表达模式已被认为是在全球范围内的乳腺癌的不同分子表型的基础。我们希望确定哪些乳腺癌的分子表型将被特定的表观遗传途径抑制剂靶向。在这个提议中，我们将使用携带六种不同组蛋白脱乙酰酶（HDAC）或DNA甲基转移酶（DNMT）家族成员基因的腺病毒激活正常人乳腺上皮细胞中不同的表观遗传途径，以定义六种途径表达特征，其特征在于激活和沉默基因的全系统模式。将针对六种表观遗传途径特征中的每一种查询一组超过1800种乳腺癌，按分子表型（例如基底、管腔）分组，以发现在每种表型中失调的特定表观遗传途径。接下来，我们将确定哪种药物最好地治疗乳腺癌的不同表型。将用六种不同的HDAC和DNMT抑制剂处理代表乳腺癌的不同分子表型的细胞系。体外药物反应与分子表型的关联将用于预测体内肿瘤反应。为此，我们将使用新鲜的人类肿瘤，通过微阵列分析分类并原位植入免疫功能低下的小鼠中，以创建一组肿瘤特异性异种移植模型，这些模型代表乳腺癌最具侵袭性的分子表型：基底，ERBB2过表达和高度增殖的管腔。我们将在小鼠模型上测试相同的六种HDAC和DNMT抑制剂，并测量它们和常规化疗剂（阿霉素）抑制肿瘤生长的效果，验证体内模型系统中的体外预测。我们希望我们的研究结果将为启动人体试验提供临床前证据，该试验采用更集中的方法来使用表观遗传过程的小分子抑制剂，方法是定义给定药物应该靶向的乳腺癌的特定表型，而不是在所有乳腺癌上测试该药物。该提案将展示肿瘤生物学和基因组特征如何转化为个性化癌症治疗策略。

DESCRIPTION (provided by applicant): Breast cancer is a heterogeneous disease. A significant challenge in the development and testing of new therapies is determining which tumors a drug will target. Initial studies with a novel class of small molecule inhibitors of epigenetic pathways show therapeutic responsiveness in some breast cancers. Here, we propose to investigate the epigenetic changes that underlie diverse molecular phenotypes of breast cancer whose expression patterns have been previously considered on a global scale. We hope to identify which molecular phenotypes of breast cancer will be targeted by specific epigenetic pathway inhibitors. In this proposal, we will activate different epigenetic pathways in normal human mammary epithelial cells using adenoviruses carrying six different histone deacetylase (HDAC) or DNA methyltransferase (DNMT) family member genes to define six pathway expression signatures, characterized by system-wide patterns of activated and silenced genes. A set of over 1800 breast cancers, grouped by molecular phenotype (e.g. basal, luminal), will be queried for each of the six epigenetic pathway signatures to discover the specific epigenetic pathways that are deregulated in each phenotype. Next, we will determine which drugs best treat different phenotypes of breast cancer. Cell lines representing different molecular phenotypes of breast cancer will be treated with six different HDAC and DNMT inhibitors. The association of drug response to molecular phenotype in vitro will be used to predict tumor response in vivo. To do this, we will use fresh human tumors, classified by microarray analysis and orthotopically implanted in immunocompromised mice, to create a panel of tumor-specific xenograft models that represent the most aggressive molecular phenotypes of breast cancer: basal, ERBB2-overexpressing, and highly proliferating luminals. We will test the same six HDAC and DNMT inhibitors on the mouse models and measure how well they and a conventional chemotherapeutic agent (doxorubicin) inhibit tumor growth, verifying the in vitro predictions in an in vivo model system. We hope that our results will provide preclinical evidence for the initiation of a human trial that employs a more focused approach to the use of small molecule inhibitors of epigenetic processes by defining specific phenotypes of breast cancer that a given drug should target rather than testing that drug on all breast cancers. This proposal should demonstrate how tumor biology and genomic signatures can be translated into strategies for personalized cancer treatment.