Identification of druggable targets for triple-negative breast cancer

描述（由申请人提供）：基因组分析将乳腺癌分子分类为几种亚型，包括两种来源于雌激素受体（ER）阳性肿瘤（腔内A和B）和两种来源于雌激素受体阴性肿瘤（基底样和her2阳性）。对激素受体阳性或基因扩增（如HER2）的乳腺癌患者进行识别和预先选择，已经转化为更个性化的治疗，显著提高了患者的生存率。相比之下，三阴性乳腺癌，即雌激素和孕激素受体表达阴性和HER2基因扩增阴性的肿瘤，具有独特的基因表达谱，分子分类为基底样，总体预后较差，并且在化疗无反应的患者中复发率高。我们迫切需要更好地了解这类乳腺癌的分子基础，并开发新的治疗策略。提出的研究的直接目标是确定和验证调节三阴性乳腺癌生存和药物敏感性的可药物基因靶点。功能丧失筛选可以识别参与肿瘤细胞生存和药物敏感性的分子途径。我们进行了一个试点功能丧失筛选，以确定确定三阴性乳腺癌候选药物基因靶点的可行性。基于初步数据，我们假设参与三阴性乳腺癌增殖和存活的基因产物（靶标）以及增强这些癌细胞化疗敏感性的靶标可以被识别和验证。为了验证这一假设，提出了两个目标。在第一个目标中，将使用可药物的基因组siRNA文库进行功能丧失筛选，以确定三阴性乳腺癌细胞增殖和存活所需的基因靶标，以及那些使细胞对紫杉醇或顺铂敏感的基因靶标。在Aim 2中，分子药物靶点将被验证和分析，以确定基因靶点在细胞增殖、存活和肿瘤发生中的作用，以及它们是否可以作为三阴性肿瘤药物反应的标志物。候选基因靶点和相关的药理学抑制剂选择基因产物和途径将与紫杉醇和/或顺铂联合使用三阴性肿瘤发生和对各种药物的敏感性进行验证和测试。此外，候选靶点将被评估作为对三阴性疾病患者治疗反应的潜在标记物。公共卫生相关性：拟议研究的发现将为未来的临床试验提供信息，以研究针对三阴性乳腺癌患者的新型单药和联合疗法。

DESCRIPTION (provided by applicant): Genomic analyses have molecular classified breast cancers into several subtypes, including two derived from estrogen receptor (ER)-positive tumors (luminal A and B) and two derived from ER-negative tumors (basal-like and HER2-positive). Identification and pre-selection of breast cancer patients with hormone receptor-positive or gene amplifications, such as HER2, has translated into more personalized therapy with significant improvements in patient survival. In contrast, triple-negative breast cancers, tumors that are negative for estrogen and progesterone receptor expression and HER2 gene amplification, have a distinct gene expression profile, are molecularly classified as basal-like, exhibit a poor overall prognosis and have a high relapse rate in those patients that do not respond to chemotherapy. There is a major need to better understand the molecular basis of this type of breast cancer as well as develop new therapeutic strategies against it. The immediate goal of the studies proposed is to identify and validate druggable gene targets that regulate survival and drug sensitivity of triple-negative breast cancers. Loss-of function screening can identify molecular pathways involved in the survival and drug sensitivity of tumor cells. We conducted a pilot loss-of-function screen to determine the feasibility of identifying candidate druggable gene targets for triple-negative breast cancer. Based on preliminary data, we hypothesize that gene products (targets) involved in proliferation and survival of triple-negative breast cancers as well as targets that enhance chemo-sensitivity of these cancer cells can be identified and validated. Two aims are proposed to test this hypothesis. In the first aim, a loss-of-function screen will be performed using a druggable genome siRNA library to identify gene targets required for the proliferation and survival of triple-negative breast cancer cells as well as those that sensitize the cells to taxol or cisplatin. In Aim 2 molecular drug targets will be validated and analyzed to determine the role the gene targets play in cell proliferation, survival, and tumorigenesis and if they can serve as markers of drug response in triple-negative tumors. Candidate gene targets and associated pharmacological inhibitors of select gene products and pathways will be validated and tested in combination with taxol and/or cisplatin using a panel of triple-negative tumorigenesis and sensitivity to various drugs. Also, candidate targets will be assessed for their use as potential markers of response to treatment of patients with triple-negative disease. PUBLIC HEALTH RELEVANCE: Discoveries from the proposed research will inform future clinical trials to investigate novel single agent and combination therapies for patients with triple-negative breast cancer.