Genomic Approaches to Breast Cancer Subset Identification and Treatment

基因组和转录研究现已完成，可将人类乳腺肿瘤分解为 进展和对激进化疗反应不同的不同亚群。乳房肿瘤 被指定为管腔/放大和基底的亚型对激进化疗的反应最差，所以我们的目标是 现在是针对这两种亚型开发更有效的治疗方法。这将通过以下方式实现 努力实现三个具体目标。目标1.将使用自动化、高吞吐量方法来评估 对-100种FDA批准的和实验药物(包括在其他孢子中开发的药物)的反应 项目)在二维培养中生长的50个乳腺癌细胞系的集合中，以确定 对基础亚型和腔/放大亚型特别有效的药物。将对药品进行排名 基本类型和腔/放大子类型的相对有效性。那些在以下两种情况下都表现出高效率的 这些亚群将在本项目开发的其他乳腺癌细胞系中进一步评估。 然后在3D培养中，代表基本和腔/放大亚型。最有效的特定于基线的 药物将被传递给孢子项目3，用于包装成纳米颗粒结构，从而提供 它们特异性地作用于基底肿瘤细胞和/或通过我们的I-SPY在新的试验中作为现有药物进行测试 新佐剂网络或高级临床试验。目的2.CLIA兼容的多基因分子分析将 定义管腔/放大器和最容易被药物和药物攻击的基本亚型 目标1中确定的药物结构，以指导这些药物在临床试验中的部署。多基因 将通过分析福尔马林固定石蜡来改进在上一个项目期间开发的分析方法 从孢子组织和结果核心中嵌入样本，然后在237个样本中进行验证 新佐剂I-SPY 1试验，并在由I-SPY 1产生的114个新样本中进一步验证 修正审判。一旦确定了基础药物和腔/放大子亚型特定药物，多变量 检测方法将被改进，以预测个别药物的反应。目标3.分子机制/途径 将评估对目标1中选择的药物的影响反应/抗药性，以便于选择 对增效药物的研究和指导耐药性机制的阐明。

Genomic and transcriptional studies have now been completed that resolve human breast tumors into distinct subpopulations that progress and respond differently to aggressive chemotherapy. The breast tumor subtypes designated luminal/amplifier and basal respond least well to aggressive chemotherapy so our goal now is to develop more effective therapies against these two subtypes. This will be accomplished through work in three specific aims. Aim 1. An automated, high throughput approach will be used to assess responses to -100 FDA approved and experimental drugs (including those developed in other SPORE projects) in a collection of >50 breast cancer cell lines grown in two dimensional cultures in order to identify drugs that are particularly effective against the basal and luminal/amplifier subtypes. Drugs will be ranked for relative effectiveness in the basal and luminal/amplifier subtypes. Those that show high efficacy in either of these subpopulations will be further evaluated in additional breast cancer cell lines developed in this project and then in 3D cultures representative of the basal and luminal/amplifier subtypes. The most effective basalspecific drugs will be passed to the SPORE Project 3 for packaging into nanoparticle constructs that deliver them specifically to the basal tumor cells and/or tested as existing drugs in new trials via our I-SPY neoadjuvant network or in advanced clinical trials. Aim 2. CLIA compatible multi-gene molecular assays will be developed that define the luminal/amplifier and basal subtypes that can best be attacked using drugs and drug constructs identified in aim 1 in order to guide deployment of these drugs in clinical trials. Multi-gene assays developed in the last project period will be refined through analysis of formalin fixed paraffin embedded samples from the SPORE Tissue and Outcomes Core and then validated in 237 samples from the neoadjuvant I-SPY 1 Trial and further validated in 114 new samples resulting from the I-SPY 1 Amendment trial. Once basal and luminal/amplifier subtype specific drugs are identified, the multivariate assays will be refined to predict individual drug responses. Aim 3. Molecular mechanisms/pathways that influence response/resistance to the drugs selected in aim 1 will be assessed in order to facilitate selection of synergistic drugs and to guide elucidation of mechanisms of resistance.