Genomic Approaches to Breast Cancer Subset Identification and Treatment

基因组和转录研究现已完成，将人类乳腺肿瘤分解为 不同的亚群，进展和反应不同的侵略性化疗。乳腺肿瘤 指定为管腔/放大器和基底的亚型对侵袭性化疗的反应最差，因此我们的目标是 现在是开发针对这两种亚型的更有效的疗法。这将通过以下方式实现： 在三个具体目标下开展工作。目标1。将使用自动化、高通量方法评估 对约100种FDA批准和实验性药物（包括在其他SPORE开发的药物）的反应 在二维培养物中生长的>50个乳腺癌细胞系的集合中， 对基底和管腔/放大器亚型特别有效的药物。药物将根据 基底和管腔/放大器亚型的相对有效性。那些在以下任一方面表现出高疗效的药物 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 然后在代表基底和管腔/放大器亚型的3D培养物中。最有效的基底特异性 药物将被传递到孢子项目3，用于包装成纳米颗粒结构， 它们专门针对基底肿瘤细胞和/或通过我们的I-SPY在新试验中作为现有药物进行测试 新辅助治疗网络或先进的临床试验。目标2. CLIA兼容的多基因分子检测将 开发定义管腔/放大器和基础亚型，可以使用药物最好地攻击， 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应用。多基因 将通过分析福尔马林固定石蜡， 来自SPORE组织和结局核心的包埋样本，然后在来自 新辅助I-SPY 1试验，并在I-SPY 1产生的114个新样本中进一步验证 修正案审判。一旦基础和管腔/放大器亚型特异性药物被鉴定， 将改进分析以预测个体药物反应。目标3.分子机制/途径， 将评估对目标1所选药物的影响反应/耐药性，以促进选择 并指导阐明耐药机制。

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.