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，这些亚群对侵袭性化疗的进展和反应不同。乳腺肿瘤亚型称为管腔/放大器和基底对侵袭性化疗的反应最差，因此我们现在的目标是开发针对这两种亚型的更有效的疗法。这将通过三个具体目标的工作来实现。目标1.将使用自动化高通量方法来评估在二维培养物中生长的>50个乳腺癌细胞系的集合中对约100种FDA批准的和实验性药物（包括在其他SPORE项目中开发的那些）的响应，以鉴定对基底和管腔/放大器亚型特别有效的药物。药物将根据基础和管腔/放大器亚型的相对有效性进行排名。将在本项目开发的其他乳腺癌细胞系中进一步评价在这些亚群中表现出高疗效的细胞，然后在代表基底和管腔/放大器亚型的3D培养物中进行评价。最有效的基底特异性药物将被传递到SPORE项目3，用于包装成纳米颗粒结构，将它们特异性地递送到基底肿瘤细胞和/或通过我们的I-SPY新辅助网络在新试验中或在高级临床试验中作为现有药物进行测试。目标2.将开发CLIA兼容的多基因分子测定，其定义可使用目标1中确定的药物和药物构建体最佳攻击的管腔/放大器和基础亚型，以指导这些药物在临床试验中的部署。将通过福尔马林固定石蜡的分析来完善在上一个项目期间开发的多基因测定 从孢子组织和结果核心包埋样本，然后在新辅助I-SPY 1试验的237个样本中验证，并在I-SPY 1修正试验产生的114个新样本中进一步验证。一旦确定了基础和管腔/放大器亚型特异性药物，将对多变量测定进行优化，以预测个体药物反应。目标3：将评估影响对目标1中所选药物的应答/耐药性的分子机制/途径，以促进协同药物的选择并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 basal-specific 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.