Genomic Approaches to Breast Cancer Subset Identification and Treatment

基因组和转录研究现已完成，这些研究将人类乳腺肿瘤分解成不同的亚群，这些亚群的进展和对激进化疗的反应不同。被指定为腔/放大和基底的乳腺肿瘤亚型对积极的化疗反应最差，所以我们现在的目标是开发针对这两个亚型的更有效的治疗方法。这将通过三个具体目标的工作来实现。目的1.一种自动化、高通量的方法将被用来评估在二维培养中生长的50个乳腺癌细胞系中的大约100种FDA批准的和实验药物(包括那些在其他孢子项目中开发的药物)的反应，以确定对基础和腔/放大亚型特别有效的药物。药物将根据基础和腔/放大子类型的相对有效性进行排序。在这两个亚群中表现出高效的那些将在本项目中开发的其他乳腺癌细胞系中进一步评估，然后在代表基础和腔/放大亚型的3D培养中进行评估。最有效的基础特定药物将被传递给孢子项目3，包装成纳米颗粒结构，专门将它们输送到基础肿瘤细胞和/或通过我们的I-SPY新佐剂网络在新试验中作为现有药物进行测试或在高级临床试验中进行测试。目的2.将发展与CLIA兼容的多基因分子分析方法，以确定最能利用目标1中确定的药物和药物结构攻击的鲁米纳/放大因子和基本亚型，以指导这些药物在临床试验中的部署。在最后一个项目阶段开发的多基因分析将通过福尔马林固定石蜡的分析来改进 从孢子组织和结果核心嵌入样本，然后在新佐剂I-SPY 1试验的237个样本中验证，并在I-SPY 1修正案试验产生的114个新样本中进一步验证。一旦确定了基础和腔/放大亚型特定药物，将改进多变量分析以预测个别药物的反应。目的3.将评估影响对目标1中选择的药物的反应/耐药性的分子机制/途径，以促进协同药物的选择和指导耐药机制的阐明。

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.