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