Genomic Approaches to Breast Cancer Subset Identification and Treatment
Principal Investigator - Joe W. Gray, PhD
Clinical Co-Principal Investigator - Laura Esserman, MD, MBA
Advocate: Linda Vincent, Susan Samson
Genomic and transcriptional studies resolve human breast tumors into subpopulations with distinct molecular features that progress and respond differently to aggressive chemotherapy. Breast tumor subtypes designated luminal/amplifier and basal respond least well to aggressive chemotherapy, so our goals are now to develop more effective therapies against these two subtypes and to identify specific molecular markers that stratify between responders and non responders within these subgroups. These goals will be pursued in three aims.
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 effective against the basal or 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 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 basal tumor targeted nanoparticle constructs and/or tested as existing drugs in new trials via our I-SPY neoadjuvant network or in advanced clinical trials.
CLIA compatible multi-gene assays of transcription levels and/or genomic aberrations will be developed to guide clinical deployment of these drugs tested in aim 1. Transcriptional assays will use the Panomics branch capture platform for analysis of formalin fixed paraffin embedded (FFPE) samples. Initial priority will be given to assessment of markers for: (a) Basal and luminal/amplifier subtypes. These will be tested in samples from the neoadjuvant I-SPY 1 trial and further assessed in new samples resulting from the I-SPY 1 Amendment trial. (b) Markers to predict response to lapatinib, paclitaxel and/or capecitabine. These will be tested in four lapatinib based clinical trials; EGF20009 (ERBB2-positive patients treated with single-agent lapatinib), EGF30001 (ERBB2-positive and negative patients treated with lapatinib plus paclitaxel vs. paclitaxel only), EGF105764 (ERBB2-positive patients treated with lapatinib plus paclitaxel), EGF100151 (ERBB2-positive patients treated with lapatinib plus capecitabine vs. capecitabine) and EGF30008 (ERBB2 positive and negative patients treated with letrozole plus lapatinib vs. letrozole only). (c) Markers predicting response to the AKT inhibitor GSK690693. These will tested in collaboration with investigators at GlaxoSmithKline in early Phase II trials.
Molecular mechanisms/pathways that influence response/resistance to the drugs selected in aim 1 will be assessed in order to elucidate mechanisms of resistance and response and to facilitate selection of synergistic drugs.