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Development of Marlers that Predict Resistance to Omnitarg in Breast Cancer
BACKGROUND: Deregulation of receptor tyrosine kinase (RTK) signaling alters growth, division, differentiation, adhesion, motility, and apoptosis in many breast cancers. Amplification and over expression of ERBB2 is a significant deregulating event in ~30 % of breast cancers. Two antibody-therapies, Herceptin/trastuzumab and Omnitarg(2C4)/pertuzumab, targeting different parts of the ERBB2 receptor have been generated to inhibit ERBB2 signaling. Herceptin is now in routine clinical use for treatment of metastatic breast cancers that over express ERBB2. Omnitarg, is a next generation agent designed sterically hinder recruitment of ERBB2 into ERBB ligand complexes. Preclinical studies suggest that Omnitarg may be effective in tumors that do not over express ERBB2 but insufficient effort has been given to identifying markers that can be used to identify subsets of patients that are most likely to respond. OBJECTIVES/HYPOTHESIS: Our objective is to develop markers that predict Omnitarg resistance through comprehensive biological and molecular analyses of cellular responses to Omnitarg in a set of 55 breast cancer cell lines carrying same spectrum of genetic aberrations and heterogeneity as primary tumors. We will focus our marker discovery efforts on interacting RTK signaling pathway members since aberrations involving these pathways are known to influence response to Herceptin. SPECIFIC AIMS: 1) To identify up- and downregulated RTK pathway genes associated with the development of Omnitarg resistance. 2) To validate Omnitarg resistance genes identified in Aim 1 in vitro. 3) To evaluate utility of Omnitarg resistance markers in predicting responses to Omnitarg in vivo. STUDY DESIGN: RNA and protein expression profiles will be measured for 55 breast cancer cell lines and associated with biological responses to Omnitarg including proliferation, apoptosis, motility and mitotic index. Omnitarg-resistance associated genes will be modulated using shRNA technology to block upregulated genes and cDNA expression vectors to increase expression of downregulated genes. Genes whose modulation affects response to Omnitarg in vitro will be further tested for predictive utility in human breast cancer xenografts in vivo. Potential OUTCOMES AND BENEFITS OF THE RESEARCH: Markers that accurately predict response can be used to focus later phase clinical trials on tumors most likely to respond. If Omnitarg is eventually approved for routine clinical use, predictive markers can be used to identify individual patients that will benefit from treatment.
Breast cancer is a leading cause of cancer death in women of the western world but new molecularly targeted therapeutic agents show promise of significantly reducing mortality. Cellular receptor tyrosine kinases (RTK) and their interacting signaling pathway members normally regulate vital cellular functions including proliferation, structural organization, and death. Unfortunately, deregulation of RTKs plays a causal role in many breast cancers. Molecular comparisons of cells from cancer patients and from normal individuals have revealed differences in RTK signaling that can be targeted therapeutically. However, breast tumors are remarkably heterogeneous so that not all respond to therapeutic RTK pathway inhibitors as expected. For example, less than 30% of patients that over express ERBB2 will respond to the anti-ERBB2 therapeutic agent, Herceptin. We propose here to develop markers of resistance to a new ERBB pathway therapeutic agent, Omnitarg(2C4)/pertuzumab, that is now being evaluated in phase II clinical trials. Predictive markers can be used to focus later phase clinical trials on tumors most likely to respond. If Omnitarg is eventually approved for routine clinical use, predictive markers can be used to identify patients that will benefit most from treatment. We will identify predictive molecular markers by measuring molecular and cellular responses to Omnitarg in 55 breast cancer cell lines grown in vitro. We have already shown that these lines represent both the recurrent aberrations and the heterogeneity found in primary human tumors. We will evaluate surface RTKs and downstream signaling pathway components as possible markers that predict Omnitarg resistance since aberrations involving these pathways are known to influence response to Herceptin in ERBB2 positive breast cancers. Changes in gene expression that we find to be associated with resistance to Omnitarg will be validated by determining whether sensitivity to Omnitarg is altered when expression levels of these genes are manipulated experimentally (e.g. by decreasing expression of genes thought to cause resistance when over expressed or by increasing expression of genes thought to cause resistance when down-regulated). These studies will identify genes whose expression levels predict response to Omnitarg in vitro. We will test the predictive power of gene-expression-level assays in human Xenograft models treated with Omnitarg. Markers that predict responses in xenograft models will be tested clinically under the auspices of the Bay Area Breast Cancer SPORE.