Breast cancer is a phenotypically and genotypically diverse disease whose clinical behavior is variable. Novel therapeutics targeting components of known pathways that are felt to be related to malignant behavior are now entering clinical trials. As with conventional agents, it is likely that the clinical benefit to newer therapies will depend on a number of clinical and biological factors. Furthermore, anti-tumor agents are felt to operate through complex pathways, some of which involve alterations in the expression of specific genes or functional gene groups (hereafter referred to collectively as genes). We hypothesize that certain gene expression profiles at baseline and following exposure to therapy (dynamic) may be predictive of clinical response to therapy, particularly ErbB2 (HER2/neu) oncogene-targeted agents and specifically, novel doxorubicin-containing anti-ErbB2 immunoliposomes (ILs). Our long-term goals are to correlate baseline and dynamic tumor tissue gene expression profiles with indices of clinical benefit such as survival, tumor response, and novel imaging techniques described in this overall proposal. This project will refine and validate methods of amplifying RNA from small tissue biopsy specimens while preserving the ability to quantify relative gene expression levels. Intratumoral heterogeneity at the expression level will also be examined. We will also define genes of interest for further study in human trials by using appropriately chosen cancer cell lines and animal xenograft models treated with the clinically approved humanized anti-ErbB2 antibody trastuzumab, doxorubicin. and ILs. Baseline and dynamic gene expression at various time points will be assessed using multi-gene expression arrays. Specialized statistical tools will be applied to prioritize a smaller subset of genes for study and to define optimal time points for post-treatment tissue biopsies in future human trials. We will also take advantage of results from the ongoing Program Project at UCSF (P-O1CA44768, Waldman, PI) in which gene expression of frozen human primary breast tumors will be characterized in relationship to specific characteristics of interest such as ErbB2 amplification/over expression. We will additionally use information generated from another project within the Program Project (Benz, Project PI) aimed at characterizing specific genes in mouse xenografts of MCF7 cell line subclones that over express ErbB2 or contain alterations in other components of the ErbB2 pathway (e.g. over expression of heregulin). Ultimately, this approach can be used to correlate specific baseline and dynamic gene expression profiles with clinical response and other novel correlative imaging and tumor assessment techniques.
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