Magnetic Resonance Imaging Biomarkers For Targeted Cancer Therapies

Abstract

In 2007, there will be an estimated 178,480 new cases of breast cancer diagnosed in women in the United States. The elucidation of the vast heterogeneity of individual tumors has led to a paradigm shift from a one-size fits all treatment strategy to more individualized treatment based on the molecular profile of the tumor. Identifying biomarkers that respond to or predict the action of drugs is important in identifying efficacious targets and drugs that will improve clinical outcome. To examine this, we first identified two breast cancer cell lines (ACC-3199 and ACC-3171) from a panel of low passage breast cells lines that were capable of growing serially as tumor xenografts. This was followed by the in vivo molecular characterization of these two cell lines. In ACC-3199 tumors, we identified a gain of pAKT expression compared to cultured cells. Based on this finding, we investigated the role of diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) as potential imaging biomarkers in identifying early response to PX-866, a PI3K inhibitor, in ACC-3199 tumors as represented by changes in tumor cellularity and hemodynamic parameters, respectively. Our results indicated that DW-MRI was able to identify an early response to PX-886 in ACC-3199 tumors as defined by an increase in the apparent diffusion coefficient (ADC) value of the tumors prior to changes in tumor volumes. Using DCE-MRI, we were able to conclude that PX-866 was not an effective anti-angiogenic agent as indicated by an increase in tumor permeability following therapy. Based on the VEGFR2 expression observed in ACC-3171 tumor xenografts, we examined the response of MDA-MB-231/GFP and ACC-3171 tumor xenografts to the anti-angiogenic agent, sunitinib, using the same imaging modalities. DW-MRI was able to detect increases in ADC values as early as 12 h post-treatment in both MDA-MB-231/GFP and ACC-3171 tumors. Thus, it appears that DW-MRI may be a useful clinical test in predicting the early response to PI3K and anti-angiogenic inhibitors. These imaging approaches, in addition to the further molecular characterization of breast tumors may lead to the improvement and development of medical therapies for breast cancer patients.