Using patient-derived normal and tumor tissues, we have performed whole genome wide expression analysis to identify genes aberrantly regulated in human cancers. We have focused upon kidney cancer (renal cell carcinoma) and thyroid cancer. We have identified numerous aberrant signaling pathways upregulated or lost in these two cancers. Using human cell lines (some of which we established from patient-matched normal and tumor tissues), identified genes are silenced or re-expressed establishing transgenic cell lines to determine the role of the gene in tumor survival, proliferation, invasion and metastasis. Identification of aberrant signalling pathways will allow for an understanding of the molecular pathways governing each cancer subtype. Utilizing this information provides a rational approach in designing combinatorial molecular targeted therapies and will lead to personalized medicine for diagnosis and treatment.

Our overarching goal is to understand molecular mechanisms of carcinogenesis and tumor progression. In understanding these molecular mechanisms, our vision is that combinatorial targeted molecular therapies will be identified that either cure or block tumor progression (allowing one to live with a chronic disease). In renal cell carcinoma (RCC), we have identified aberrant signaling pathways including transforming growth factor beta (TGF-beta) and Wnt in clear cell RCC (cRCC). With regards to TGF-beta signaling, a loss of the type III TGF beta receptor (TBR3) is found in early stage I cRCC of patient tumor tissues suggesting that loss of TGFbeta signaling may be one key event in either tumor formation and/or tumor survival. Our working hypothesis is that TGF-beta signaling is turned off in renal tumor epithelial cells to block the growth inhitory effects of TGF-beta. Using transgenic cRCC cell lines re-expressing TBR3, we have demonstrated inhibition of tumor growth in preclinical animal models. We are currently dissecting the molecular pathway by which TBR3 induces tumor regression. Similarly, we have identified loss of secreted frizzled receptor protein 1 (sFRP1), a soluble negative regulator of the canonical and noncanonical Wnt signaling pathway. Loss of sFRP1 is another early event in cRCC and may represent another key signaling pathway blocking tumor formation and/or growth.

In thyroid cancer, we recently identified effective combinatorial therapy against anaplastic thyroid carcinomas (ATC). In ATCs (mean survival of 3 months; 99% lethal), we have identified that the transcriptional factor, PPARgamma, is a molecular target for therapeutic intervention in ATC. We have mapped a novel molecular signaling pathway by which PPARgamma agonists block ATC growth and have shown that when combined with paclitaxel, synergistic antitumor activity occurs in a preclinical animal model. Based upon these preclinical data, a Phase 1/2 clinical trial is in development. Using genomic profiling, we have also identified a set of molecular markers for response to PPARgamma therapy which will be tested in patient biopsy tissues in the Phase 1/2 clinical trial. Current efforts are to better understand the molecular underpinnings of synergistic antitumor activity of this combinatorial regimen in order to provide the ability to better select patients who will respond to therapy.