2008
Advances In Targeted Therapy And Tissue Engineering In Urology
UroToday.com - Dr. Evans presented a lecture on targeted therapies. Most drugs have a mechanistic “target”, such as the enzymes 5-α reductase in the treatment of BPH or 5-phosphodiesterase in the treatment of erectile dysfunction. However, in the current presentation, “targeted therapy” is defined as molecular targeting.
Historically, the selection of systemic therapies for most cancer patients has been largely empiric. However, recent advances in cancer molecular biology suggest that defining biomarkers predictive of response and survival are achievable goals. The Human Genome Project, the International HapMap and progress in high-throughput assays have made genetic testing and individualized therapy a tangible reality. Using pharmacogenomic approaches to cancer therapeutics, one translational approach is to exploit the underlying molecular profile of the tumor (DNA, RNA, protein) or the host (patient genomic DNA) to improve treatment outcomes. To do this researchers must take into account both inter-individual differences (between individual patients) and population-related differences (ethnic/racial differences).
While patients may carry the same diagnosis and clinical features, they possibly harbor different molecular profiles. Among patients carrying the same disease diagnosis, a subset that exhibit toxicity or non-response to standard therapy may have molecular attributes that identify them for alternate therapy. The concept of prognostic biomarkers is well established, but predictive biomarkers that confirm a molecular target or reflect the impact of a therapeutic intervention are newer. For example, while HER2 status delineates poor prognosis in breast cancer, it has positive predictive value for benefit from trastuzumab. On the other hand, the epidermal growth factor receptor inhibitor gefitinib was not initially appreciated to have selectivity for lung cancer patients with mutated EGF receptor (and gene copy number by FISH) and because of this 4,000 patients in 4 major clinical trials were not optimally selected to benefit.
Urologists perhaps became most aware of targeted therapy with the introduction of tyrosine kinase inhibitors for renal cell carcinoma. They resulted from the discovery that most patients with conventional cell renal cancer demonstrated mutation or silencing of the VHL gene, with subsequent delineation of pathways modified by pVHL. Sorafenib and sunitinib are “multikinase” inhibitors that target several kinases to include KIT, FLT3, PDGF and VEGF receptors. But in other histologic types of kidney cancer, different molecular alterations will drive therapy; mutations in the MET proto-oncogene in hereditary papillary renal carcinoma or mutations in the fumarate hydratase gene in hereditary leiomyomatosis renal cell carcinoma for examples. As such, receptors or pathways related to these specific alterations provide different targets. In bladder and prostate cancer numerous potential targets exist, based upon oncogenes, survival genes, gene products and suppressor gene mutations. In addition to testing as monotherapy, many targeted drugs are under investigation as combination therapy, such as the targeted endothelin-1 receptor A inhibitor atrasentan and docetaxel.