Advances In Targeted Therapy And Tissue Engineering In Urology

Main Category: Urology / Nephrology
Also Included In: Cancer / Oncology;  Genetics;  Clinical Trials / Drug Trials
Article Date: 18 Apr 2008 - 0:00 PDT

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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.

As a bench to bedside example of targeted therapy, Dr. Evans' group has researched Src kinase, a prototypical non-receptor tyrosine kinase and the first identified oncogene. Androgen withdrawal promotes prostate cancer cells to transdifferentiate to a NE phenotype and express neuropeptides and growth factors. We identified androgen-independent activation of the androgen receptor mediated by neuropeptides, epidermal growth factor (EGF), and interleukin (IL)-8 to be mediated by Src activation. In clinical samples, Src hyperactivation correlates with aberrant androgen receptor activation of high-grade prostate cancer cells and also androgen-independent disease.

To explore Src as a target, the investigators hypothesized that NE cells are androgen-independent and secrete neuropeptides that further support androgen sensitive cell proliferation in the absence of androgens. They developed an in vitro and in vivo model by stable overexpression of the neuropeptide gastrin-releasing peptide (GRP) in LNCaP cells (LNCaP-GRP) through transfection and selection. LNCaP-GRP cells demonstrated androgen- and anchorage-independent growth and enhanced cell motility via Src activation. LNCaP-GRP cells developed orthotopic tumors in castrated nude and SCID mice and metastasized to regional lymph nodes in the SCID mice. The tumors expressed GRP, PSA and demonstrated nuclear translocation of the androgen receptor. These xenografts were re-cultured and provided paracrine growth support and migratory stimulation to wild-type LNCaP cells under androgen-deprived conditions in vitro and in vivo. They confirmed the signaling mechanism by which neuropeptides activate the androgen receptor in the absence of androgens to be activation of a non-receptor tyrosine kinase complex of Src, FAK and Etk. Using a novel and specific Src kinase oral inhibitor AZD0530, they demonstrated inhibition of growth and metastases in vivo. These observations have resulted in a National Cancer Institute sponsored Phase II trial using AZD0530 in patients with hormone refractory prostate cancer. Biomarkers predictive of drug activity (such as activated Src in circulating mononucleocytes) or target specificity (such as tyrosine kinase activity in tumor biopsies) are central to clinical target validation.

Presented by: Christopher P. Evans, MD at the European Association of Urology - 23rd Annual EAU Congress - March 26 - 29, 2008 - Milan, Italy

Reported by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

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