Prostate cancer is one of the most common types of cancer in men and a leading cause of cancer related death in this population. In the earlier stages of disease, prostate cancer cells depend on male hormones, androgens, for growth and proliferation, and androgen-ablation is the main line of therapy. After initial response to treatment, however, most prostate tumors go on to become hormone-refractory and lethal. The major cause of morbidity and mortality from prostate cancer is from advanced stage, androgen-independent disease.
There is currently no effective therapy for androgen-independent prostate cancer and the molecular mechanisms that drive hormone-dependent prostate cancers to become hormone-independent are not well understood. Elucidation of the mechanism of androgen-independent growth would provide the framework for the development of rational therapies. While at the Dana-Farber Cancer Institute, Dr. Işıl Güney set out to identify novel therapeutic targets for the treatment of hormone-resistant prostate cancer. She used cutting-edge moleuclar tools to perform an in vivo high throughout genetic screen in mice to search for kinases (a class of druggable molecules implicated in cancer) that confer androgen dependent human prostate cancer cells the ability to form tumors in the absence of androgens. Her initial screens identified 16 candiate kinases that permit androgen dependent prostate cancer cells the ability to form tumors in castrated mice.
Dr. Güney then worked with colleagues at Dana-Faber and the Broad Institute of Harvard and MIT to analyze early stage and advanced stage patient tumor specimens to determine whether any of the 16 kinases were indeed implicated in disease progression in humans. Genomic data demonstrated that six of the 16 kinases were in regions of gene amplification in advanced stage but not early stage patient tumors. One of these kinases, Thymidine Kinase 1, which particularly conferred a strong phenotype, was further observed by immunohistochemical analyses to be expressed in a significantly higher percentage of hormone manipulation-resistant tumors compared to hormone manipulation-sensitive tumors, corroborating the physiological relevance of this molecule in the progression of human prostate cancer. Dr. Güney’s discoveries were patented and further work was conducted to dissect the mechanism by which TK1 promotes hormone-resistance.