Biography Nicholas Bruchovsky, MD, PhD, FRCPC
Research Interests - Past and Present In 1967, Dr. Bruchovsky discovered that dihydrotestosterone is the active form of testosterone, the principal male sex hormone produced by the testis. At the time of this discovery, he was working with Dr. Jean D. Wilson at the Southwestern Medical School in Dallas, Texas. The report of these experimental results was published in the Journal of Biological Chemistry and became a Current Contents Citation Classic. Also Dr. Bruchovsky demonstrated that the prostate gland is characterized by the ability to make its own dihydrotestosterone owing to the presence of the enzyme 5 alpha-reductase and subsequently documented the existence of two different forms of the enzyme. Complementing this research was the additional discovery of the nuclear androgen receptor through which dihydrotestosterone exerts its action. The Dallas experiments set the stage for new directions in the study of the syndromes of androgen insensitivity characterized by the absence of androgen receptor or a deficiency in 5 alpha-reductase activity. After moving to the University of Alberta in Edmonton, Dr. Bruchovsky expanded his earlier work to show that all natural androgens have to be converted to dihydrotestosterone before they are active. This demonstration constituted a breakthrough in the understanding of the mechanism of action of androgens in general, because it established the existence of a final common pathway for male pattern development. It also provided the theoretical basis for the design of two new classes of drugs, antiandrogens and 5 alpha-reductase inhibitors, now used extensively to prevent the action of dihydrotestosterone in hyperplastic and malignant conditions of the prostate. Later, in collaboration with Dr. Larry Goldenberg and Dr. Paul Rennie at the BC Cancer Agency in Vancouver, Dr. Bruchovsky introduced the combination of cyproterone acetate and low-dose diethylstilbestrol, a novel form of androgen blockade for the treatment of prostate cancer, which has proven highly effective and cost efficient. In the early 1970's, Dr. Bruchovsky embarked on a long-term project to define those factors involved in the regression of androgen-dependent tissues after the withdrawal of dihydrotestosterone. In association with Dr. Rennie and Dr. Barry Lesser, three essential mechanisms governing the growth and maintenance of the prostate were described, and it was shown that cell death after removal of androgens in such tissues as the prostate is an active process which was termed autophagic lysis, now better known as apoptosis. To examine the idea of inducing multiple regressions of prostate cancer by hormonal manipulation, Dr. Bruchovsky modified the Shionogi mouse mammary carcinoma so that it could be used as an experimental model system to mimic the clinical course of prostate cancer. The tumour was designed to grow under the influence of androgens, regress predictably after androgens were withdrawn and progress to an androgen-independent state if androgens were not replaced. This model then afforded Dr. Bruchovsky and Dr. Rennie the opportunity to demonstrate that progression to androgen independence involves the sequential loss of the three essential mechanisms of androgen regulation described earlier. An in vivo assay for stem cells was developed and with this it was shown that the replacement of one-third or more of the total stem cell compartment of the tumour by androgen-independent stem cells represented a sufficient condition for the establishment of androgen independence. In attempting to avert or delay progression to the androgen-independent state, they hypothesized that if malignant cells which survive androgen withdrawal are forced into a normal pathway of differentiation by androgen replacement, then apoptotic potential might be restored, thus setting the stage for another response to androgen withdrawal. This theory was confirmed when apoptosis was induced multiple times in the Shionogi tumour model by repeated cycles of androgen withdrawal and replacement. With the participation of Dr. Goldenberg, Dr. Koichura Akakura and Dr. Martin Gleave, the same treatment protocol was applied to clinical prostate cancer affording an entirely new method of treating this disease which was termed intermittent androgen suppression. The principle of intermittent androgen suppression has been applied to all stages of prostate cancer including neoadjuvant treatment before radical prostatectomy or prostatic irradiation with early indications of improved outcomes. Its use for these purposes is a significant departure from traditional methods of treatment, but already has found widespread acceptance as the preferred therapeutic option for many men diagnosed with the disease. From biochemical monitoring of patients with prostate cancer over multiple cycles of androgen withdrawal and replacement, Dr. Bruchovsky was able to document the changes in the characteristic pattern of response to treatment which denote early progression to androgen independence. Extrapolating from the experimental studies of Dr. Marianne Sadar on ligand-independent activation of the androgen receptor (LIAAR), he found that it was possible to inhibit this receptor-related mechanism of early tumour progression in patients with prostate cancer by taking advantage of the little known anti-LIAAR action of antiandrogens. In a further effort to improve the treatment of early tumour progression, he collaborated with Dr. Sadar and Dr. Peter Gout in a program to develop a new class of drugs which could act as therapeutic decoy molecules to prevent the androgen receptor from being activated in the absence of androgens. Dr. Bruchovsky retired in September 2001 from active clinical and administrative duties, but remains affiliated with the Prostate Centre at Vancouver General Hospital as an Emeritus Clinician Scientist and an Honorary Professor of Medicine. Although retired, he continues to be involved in the evaluation of the clinical effectiveness of intermittent androgen suppression. The introduction of novel approaches to the therapeutic suppression of androgens by Dr. Bruchovsky and his colleagues has been associated with a steady and striking decline in mortality from prostate cancer in BC over the past decade. Citing his achievements, the BC Medical Association honoured Dr. Bruchovsky with the distinction of being the 2001 recipient of the Terry Fox Medal for outstanding contributions to cancer medicine. In 2003, he was awarded the Commemorative Medal for the Golden Jubilee of Her Majesty Queen Elizabeth II for outstanding contributions to medicine and the medical profession.
Vancouver, B.C. |
