Progress in prostate cancer through research- BRADY TRADITION CONTINUES

The Brady Urological Institute has always been at the forefront in advancing our understanding of benign and malignant tumors of the prostate. With four Ph.D. faculty members conducting full-time research and a large group of talented young predoctoral and postdoctoral fellows involved in these research projects on the prostate, we have developed many new approaches and concepts that hold promise for new methods to manage localized and advanced prostate cancer.

At present, the research projects in the laboratory range from basic molecular studies to new surgical and medical procedures that are immediately applicable to the benefit of the patient. These contributions have received wide recognition. Dr. Donald Coffey, who is the research director of the laboratories, is also the national chairman charged with developing new concepts and monitoring research on prostate cancer throughout the United States for the National Cancer Institute. The following briefly describes some of the research that we are excited to share with you.

Molecular studies in the laboratory have focused on understanding an enzyme, called topoisomerase, that has the ability to wind and unwind the DNA tape that contains the genetic information for the cell. The control of DNA is important because the inappropriate reading of this genetic tape and the loss of control of its duplication is at the very heart of the cancer process and reflects itself in an abnormal replication and differentiation of the cancer cell. The research team is studying inhibitors of topoisomerases and has learned that when these inhibitors are combined with either standard chemotherapy or biological response modifiers, the end result is a markedly enhanced therapeutic advantage. This is a new and exciting approach for the potential management of advanced tumors and has been tested in an animal system as part of a new drug development program chosen in the five most promising areas of research by the National Cancer Institute. Much knowledge and research will be required before the application can be studied in clinical trials in humans but this team is investigating promising leads.

Prostate cancer cells require hormones for their growth. These hormones come primarily from the testes and are termed androgens. The laboratory has been at the forefront of understanding how prostate cancer cells develop resistance to this requirement for androgens in their growth. The laboratory has traced one possible site for this important resistance to the structure of the nucleus. The nucleus is like a cassette at the center of the cancer cell that contains the DNA tape. It appears that this nucleus is misshapen in the cancer cell and this may be caused by changes in the skeletal framework of the nucleus, a structure that has been discovered in this laboratory and termed the nuclear matrix. Recent interest in this nuclear structure is related to the fact that it contains recording heads that duplicate the DNA tape, as well as the topoisomerase enzyme that must unwind the tape during DNA replication. The research team has also shown that the androgen hormones that are required for tumor growth also reside on this nuclear matrix in the form of specific receptors that bind to the androgens and induce growth. It is hoped that the elucidation of these nuclear structures will reveal mechanisms that may improve our ability to manipulate the growth of prostate tumors.

Through the years the Brady Urological Laboratory has also developed and characterized excellent animal models for the study of prostate cancer which closely mimic the natural disease in man. These models have been ideal for investigating hormonal, chemotherapeutic, immunotherapeutic, and surgical approaches to prostate cancer. Recognizing the importance of these animal models of prostate cancer, the laboratory has supplied these models free to more than 100 research teams around the world.

Over the past five years we have carefully charted the anatomical course of the nerves that control erection and have improved upon the surgical techniques for their preservation. However, in some patients it is necessary to excise these nerves, on one or both sides, because of the location of the tumor or its extensive nature. We have currently embarked upon a series of studies to determine how the nerves could be restored in these patients and potential techniques which may encourage nerve regeneration.

In addition to these basic studies we have a broad variety of clinical programs investigating the pathology of prostate cancer, the usefulness of tumor markers such as prostatic specific antigen, and most importantly, imaging techniques which may improve upon our ability to determine which cancer cells are the most aggressive and have the greatest potential for escaping the prostate gland. In the past, our ability to estimate the aggressive nature of these cancers has been limited mainly to crude estimations of prostatic size based upon physical examination and microscopic examination of the biopsy specimens. However, we have some exciting data using an entirely new approach to the evaluation of cancer cells. Through the work of Dr. Coffey and his students, techniques have been developed for growing prostate cancer cells in tissue culture and observing their cell movement directly under a microscope as they grow. These investigators have learned that specific patterns of cell movement can predict metastatic potential in our animal model series. We hope to extend these studies to human prostate cancer cells.

We are very excited about the future of research and its direct application to patient care. We know we have a responsibility to all men with prostate cancer to improve their care and we will not rest until we have discovered improved approaches for the diagnosis and management of this most common malignancy in man.