A Publication of the James Buchanan Brady Urological Institute Johns Hopkins Medical Institutions

Experimental Approaches to Improved Drug Therapy of Advanced Prostate Cancer


Hormone therapy kills prostate cancer cells through a process known as "programmed cell death". Although hormonal therapy can be effective for a long period of time, eventually hormone independent metastatic prostate cancer cells grow and become dominant. Although these hotmone independent cancer cells do not develop programmed cell death when hormone levels are lowered, they do retain the ability to be "tricked" into activating this death pathway by exposure to a natural compound, termed Thapsigargin. This is a compound isolated from the Thapsia Gargancia plant. In order to target the killing effect of this agent specifically to metastatic prostate cancer cells and not to other normal cells, Dr. John Isaacs is chemically modifying Thapsigargin to a "pro drug" form. This pro drug form is designed to be inactive until specifically converted to the active drug by proteins present only in normal and cancerous prostate cells. Thus, even though the pro drug would circulate throughout the entire body of the patient, it would only be converted to active drug in the metastatic cancer cells, thus greatly minimizing non-tumor cell side effects. Presently, this pro drug concept is being tested in pre-clinical animal models.

Dr. William G. Nelson has approached this problem in a slightly different way. p53 is a tumor suppressor gene that plays a major role in activating programmed cell death. When cancer cells are injured by exposure to chemotherapeutic drugs, they often die as a result of this process. However, cancer cells with a mutated form of the p53 gene fail to activate these cell suicide pathways in response to chemotherapy. Dr. Nelson, working in collaboration with Dr. Michael Kastan, has identified the major intracellular signal that activates the p53 dependent cell suicide pathways in prostate cancer cells when they are exposed to chemotherapy. By understanding these pathways, they hope to design new treatment strategies targeted at other preserved cell suicide pathways in cancer cells that contain p53 mutations. Hopefully, such new treatment strategies may prove to benefit men with advanced prostate cancer.

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