Targeting Mitochondrial Inhibitors for Metastatic Castrate-Resistant Prostate Cancer
Abstract
Only localized prostate cancer is presently curable via total annihilation of the entire cancer neighborhood using either surgical removal or local radiation. Unfortunately, once prostate cancer spreads outside the prostate gland, no available therapy is curative. Thus, approximately 28,000 US men die each year due to this devastating disease. The vast majority will die despite receiving multiple types of treatments that include hormone therapy and toxic chemotherapy, both of which have significant side effects. Thus, the goal of our proposal is to develop a novel type of therapy that can kill prostate cancer cells but not kill normal cells within normal tissues. We hope through our planned experiments to generate enough information to support eventual testing of these new therapies in clinical trials in men with metastatic prostate cancer that has become resistant to hormone therapies. The leaders of this proposal have worked together for more than 20 years with the shared focus on developing new treatments for prostate cancer that could result in a reduction in the death rate from this disease. This goal requires not only the discovery of new therapeutic ideas in the laboratory but also the expertise to take these basic science findings and test them in human trials. Working together, Dr. Denmeade, who is a medical oncologist, and Dr. Isaacs, who is a laboratory scientist, have established a track record of translating preclinical discoveries into clinical trials (co-inventors on 17 patents and 4 drugs taken into clinical trials). Thus, these investigators understand what is required in preclinical discovery studies to translate these results into clinical development and have both the expertise and the personal drive to accomplish this goal. To achieve this goal, they will take advantage of the unique biology of prostate cancer cells. Like the normal prostate cells, prostate cancer cells make large amounts of a protein called prostate-specific antigen (PSA). PSA functions as a "molecular scissor" capable of cleaving (i.e., "cutting") chemical bonds. Drs. Denmeade and Isaacs describe an innovative approach in which they will make "molecular grenades" consisting of a small piece of protein recognized and cut by PSA coupled to a toxin that will kill prostate cancer cells. The toxin in this case is a chemical that poisons a part of the cell called the mitochondria. The mitochondria s function is to turn nutrients like sugar and fat into energy for the cell. Since this is a critical requirement for cells to survive, blocking mitochondrial function is devastating for the cell and causes death of all cell types. PSA represents an ideal way to target these non-specific cell toxins to prostate cancer cells. Since normal cells do not make any PSA, they are unable to "pull the pin" on the grenades and thus will not be killed, thereby limiting side effects. Additionally, the cutting ability of PSA is blocked once it enters the blood. Thus, these molecular grenades will also be inactive in the blood. PSA only works at sites of prostate cancer cells. Therefore, within the prostate cancer environment, PSA can efficiently "pull the pin" on the grenades and cut free the toxin that is released (i.e., detonated) to kill prostate cancer cells. Finally, this treatment strategy is different from other targeted types of treatment where the doctors can only guess if the target is present in the cancer. For this PSA-directed therapy, the doctor already knows the PSA-target is present because PSA is used as the main marker for the disease. Therefore, clinical use of such PSA detonated molecular grenades is "personalized" based upon the ability to detect of PSA in the patient s blood.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610410
Entities
People
- John T Isaacs
Organizations
- Johns Hopkins University
- United States Army