Selective Activation of a Perforin-Granzyme B Fusion Protein Toxin by PSA as Therapy for Metastatic Prostate Cancer
Abstract
Cancer produces its lethal effects because it continues to grow. Growth occurs because the number of cancer cells producing daughter cells (i.e., division) is greater than the number of cells dying. Within prostate cancer patients, however, the number of cancer cells dividing is remarkably low. The reason prostate cancers continue to grow is that the number of cancer cells dying is even lower. Despite the very small difference in the rate of division vs. death of prostate cancer cells, this imbalance will result in the death of 28,000 men in the United States this year due to the continuous growth of prostate cancer cells spreading throughout the body. Chemotherapy usually kills cells only when they are dividing. In men with widespread prostate cancer, the rate of division of prostatic cancer cells is so low that these cells are only minimally killed by chemotherapy. A number of new chemotherapies are being developed to kill prostate cancer cells without requiring cell division. These chemotherapies are designed to block certain critical components of the cancer cell machinery that signal the cell to divide or help the cell to survive better. Cancers often become resistant to this targeted approach because some of the cancer cells do not produce or rely on the particular pathway. Thus, inhibition of the pathway does not kill these resistant cells. Our alternative approach to killing prostate cancers without requiring cell division does not rely on inhibiting a specific protein target but instead uses a therapy that is used by the native immune system to kill abnormal cells such as tumor cells or cells that have become infected with viruses. Cancer cells can evade the immune system by a variety of ways. However, if the immune system correctly identifies a tumor cell, it has the weaponry that can kill the cancer cell. This weaponry involves the release of a protein called granzyme B into the cell. Once granzyme B gets into a cancer cell, it stimulates the cell to actively kill itself. Tumor cells do not easily become resistant to this type of killing. What we propose to do in this grant is to redirect and reengineer this highly toxic weapon made by the immune system to selectively kill prostate cancer cells without killing normal tissues. To accomplish this targeting, we will connect the granzyme B toxic protein to a molecule that can bind selectively to Prostate-Specific Membrane Antigen (PSMA), a protein that is made on the surface of prostate cancer cells. To make the toxin even more specific, we will all explore the effect of using a linker that is designed to be recognized by the prostate cancer cell specific protein prostate-specific antigen (PSA). PSA is a type of protein known as a protease, which is a type of molecular scissors that can cut the protein into two pieces. With our design, the granzyme B is not toxic to cells until it is activated by PSA and binds to PSMA. However, when either of these prostate proteins is not present, the granzyme B is inactive and should be non-toxic to normal cells. Our goal is to develop and test these granzyme B proteins as treatment for patients with advanced prostate cancer that has spread outside of the prostate gland. If the treatment works as we envision, we should be able to give this treatment as an intravenous injection and selectively eliminate prostate cancer cells without toxicity to normal tissues because the only site that produces PSA in a man is the prostate gland and prostate cancer. An added advantage of our strategy is that, unlike other strategies that use proteins from bacteria, viruses, or other animals, our approach uses a human protein. This means that the patient will not develop an immune response to the therapy like they would if the therapy was derived from another non-human species. This means that the treatment could be given in multiple doses over time to maximize the antitumor effect. In summary, this approach to redirect
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510382
Entities
People
- Samuel Denmeade
Organizations
- Johns Hopkins University
- United States Army