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Prostate Cancer Research
Prostate cancer is the most common male malignancy in the United States: it is estimated that 192,280 new cases of prostate cancer were diagnosed in 2009 alone. Over the past 25 years, dramatic improvements have been made in patient survival of this disease; in fact, the 5-year survival rate has increased from 69% to nearly 99%. However, once the cancer has spread, or "metastasized," the disease is fatal. Currently, no eff ective treatment is currently available. That is why prostate cancer remains the second leading cause of cancer death in American males, and an estimated 27,360 patients will lose their battle to the disease this year, dying predominantly from metastatic prostate cancer.

Patients with late stage prostate cancer may benefi t from hormone therapy (androgen ablation), which removes the main source of fuel to tumor growth by suppressing male hormones (androgens). Unfortunately, patients ultimately become non-responsive to this treatment after a few years, resulting in uncontrolled disease status and patient death. New and more effective treatments must be developed quickly to address this critical issue.

NFCR is currently supporting two scientists whose research is focused on unraveling the root causes of prostate cancer metastasis and developing new and eff ective treatment for patients with metastatic prostate cancer.

Paul B. Fisher, M.Ph., Ph.D.
NFCR Project Director
Virginia Commonwealth University School of Medicine, Richmond, VA

NFCR Scientist Paul B. Fisher, M.Ph., Ph.D., has developed an innovative gene therapy to treat prostate cancer - especially metastatic prostate cancer, which aff ects 60% of patients. This new therapeutic is a genetically reprogrammed virus, called "Cancer Terminator Virus" (CTV). CTV is designed to specifi cally infect tumor cells and destroy them by replicating itself within the cells. The secret of restricted tumor targeting lies in a special control system employed in CTV. Dr. Fisher's therapeutic virus employs a special gene element he discovered earlier which can only turn on virus replication in tumor cells, but not in normal cells. Once turned on, the virus copies itself inside a tumor cell and eventually causes cell death. On the other hand, the normal cells are prevented from being harmed because CTV can not replicate in them. This smart control system ensures that this small biological killing machine only fires on tumor cells.

To further improve its killing eff ects, Dr. Fisher's team made the virus capable of producing another tumor-killing molecule, interferon gamma (IFNγ), when replicating in the tumor cells. IFNγ, a natural product of our immune system, can directly kill tumor cells as well as indirectly by eliciting immune responses.

Intriguingly, both the viruses and IFNγ generated by them go and seek out tumor cells, whether localized or metastatic, and destroy them, without harming normal healthy cells in the body. This unique feature could make it especially useful for patients whose prostate cancer has already metastasized.

Currently, Dr. Fisher is further testing CTV in prostate cancer cell lines and tumor models to confirm its effects and observe potential side effects. In fact, this novel gene therapy has been tested in pancreatic cancer cells and tumor models and the results are very encouraging. If tests in the laboratory run well, CTV may soon be used in clinical studies and provide a more eff ective treatment to late stage prostate cancer patients. This new "lethal weapon" could be especially encouraging to patients whose prostate cancer has stopped responding to other treatments.

Stanley N. Cohen. M.D.
NFCR Fellow
Stanford University School of Medicine, Stanford, California

Cancer is a disease that is due to uncontrolled cell growth and the treatments of chemotherapy and radiation are mainly affective only in early stages and not after the cancer has spread or metastasized. Dr. Stanley Cohen is an innovative scientist in the field of genomics - an emerging field in which scientists examine all the genes in an organism to see how they interact and influence biological properties. His research seeks to identify unknown genes involved in uncontrolled cell growth and that have a role in chemotherapy resistance.

Dr. Cohen is a "genetic mapmaker" working to isolate previously unidentified genes which, because they are inactive in mammalian cells, could possibly be part of the mechanism that prevents metastasis or prevents resistance to chemotherapy. Recently, his laboratory invented the genetic tool called random homozygous knock out (RHKO) that uses a retrovirus and antisense RNA strategy to inactivate both copies (thus, homozygous) of mammalian genes in cell lines. When genes are inactivated, the loss of their function leads to altered biological properties in the cell or organism. Dr. Cohen uses RHKO and other cutting-edge technologies to discover genes that control cancer metastasis and genes which may be responsible for building resistance to chemotherapy drugs.

Using RHKO, his lab has made a major discovery of a novel mechanism of tumor resistance against taxanes - a group of chemotherapeutic drugs that are commonly used to treat prostate, breast, ovarian, and non-small cell lung cancer but which resistance eventually develops. Using taxane-resistant human prostate cancer cells as a model, they found that a previously uncharacterized gene, txr1, interferes with taxane's ability to cause cancer cell death. In taxane-resistant cancer cells, the txr1 gene product is markedly increased, making taxane lose its killing power to those cells. This discovery has significant implications in the treatment of taxane-resistant cancer cells. By decreasing the level of txr1 protein, cancer cells can be re-sensitized to taxane and get killed. The potential clinical applications of this strategy could provide a new way to combat drug-resistant cancers.

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