High-Impact Results

PCF funding has led to the development of a number of drugs that have proven successful in improving outcomes in patients with prostate cancer. The PCF's strategic goal of achieving high-impact results in drug discovery and development can best be illustrated by its support of research into the following:

• PSMA monoclonal antibodies
• The proteasome inhibitor bortezomib (Velcade^TM; Millennium)
• The intravenous bisphosphonate zoledronic acid (Zometa^TM; Novartis)
• The endothelin-1 receptor antagonist atrasentan (Abbott Laboratories)
• The therapeutic vaccine GVAX^TM (Cell Genesys)
• The monoclonal antibody 2C4 (Omnitarg^TM; Genentech)

In each of these cases, PCF funding proved crucial to the investigators, enabling them to develop effective drugs that would otherwise have gone unfunded. Following are more detailed descriptions of each research project.

PSMA Monoclonal Antibodies
Prostate-specific membrane antigen (PSMA) is a molecule selectively expressed on the surface of prostate cancer cells. The intravenous injection of monoclonal antibodies against PSMA in advanced prostate cancer patients has been demonstrated to localize at sites of prostate cancer previously shown to exist by bone and CT scans. This result suggests that PSMA monoclonal antibodies can be used to deliver lethal doses of radiation or toxins to sites of local or metastatic prostate cancer, thereby eradicating or reducing the tumor.

Since 1993, PCF has funded the research of Neil Bander, M.D., of New York Presbyterian Hospital at Cornell University to develop PSMA antibodies. Dr. Bander's work is moving forward at a rapid pace through the necessary clinical trials in conjunction with Millennium Pharmaceuticals. If successful, Millennium will commercialize PSMA monoclonal antibodies for the treatment of prostate cancer and potentially other solid tumors.

Bortezomib (Velcade)
In 1998, the proteasome inhibitor bortezomib (then known as PS-341) was in development at ProScript, a cash-strapped biotechnology company based in Cambridge, MA. At the urging of Chris Logothetis, M.D., Chair of Genitourinary Medical Oncology at M.D. Anderson Cancer Center, the PCF funded a small Phase I clinical trial to test the agent in patients with cancer. That promising trial kept the drug alive until ProScript, through a series of mergers and acquisitions, was acquired by Millennium Pharmaceuticals in 1999.

Five years after the initial funding by the PCF, bortezomib (Velcade) was approved by the FDA for use in multiple myeloma, a cancer of the blood that affects approximately 45,000 adults in the U.S. trials evaluating the combination of Velcade and chemotherapy for advanced prostate cancer are currently underway.

Zoledronic Acid (Zometa)
Androgen deprivation therapy, a mainstay of prostate cancer therapy, has the unfortunate side effect of increasing the risk of osteoporosis and bone fractures. In 1998, PCF funded the research of Matthew Smith, M.D., Ph.D., of Massachusetts General Hospital to conduct a clinical trial evaluating the use of the bisphosphonate pamidronate (Aredia) to prevent bone loss in patients with advanced prostate cancer who are being treated with androgen deprivation therapy. In 2001, a study published in the New England Journal of Medicine showed that Aredia^TM minimizes bone loss and associated skeletal-related events in men undergoing the therapy.

Based on these encouraging results, Novartis, the manufacturer of Aredia^TM, committed significant resources to the development of a more potent bisphosphonate, zoledronic acid (Zometa). In 2001, Novartis gained FDA approval for the use of Zometa in prostate cancer and other cancers that affect bone tissue.

Continued research into this and other bisphosphonates will help better explain the mechanisms behind the bone loss associated with prostate cancer. 

Atrasentan
With funding from the PCF, three researchers at The Johns Hopkins University found that the endothelin-1 receptor antagonist atrasentan slowed the growth of prostate cancer cells in vitro and in rodents. Additional research by Jonathan Simons, M.D., Joel Nelson, M.D., and Michael Carducci, M.D., showed that the agent attacks prostate cancer in the bone environment. These results suggested to the investigators that atrasentan could play a role in the treatment of advanced prostate cancer.

Although clinical trials did not demonstrate the effectiveness of atrasentan in men with advanced prostate cancer, it is anticipated that continued work on this pathway will spur the development of other novel experimental treatments for advanced prostate cancer.

GVAX
In 1995, the PCF provided a grant to Jonathan Simons, M.D., of The Johns Hopkins University to develop GVAX, a therapeutic prostate cancer vaccine currently in clinical development by Cell Genesys (Dr. Simons is now the head of the Winship Cancer Institute at Emory University.)

GVAX contains a prostate tumor cell preparation that has been genetically engineered to express the protein GM-CSF, which stimulates the patient's immune system to respond to prostate cancer proteins.  This project is another example of how therapeutic strategies formulated by leading scientists such as Dr. Simons become promising therapies being developed with the significant resources of a biotechnology company.

2C4 (Omnitarg)
Cedars Sinai Medical Center launched the first phase of clinical testing of a new drug for prostate cancer produced by the biotechnology company Genentech. The drug, known as 2C4 (Omnitarg), is a monoclonal antibody engineered to inhibit the cancer cell growth-inducing molecule Her-2/neu. Laboratory work performed by Dr. Agus showed that 2C4 inhibits prostate cancer growth in both hormone-sensitive and hormone-resistant disease.

Although clinical trials did not demonstrate the effectiveness of 2C4 in men with prostate cancer, it is anticipated that continued work in this area will spur the development of other novel experimental treatments for prostate cancer.

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