Targeting Phosphatidylserine to Improve Hormone Therapy of Prostate Cancer

Principal Investigator: THORPE, PHILIP E
Program: PCRP
Proposal Number: PC081501
Award Number: W81XWH-09-1-0470
Funding Mechanism: Idea Development Award
Partnering Awards:
Award Amount: $587,722.00


There is presently no cure for prostate cancer (PCa) once it has spread throughout the body. The most common treatment today is to reduce the patient's levels of the male sex hormone that the cancer cells need for survival and growth. However, this treatment only gives temporary benefit because mutant cancer cells that do not need the hormone survive. This proposal is aimed at developing a new drug (an antibody) that will improve the effectiveness of hormone therapy.

We have made an antibody that binds to tumor blood vessels and cancer cells in prostate cancers when animals are treated with hormone therapy. The antibody binds to a molecule called phosphatidylserine (PS), which becomes exposed on tumor blood vessels and cancer cells in response to stresses caused by hormone therapy. Then, when we administer the anti-PS antibody, it binds to the cancer blood vessels and guides cells of the immune system to attack and destroy the tumor's blood vessels. The cancer cells then die because they are starved of the oxygen and nutrients needed for survival and growth. Also, the same PS molecule is used by cancer cells as a way of disguising themselves as dying normal cells so that they will be ignored by the immune system. Our antibody blocks this immunosuppressive effect of PS and should allow the patients to make immune cells, called T-cells, which can kill cancer cells directly. We have already demonstrated that the antibody treatment, given together with hormone therapy, is much more effective than hormone treatment alone, and, most importantly, delays the development of hormone-independent cancer.

Our plan is to test these strategies in mice with prostate cancer in their prostate glands. We shall treat the mice when their disease has just become established and is still hormone dependent to mimic early disease in patients. Then we shall treat later cancers that have become hormone independent, and cancers that have spread, or "metastasized," from their original site. The effects on the tumor will be monitored non-invasively in living animals by sophisticated scanning techniques that allow us to measure the tumors inside the prostate glands. We will correlate the antitumor effect of the combination treatment with the levels of PS on cancer blood vessels and cancer cells, and will identify blood vessel damage in tumors under the microscope. We will also look for the presence of immune cells that can kill PS-expressing blood vessels and tumor cells themselves.

The impact this research could have on the treatment of prostate cancer is profound. Most importantly, we are already testing a version of the antibody, called bavituximab, in Phase I and Phase II clinical trials. Bavituximab is a chimeric (partly mouse, partly human) antibody. The present studies, if successful, would provide the foundation for combining bavituximab, or a new, fully human anti-PS antibody called 1N11, with hormone therapy to treat prostate cancer. The data we have so far indicate that the combination treatment should improve the hormone therapy of prostate cancer in man without contributing toxicity.