The goal of the present study is to make docetaxel a safer and more effective treatment for prostate cancer by combining it with the novel vascular-targeting antibody, 3G4. It is well-recognized that tumors depend on blood vessels for the oxygen and nutrients that they need for survival and growth. In addition, tumor blood vessels provide a major route for spread of tumor cells and formation of metastatic tumors in various parts of the body. Thus, the tumor vascular system has become an important target in the fight against cancer. We have recently developed a novel potent tumor vascular-targeting agent called 3G4. 3G4 is a monoclonal antibody that recognizes phosphatidylserine (PS), a negatively-charged phospholipid. While this molecule is found in normal cells, it is distributed differently on vessels in tumors providing an extraordinarily specific marker of tumor vasculature because it is selectively and abundantly expressed on tumor vessels and is readily accessible. We have demonstrated that 3G4 can specifically home to tumor vessels but not to vessels in normal organs. 3G4 markedly inhibits the growth of various tumors, including human prostate tumors. No toxicity has been observed in 3G4-treated monkeys, mice, rats, or atherosclerotic rabbits, even at doses tenfold the therapeutic dose.
Docetaxel is one of the most effective chemotherapy drugs against prostate cancer. It has recently been approved by the Food and Drug Administration(FDA) for the treatment of prostate cancer. Despite its potent antitumor activity, its clinical efficacy is limited by its toxicity and by the survival of drug-resistant tumor cells. The emerging dogma is that combination therapy is required to achieve better efficacy. A large body of evidence suggests that combination of a chemotherapeutic agent with an agent that cuts off the tumor's blood supply could act synergistically, leading to superior antitumor effect, reversal of drug resistance as well as lower toxicity.
The central hypothesis of the present proposal is that combining docetaxel with 3G4 will provide superior therapeutic efficacy for the treatment of prostate cancer. Our preliminary data strongly support this hypothesis. The combination of 3G4 with docetaxel has shown synergistic antitumor activity in human breast tumor models. Tumor growth was inhibited by 92.5% in the combination treatment group, as compared with 68% and 60% in groups treated with docetaxel alone and 3G4 alone. The combination therapy decreased tumor burden in the liver and lungs by more than 90%, as compared with 45% for 3G4 treatment alone and 56% decrease for docetaxel treatment alone.
We propose first to assess the combined therapy for the treatment of androgen-dependent and androgen-independent prostate tumors. We will then assess the effect of the combined therapy on the spread or metastasis of the initial tumor to other parts of the body. Localized prostate cancer is curable whereas metastasized prostate cancer usually is not, thus the development of new drugs that inhibit metastasis of prostate cancer would be of great clinical importance. Finally, we will attempt to clarify the mechanism of the antitumor effect. An understanding of mechanisms should provide data that might lead to the design of even better drugs.
A chimeric version of 3G4 that can be used in human cancer patients has been developed by Peregrine Pharmaceutical, Inc. The drug has received approval by the FDA to enter Phase I clinical trials in patients with diverse tumor types. The studies outlined in this proposal are needed to establish that the 3G4/docetaxel combination is effective at treating prostate cancer in mice. A successful determination of efficacy will lead to clinical trials of the combination in patients with prostate cancer.