This project is focused on translational clinical trials for the treatment of prostate cancer. Particularly promising are two trials which are currently open and accruing patients with metastatic androgen independent prostate cancer (AIPC). Phase II Trial of Docetaxel, Thalidomide, Prednisone, and Bevacizumab in Patients with Androgen-Independent Prostate Cancer We have shown that the combination of docetaxel and thalidomide is clinically promising in AIPC. In microarray experiments using thalidomide and thalidomide analogs (the analogs are similar to the active metabolite of thalidomide), multiple angiogenesis factors are downregulated (KIF5A, TTK, etc) but not VEGF. VEGF expression was not altered in xenograft experiments using these analogs; however, PDGF was significantly reduced. The CALGB has published data suggesting an elevation in VEGF is a poor prognostic factor in prostate cancer and the reduction of VEGF may result in an important anti-cancer tool. Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody composed of human IgG1 framework regions and antigen-binding complimentary determining regions from a murine monoclonal antibody which blocks the binding of human VEGF receptors. Our hypothesis is that by combining the anti-VEGF activity of bevacizumab with the antiangiogenic activity of thalidomide against multiple targets, but not VEGF, we will effectively suppress the most important angiogenic factors. This approach will test the hypothesis that the blockage of multiple factors in angiogenesis is the most effective anti-tumor strategy. To date 58 patients have been accrued to the trial (out of a planned 60). Eighty-five percent have had a Prostate Specific Antigen (PSA) decline of at least 50%, many for prolonged periods of time. Accrual is continuing to better determines the activity of this combination as well as to study the effect of these agents on markers of angiogenesis. Phase II trial of AZD2171in Androgen Independent Prostate Cancer. AZD2171 (NSC 732208), an orally available small molecule, is a potent inhibitor of receptor tyrosine kinases (RTKs) which influence a key angiogenic factor, vascular endothelial growth factor-A (VEGF). VEGF is implicated in tumor blood vessel formation and in disease progression in a wide range of solid tumor malignancies. Expression of this factor is increased by diverse stimuli which include proto-oncogene activation and hypoxia, with the hypoxic state frequently occurring in solid tumors because of inadequate perfusion. In addition to its angiogenic role, VEGF also profoundly increases the permeability of the vasculature and thereby potentially contributes to tumor progression a leaky tumor endothelium enhances nutrient and catabolite exchange and represents less of a barrier to tumor cell migration during metastasis. With the goal of suppressing neovascularization and thus inhibiting tumor growth and metastasis, numerous antiangiogenic agents have been developed. In contrast to many of these intravenously-administered antiangiogenic agents, a recently emerging class of novel orally-administered VEGF TK inhibitors including AZD2171 has been developed. Of the initial 11 treated patients, tumor responses have been seen in metastatic lymph nodes, liver lesions and bone lesions. This is extremely encouraging in a population of patients all who have been treated with prior chemotherapy. As would be expected in a drug in this class the primary toxicities have been hypertension, fatigue and diarrhea. In addition to clinical outcomes, correlative studies include the measurement of angiogenic growth factors and circulating tumor cells as well as the use of DCE-MRI to measure tumor permeability are included as part of this trial. Further preclinical and clinical studies are planned to evaluate the effect of AZD-2171 on PSA expression and its therapeutic impact in metastatic AIPC using clinical and radiographic evidence of disease progression
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