The angiogenic property of thalidomide reported by D'Amato and colleagues has prompted its clinical evaluation in various solid tumors including prostate cancer. Our laboratory previously showed that one of the products of cytochrome P450 2C19 isozyme biotransformation of thalidomide, 5'-OH-thalidomide, is responsible for the drug's antiangiogenic activity. Based on the chemical structure of this metabolite, we have synthesized 118 analogs of thalidomide and have evaluated them using four in vitro models to assess activity in the inhibition of angiogenesis (rat aorta model, human saphenous vein model, cultured endothelial cells, and tube formationassay). We have identified the most potent of these and have patented them. We are continuing to develop these compounds. These compounds appear have minimal side effects in initial preclinical toxicology studies. Using a randomized Phase II trial design we compared weekly docetaxel (30 mg/m2) with or without 200 mg/d of thalidomide. The objective of this study was to determine whether the combination of thalidomide and docetaxel could produce a sufficiently high clinical response rate to warrant further investigation. A total of 75 patients were enrolled onto this trial, 25 patients in docetaxel alone arm and 50 patients in the combination arm. Both at the midpoint evaluation and at the conclusion of the trial, the proportion of patients with a >50% decline in PSA was higher in the combination arm (25 of 47 patients, 53%) than in the docetaxel alone arm (9 of 24 patients, 37%). The 18 mo survival was 42.9% in the docetaxel alone group and 68.2% in the combined group. The median overall survival in the docetaxel alone group was 14 mo compared with 28 mo for the combination arm (p=0.11) Thalidomide, Docetaxel and Bevacizumab: Dr. Dahut and myself are conducting a Phase II trial of thalidomide, docetaxel, prednisone and bevacizumab in chemo-naive AIPC patients. We previously demonstrated that thalidomide appears to add to the activity of docetaxel in metastatic CRPC. Phase II studies combining docetaxel with bevacizumab have had substantial anti-tumor activity. We hypothesized that the combination docetaxel plus these antiangiogenic drugs with different targets would have substantial clinical activity. To explore safety and efficacy, this was tested in both mouse and patients. Sixty patients with progressive metastatic CRPC received i.v. docetaxel and bevacizumab plus oral thalidomide and prednisone. In the mouse model, combination therapy of docetaxel, bevacizumab, and thalidomide inhibited tumor growth most effectively. The primary endpoint was a PSA decline of ≥50%. Secondary endpoints included time to progression, overall survival, and safety. In the clinical trial, 90% of patients receiving the combination therapy had PSA declines of ≥50% and 88% achieved a PSA decline of ≥30% within the first 3 months of treatment. The median time to progression was 18.3 months and the median overall survival was 28.2 months in this group with a Halabi predicted survival of 14 months. While toxicities were manageable, all patients developed grade 3/4 neutropenia. The addition of bevacizumab and thalidomide to docetaxel is highly active with manageable toxicities. The estimated median survival is encouraging given the generally poor prognosis of this patient population. These results suggest that definitive clinical trials combining antiangiogenic agent combinations with docetaxel are warranted in order to improve treatment outcomes for patients with metastatic CRPC. Thalidomide in Stage D0 Androgen Dependent Prostate Cancer (ADPC) In 1998, I designed a unique double-blinded randommized Phase III trial to determine if thalidomide could improve the efficacy of LHRH agonists in patients with AIPC, that had a rising PSA level after primary definitive therapy (XRT or radical prostatectomy). A total of 159 patients were enrolled in a double-blind randomized trial to determine if thalidomide can improve the efficacy of a gonadotropin-releasing hormone agonist in hormone responsive patients with an increasing PSA after primary definitive therapy for prostate cancer. Patients were randomized to 6 months of gonadotropin-releasing hormone agonist followed by 200 mg per day oral thalidomide or placebo (oral phase A). At the time of PSA progression gonadotropin-releasing hormone agonist was restarted for 6 additional months. Patients were then crossed over to the opposite drug and were treated until prostate specific antigen progression (oral phase B). During oral phase A the median time to PSA progression was 15 months for the thalidomide group compared to 9.6 months on placebo (p = 0.21). The median time to PSA progression during oral phase B for the thalidomide group was 17.1 vs 6.6 months on placebo (p = 0.0002). No differences in time to serum testosterone normalization between the thalidomide and placebo arms were documented during oral phase A and oral phase B. Thalidomide was tolerable although dose reductions occurred in 47% (58 of 124) of patients. Despite thalidomide having no effect on testosterone normalization, there was a clear effect on prostate specific antigen progression during oral phase B. This is the first study to our knowledge to demonstrate the effects of thalidomide using intermittent hormonal therapy. Epidithiodiketopiperazines block the interaction between hypoxia inducible factor-1alpha (HIF-1alpha) and p300 by a zinc ejection mechanism. The hypoxic response in humans is regulated by the hypoxia inducible transcription factor system; inhibition of HIF activity has potential for the treatment of cancer. Chetomin, a member of the epidithiodiketopiperazine (ETP) family of natural products, inhibits the interaction between HIF-alpha and the transcriptional coactivator p300. Structure-activity studies employing both natural and synthetic ETP derivatives reveal that only the structurally unique ETP core is required and sufficient to block the interaction of HIF-1alpha and p300. In support of both cell-based and animal work showing that the cytotoxic effect of ETPs is reduced by the addition of Zn2+ through an unknown mechanism, our mechanistic studies reveal that ETPs react with p300 causing zinc ion ejection. Cell studies with both natural and synthetic ETPs demonstrated reduction in VEGF reduction and anti-proliferative effects that were abrogated by zinc supplementation. The results have implications for the design of selective ETPs and for the interaction of ETPs with other zinc ion binding protein targets involved in gene expression. Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation. In collaboration with Dr. Neil Vargesson, we further investigate the mechanism of action of thalidomide's teratogenic effect. Here we demonstrate that loss of immature blood vessels is the primary cause of thalidomide-induced teratogenesis and provide an explanation for its action at the cell biological level. Antiangiogenic but not antiinflammatory metabolites/analogues of thalidomide induce chick limb defects. Both in vitro and in vivo, outgrowth and remodeling of more mature blood vessels is blocked temporarily, whereas newly formed, rapidly developing, angiogenic vessels are lost. Such vessel loss occurs upstream of changes in limb morphogenesis and gene expression and, depending on the timing of drug application, results in either embryonic death or developmental defects. These results explain both th [summary truncated at 7800 characters]
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