William L. Dahut, M.D.
Genitourinary Malignancies Branch
Acting Scientific Director for Clinical Research
Building 10, CRC 3-2571
Bethesda, MD 20892
New Therapeutics for Patients With Genitourinary Malignancies
The Development of Novel Therapeutics for Prostate Cancer. Prostate cancer is the most common non-dermatologic malignancy and the second leading cause of cancer related death in American men. During 2004, an estimated 230,100 men will have prostate cancer diagnosed, and 29,100 men will die of this disease in the United States.
This project is focused on translational clinical trials for the treatment of prostate cancer. The research program in prostate cancer has been focused on attempting to develop hypothesis-driven novel therapies for each disease state that a prostate cancer patient may experience. Treatment needs to balance the biology of the tumor at that point with the clinical goals of maintaining quality of life and prolonging survival. In addition, in the unique environment of the NCI we have been able to combine each clinical trial with important biologic endpoints. Many of these trials involve antiangiogenic agents, novel small molecules or unique vaccines. Currently 8 trials are involved in the active treatment of patients.
Clinical Trials Using Antiangiogenic Agents. As prostate cancer advances from an indolent to a more lethal state it becomes dependent on angiogenesis. Angiogenesis is also required at sites of secondary colonizations in order for prostate cancer metastases to proliferate and expand. Without angiogenesis, primary prostate tumors typically are confined to a diameter of 1 to 2 mm and remain indolent. Tumor specimens from men with clinical prostate cancer have been characterized by a remarkably high degree of vascularization compared with autopsy-identified prostate tumors from men without clinical disease.
We believe that the inhibition of angiogenesis is an attractive target in the treatment of prostate cancer. We have collaborated actively with the laboratory of Dr. William Figg, both in the development of agents targeting blood vessel growth as well as in the performance of ancillary studies designed to determine the impact of new agents on markers of angiogenesis.
Thalidomide in the Treatment of Prostate Cancer. Thalidomide is a potent teratogen that causes dysmelia (stunted limb growth) in humans. It was marketed in Europe as a nonbarbiturate sedative but was withdrawn 30 years ago because of its teratogenic effects. It has been postulated that thalidomide-induced limb defects were secondary to an inhibition of blood vessel growth in the developing fetal limb buds. In 1994, D'Amato et al. demonstrated that thalidomide inhibited bFGF-induced angiogenesis. Bauer et al. subsequently determined that a metabolite (5'OH thalidomide) of thalidomide was responsible for this antiangiogenic activity. These preclinical findings prompted investigators to evaluate thalidomide as an inhibitor of angiogenesis, which has been implicated in the pathogenesis of various types of hematologic malignancies and solid tumors.
We evaluated thalidomide in patients with androgen-independent prostate cancer and found 18% of patients to have significant PSA declines. Preclinical data suggested that the addition of a cytotoxic agent to an anti-angiogenic agent was more than additive. In order to test this hypothesis we conducted a randomized phase II trial combining thalidomide with docetaxel. A total of 75 patients with progressive androgen-independent prostate cancer were accrued (25 patients to the docetaxel alone and 50 to the combination group). Both at the midpoint evaluation and after conclusion of the trial, the proportion of patients with a greater than 50% decline in PSA was higher in the combination arm: 9 of 24 patients (37%) in the docetaxel alone arm and 25 of 49 patients (51%) in the combined group. There also was a trend towards improved survival. The median survival in the combination arm was about double that of docetaxel alone.
It is postulated that the efficacy of anti-angiogenic agents, such as thalidomide, will be greatest in the setting of minimal disease burden. We are testing that hypothesis in a phase III trial in patients with a biochemical recurrence after initial local therapy. In addition, we are currently conducting 2 phase I trials of oral anti-angiogenic agents (2-methoxyestradiol and CC-5013), which we believe are well suited for prostate cancer patients.
Small Molecules in the Treatment of Prostate Cancer. Perifosine represents a new class of anti-cancer compounds. It is an akylphospholipid related to miltefosine. Perifosine was show to have a unique pattern of growth inhibition with in vitro systems. Modulation of cell surface receptors and inhibition of lipid-mediated signal transduction appear to be important in its activity. Perifosine has been shown to lead to loss of cyclin-dependent kinases (cdk) activity and subsequent cell cycle arrest in G1-S and G2-M phases. Treatment with this drug has been shown to increase p21WAF1 expression resulting in inactivation of the cdk/cyclin complex and subsequent cell cycle arrest. In cell culture with PC3 cells, clear induction of apoptosis was observed. We have postulated that cell cycle arrest will lead to a prolongation of time to progression in patients. We are testing this hypothesis in a Phase II trial in patients with metastatic advanced prostate cancer. Results of this trial as well as correlative lab studies measuring cell cycle parameters will guide in the future development of this agent.
Vaccines in the Treatment of Prostate Cancer. In collaboration with the laboratory of Dr. Jeffrey Schlom, we have performed a series of clinical trials using recombinant poxvirus PSA vaccines. We have hypothesized that vaccines may be more effective when combined with more traditional anti-cancer treatments such as radiotherapy and cytotoxics. We have performed randomized phase II trials comparing vaccine and radiotherapy to radiotherapy alone and comparing vaccine to docetaxel and vaccine. Both of these trials were performed in order to understand the effect of combination therapy on the immune system prior to embarking on larger trials with clinical endpoints. Initial immunologic data supports the ability to combine these treatments and plans are underway to test these combinations with clinical endpoints.
Our collaborators are Philip Arlen, William Figg, W. Marston Linehan, James Gulley, Jeff Schlom, and Elise Kohn, NIH; and Dan Petrylak, Columbia University.
Ning YM, Gulley JL, Arlen PM, Woo S, Steinberg SM, Wright JJ, Parnes HL, Trepel JB, Lee MJ, Kim YS, Sun H, Madan RA, Latham L, Jones E, Chen CC, Figg WD, Dahut WL. Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28(12):2070-6.
Gulley JL, Arlen PM, Madan RA, Tsang KY, Pazdur MP, Skarupa L, Jones JL, Poole DJ, Higgins JP, Hodge JW, Cereda V, Vergati M, Steinberg SM, Halabi S, Jones E, Chen C, Parnes H, Wright JJ, Dahut WL, Schlom J. Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer. Cancer Immunol Immunother. 2010;59(5):663-74.
Arlen PM, Gulley JL, Parker C, Skarupa L, Pazdur M, Panicali D, Beetham P, Tsang KY, Grosenbach DW, Feldman J, Steinberg SM, Jones E, Chen C, Marte J, Schlom J, Dahut W. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin Cancer Res. 2006;12(4):1260-9.
Gulley JL, Arlen PM, Bastian A, Morin S, Marte J, Beetham P, Tsang KY, Yokokawa J, Hodge JW, Ménard C, Camphausen K, Coleman CN, Sullivan F, Steinberg SM, Schlom J, Dahut W. Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer. Clin Cancer Res. 2005;11(9):3353-62.
Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA. 2005;294(2):238-44.
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This page was last updated on April 26th, 2018