BERKELEY, CA (UroToday.com) - There is currently no curative treatment for castration-resistant prostate cancer (CRPC). Causing the accumulation of ubiquitinated proteins is an innovative approach to cancer treatment, but it has never been clinically tried in prostate cancer or other urological malignancies. The authors’ group has investigated this approach in urological malignancies and their work has been highly regarded, receiving the 99th Japanese Urological Association Annual Meeting Award, and Best Poster Awards at the 26th European Association of Urology (EAU) Congress and the 28th EAU Congress.
In the present study, the authors developed a novel combination therapy against prostate cancer by using the clinically feasible agents vorinostat and bortezomib to cause the accumulation of ubiquitinated proteins. Vorinostat is a histone deacetylase inhibitor that has been used elsewhere for the treatment of cutaneous T cell lymphoma and has recently also been approved for this use in Japan. Bortezomib, on the other hand, is a proteasome inhibitor widely used to treat multiple myeloma. Unfortunately, either vorinostat or bortezomib alone has been reported to be ineffective in patients with advanced prostate cancer.[2, 3] The present study demonstrated a synergistic effect of vorinostat and bortezomib that is due to a novel mechanism of action, and it encourages clinical trials of the use of these agents in combination therapy for patients with advanced prostate cancer, including those with CRPC.
Vorinostat inhibits histone deacetylases and suppresses the function of heat shock protein 90, leading to the accumulation of misfolded proteins. The authors postulated that combining bortezomib with vorinostat would effectively kill cancer cells by inhibiting the degradation of these misfolded proteins and thereby enhancing the accumulation of ubiquitinated proteins. They found that the combination dramatically enhanced ubiquitinated protein accumulation and inhibited prostate cancer growth synergistically both in vitro and in vivo. They also showed that the combination decreased the expression of cyclin D1 and cyclin-dependent kinase (CDK) 4 and increased the expression of p21, thus inhibiting both the expression and function of cyclin D1/CDK4 complexes. This is another important mechanism of the combination’s action. Furthermore, they have found that expression of the androgen receptor (AR) interferes with bortezomib activity. This explains why bortezomib alone was not effective in clinical settings, where many CRPC patients still express AR. They also showed that vorinostat inhibits the expression of AR and therefore sensitizes the prostate cancer cells to bortezomib. More interestingly, the authors showed that the combination enhanced histone acetylation synergistically and this acetylation was due to the accumulation of ubiquitinated proteins.
Thus the combination of vorinostat and bortezomib was effective against prostate cancer cells because it enhanced the accumulation of ubiquitinated proteins and enhanced histone acetylation. This is the first study to introduce this novel treatment concept to the treatment of prostate cancer. This paper was cited in the “This Month in Investigative Urology” section of the Journal of Urology and was also featured as a “Key Scientific Article” by Global Medical Discovery, demonstrating the global impact of this innovative treatment strategy. Because of the mechanism of action of this combination is completely different from the mechanisms of action of previously attempted therapies, and also because of the global attention to this paper, it is worthwhile testing this combination in patients with CRPC who are refractory to other currently available treatment modalities. The combination’s safety in multiple myeloma patients has already been investigated in a phase I trial, and the phase II and III trials are ongoing. I am convinced that the present study encourages investigators to conduct clinical trials using the combination of vorinostat and bortezomib in patients with CRPC.
- Sato A. Vorinostat approved in Japan for treatment of cutaneous T-cell lymphomas: status and prospects. Onco Targets Ther 2012; 5: 67-75.
- Bradley D, Rathkopf D, Dunn R, Stadler WM, Liu G, Smith DC, Pili R, Zwiebel J, Scher H, Hussain M. Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862): trial results and interleukin-6 analysis: a study by the Department of Defense Prostate Cancer Clinical Trial Consortium and University of Chicago Phase 2 Consortium. Cancer 2009; 115: 5541-9.
- Morris MJ, Kelly WK, Slovin S, Ryan C, Eicher C, Heller G, Scher HI. A phase II trial of bortezomib and prednisone for castration resistant metastatic prostate cancer. J Urol 2007; 178: 2378-83.
- Andersson KE. This Month in Investigative Urology. J Urol 2012; 188: 2033-4.
- Global Medical Discovery [ISSN1929-8536] (http://globalmedicaldiscovery.com)
- Badros A, Burger AM, Philip S, Niesvizky R, Kolla SS, Goloubeva O, Harris C, Zwiebel J, Wright JJ, Espinoza-Delgado I, Baer MR, Holleran JL, Egorin MJ, Grant S. Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 2009; 15: 5250-7.
Masamichi Hayakawa, MD, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
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Shioya Hospital, International University of Health and Welfare