BERKELEY, CA (UroToday.com) - Patients with metastastic castrate-resistant prostate cancer (mCRPC) are currently all being treated equally with various monotherapies. Similar to breast cancer, it is expected that in the future combination therapies may exhibit additional antitumor efficacy against mCRPC. However, while multiple phase III studies have tested combination therapies in mCRPC patients, particularly with docetaxel, none of these combination therapies resulted in significant additional antitumor efficacy. These clinical studies are expensive, time-consuming, and require enrollment of patients who will receive combination therapy that appears to be ineffective, but has potentially severe adverse events. Improved pre-clinical studies are needed to provide a thorough rationale for clinical studies with novel agents and/or combination therapies. Such extensive preclinical testing is, at the moment, time-consuming as well, but prevents patients’ exposure to ineffective therapies.
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In the current study, we applied analysis of functional annotation (AFA) as a strategy to identify novel combination therapies in a fast and unbiased approach. By applying AFA, functional gene sets (e.g., genes in one pathway) are identified from multiple databases that are differentially expressed upon certain manipulations of cells (such as treatment with anticancer therapy, or time). Changes in expression -- particularly up-regulation -- of functional gene sets that seem unrelated to the mechanism of action of the therapy could invoke tumor resistance to certain therapy. Additional targeting of down-regulated functional gene sets by another type of inhibitor in the same crucial pathway could maximize tumor inhibition.
AFA was performed on various prostate cancer cell lines after treatment with histone deacetylase inhibitors (HDACIs). HDACIs inhibit histone deacetylase activity, thereby re-expressing tumor suppressor genes for which activity has been suppressed by HDAC activity of tumor cells. Two HDACIs are currently approved for clinical use (romidepsin, vorinostat); other HDACIs are in advanced stages of clinical development for the treatment of solid tumors and leukemias.
HDACIs have a wide variety of action as they affect expression of many genes. Therefore, HDACIs seem particularly suitable for combination therapy. In our study, we provide extensive lists of gene pathways that are differentially expressed upon HDACI-treatment. These findings could be used as a rationale for novel combination therapies. In the manuscript we further explore two suggestions for combination therapies that might be of use in clinical practice: HDACIs with immunotherapy, and HDACIs with mitotic kinase inhibitors. However, multiple other combination therapies, such as HDACIs with AR-targeting agents (abiraterone, enzalutamide), could be tested based on the findings we report in this study. Indeed, recent findings presented by our group, and others, suggest that combining HDACIs with mitotic kinase inhibitors such as aurora kinase inhibitors or polo-like kinase 1 inhibitors results in synergistically inhibited prostate cancer growth. Future clinical studies are needed to confirm these preclinical findings in patients and to confirm the clinical value of AFA.
Michel D. Wissing,a Madeleine S.Q. Kortenhorst,b and Luigi Marchionnic 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.
aProstate Cancer Program; Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University School of Medicine; Baltimore, MD USA; Department of Clinical Oncology; Leiden University Medical Center; Leiden, The Netherlands; Division of Pathology; University Medical Center Utrecht; Utrecht, The Netherlands
bDepartment of Gynecology; Catharina Hospital Eindhoven; Eindhoven, The Netherlands; Prostate Cancer Program; Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University School of Medicine; Baltimore, MD USA
cDepartment of Oncology; Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University School of Medicine; Baltimore, MD USA