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      Novel therapeutic approaches for the treatment of castration-resistant prostate cancer

      research-article
      a , a , a , b , a , c , a , a , a , *
      The Journal of Steroid Biochemistry and Molecular Biology
      Pergamon
      AR, androgen receptor, CRPC, castration-resistant prostate cancer, ET, endothelin, IGF, insulin-like growth factor, OS, overall survival, PCa, prostate cancer, PDGFR, platelet-derived growth factor receptor, PFS, progression free survival, PSA, prostate-specific antigen, RANK-L, RANK ligand, SD, stable disease, TKI, tyrosine kinase inhibitor, VEGF, vascular endothelial growth factor, VEGFR, vascular endothelial growth factor receptor, Castration-resistant prostate cancer, Androgen receptor, Bone metastasis angiogenesis, Immunotherapy, Radiotherapy, Chemotherapy, Growth factor receptor inhibitors

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          Highlights

          • New drugs approved for treatment of castration resistant prostate cancer.

          • Prime targets: androgen receptor, bone cells, cell division, immune system.

          • Several promising drugs disappointed in clinical trials.

          • Further efforts necessary to optimize the sequence and combinations of drugs.

          • New biomarkers required for stratification of patient and therapy selection.

          Abstract

          Prostate cancer is a leading cause of cancer death in men in developed countries. Once the tumor has achieved a castration-refractory metastatic stage, treatment options are limited with the average survival of patients ranging from two to three years only. Recently, new drugs for treatment of castration-resistant prostate cancer (CRPC) have been approved, and others are in an advanced stage of clinical testing. In this review we provide an overview of the new therapeutic agents that arrived in the clinical praxis or are tested in clinical studies and their mode of action including hormone synthesis inhibitors, new androgen receptor blockers, bone targeting and antiangiogenic agents, endothelin receptor antagonists, growth factor inhibitors, novel radiotherapeutics and taxanes, and immunotherapeutic approaches. Results and limitations from clinical studies as well as future needs for improvement of CRPC treatments are critically discussed.

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          Most cited references85

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          VEGF as a Key Mediator of Angiogenesis in Cancer

          Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein with a molecular weight of approximately 45 kDa. It is the key mediator of angiogenesis (the formation of new blood vessels), and binds two VEGF receptors (VEGF receptor-1 and VEGF receptor-2), which are expressed on vascular endothelial cells. In healthy humans, VEGF promotes angiogenesis in embryonic development and is important in wound healing in adults. VEGF is the key mediator of angiogenesis in cancer, in which it is up-regulated by oncogene expression, a variety of growth factors and also hypoxia. Angiogenesis is essential for cancer development and growth: before a tumor can grow beyond 1–2 mm, it requires blood vessels for nutrients and oxygen. The production of VEGF and other growth factors by the tumor results in the ‘angiogenic switch’, where new vasculature is formed in and around the tumor, allowing it to grow exponentially. Tumor vasculature formed under the influence of VEGF is structurally and functionally abnormal. Blood vessels are irregularly shaped, tortuous, have dead ends and are not organized into venules, arterioles and capillaries. They are also leaky and hemorrhagic, which leads to high interstitial pressure. These characteristics mean that tumor blood flow is suboptimal, resulting in hypoxia and further VEGF production. This central role of VEGF in the production of tumor vasculature makes it a rational target for anticancer therapy.
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            The insulin and insulin-like growth factor receptor family in neoplasia: an update.

            Although several early phase clinical trials raised enthusiasm for the use of insulin-like growth factor I receptor (IGF1R)-specific antibodies for cancer treatment, initial Phase III results in unselected patients have been disappointing. Further clinical studies may benefit from the use of predictive biomarkers to identify probable responders, the use of rational combination therapies and the consideration of alternative targeting strategies, such as ligand-specific antibodies and receptor-specific tyrosine kinase inhibitors. Targeting insulin and IGF signalling also needs to be considered in the broader context of the pathophysiology that relates obesity and diabetes to neoplasia, and the effects of anti-diabetic drugs, including metformin, on cancer risk and prognosis. The insulin and IGFI receptor family is also relevant to the development of PI3K-AKT pathway inhibitors.
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              Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study.

              MDV3100 is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Because growth of castration-resistant prostate cancer is dependent on continued androgen-receptor signalling, we assessed the antitumour activity and safety of MDV3100 in men with this disease. This phase 1-2 study was undertaken in five US centres in 140 patients. Patients with progressive, metastatic, castration-resistant prostate cancer were enrolled in dose-escalation cohorts of three to six patients and given an oral daily starting dose of MDV3100 30 mg. The final daily doses studied were 30 mg (n=3), 60 mg (27), 150 mg (28), 240 mg (29), 360 mg (28), 480 mg (22), and 600 mg (3). The primary objective was to identify the safety and tolerability profile of MDV3100 and to establish the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT00510718. We noted antitumour effects at all doses, including decreases in serum prostate-specific antigen of 50% or more in 78 (56%) patients, responses in soft tissue in 13 (22%) of 59 patients, stabilised bone disease in 61 (56%) of 109 patients, and conversion from unfavourable to favourable circulating tumour cell counts in 25 (49%) of the 51 patients. PET imaging of 22 patients to assess androgen-receptor blockade showed decreased (18)F-fluoro-5alpha-dihydrotestosterone binding at doses from 60 mg to 480 mg per day (range 20-100%). The median time to progression was 47 weeks (95% CI 34-not reached) for radiological progression. The maximum tolerated dose for sustained treatment (>28 days) was 240 mg. The most common grade 3-4 adverse event was dose-dependent fatigue (16 [11%] patients), which generally resolved after dose reduction. We recorded encouraging antitumour activity with MDV3100 in patients with castration-resistant prostate cancer. The results of this phase 1-2 trial validate in man preclinical studies implicating sustained androgen-receptor signalling as a driver in this disease. Medivation, the Prostate Cancer Foundation, National Cancer Institute, the Howard Hughes Medical Institute, Doris Duke Charitable Foundation, and Department of Defense Prostate Cancer Clinical Trials Consortium. Copyright 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                J Steroid Biochem Mol Biol
                J. Steroid Biochem. Mol. Biol
                The Journal of Steroid Biochemistry and Molecular Biology
                Pergamon
                0960-0760
                1879-1220
                1 November 2013
                November 2013
                : 138
                : 100
                : 248-256
                Affiliations
                [a ]Department of Urology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
                [b ]Department of Hematology and Oncology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
                [c ]Department of Radiology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
                Author notes
                [* ]Corresponding author at: Department of Urology, Division of Experimental Urology, Anichstrasse 35, 6020 Innsbruck, Austria. Tel.: +43 512 504 24818; fax: +43 512 504 24817. helmut.klocker@ 123456uki.at
                Article
                S0960-0760(13)00117-9
                10.1016/j.jsbmb.2013.06.002
                3834152
                23792785
                11de526d-66c8-4586-93c4-b300c005162b
                © 2013 The Authors

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 18 March 2013
                : 28 May 2013
                : 4 June 2013
                Categories
                Article

                Biochemistry
                ar, androgen receptor,crpc, castration-resistant prostate cancer,et, endothelin,igf, insulin-like growth factor,os, overall survival,pca, prostate cancer,pdgfr, platelet-derived growth factor receptor,pfs, progression free survival,psa, prostate-specific antigen,rank-l, rank ligand,sd, stable disease,tki, tyrosine kinase inhibitor,vegf, vascular endothelial growth factor,vegfr, vascular endothelial growth factor receptor,castration-resistant prostate cancer,androgen receptor,bone metastasis angiogenesis,immunotherapy,radiotherapy,chemotherapy,growth factor receptor inhibitors

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