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      Targeted α Therapies for the Treatment of Bone Metastases

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          Abstract

          The skeleton is the target tissue for many types of tumors, and, recently, the survival of patients with prostate cancer metastasis has been increased using α-emitting drugs known as targeted α therapies. The use of α-radiopharmaceuticals in medicine was hypothesized at the beginning of the nineteenth century after the observation that α-radionuclides were associated with high cell-killing energy and low tissue penetration in healthy tissues. In the prostate cancer (PC) scenario, current research suggests that this class of radiopharmaceuticals has limited toxicity, and that the mechanism of action does not overlap with pre-existing drugs, allowing us to extend therapeutic armaments and address medical oncology towards personalized and precision medicine. Ongoing studies may extend these benefits also to bone metastases deriving from other neoplasms. The aim of this review is to summarize the current research on targeted α therapies and try to identify the right patient to be treated in the right time in order to integrate in these medications in the every-day clinical practice.

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          Most cited references 55

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          Alpha emitter radium-223 and survival in metastatic prostate cancer.

          Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).
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            The Evolutionary History of Lethal Metastatic Prostate Cancer

            Cancers emerge from an on-going Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour 1-4 . This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths 5 . However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported 6-8 , recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and inter-clonal cooperation between multiple subclones 9,10 . In this study, we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole genome sequencing, we characterised multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen deprivation therapy in prostate cancer.
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              225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer.

              Prostate-specific membrane antigen (PSMA) is a promising target in prostate cancer. Recently, we started the first-in-human treatment with an α-radionuclide-labeled PSMA ligand. Although the case series is still ongoing, we here report in advance about two patients in highly challenging clinical situations who showed a complete response to (225)Ac-PSMA-617 therapy.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                28 December 2017
                January 2018
                : 19
                : 1
                Affiliations
                [1 ]UOC Oncologia, ULSS 1 Dolomiti, Belluno Medical Hospital “San Martino”, Viale Europa 22, 32100 Belluno, Italy
                [2 ]Bayer Spa, Viale Certosa 210, 201156 Milan, Italy; roberto.barsanti@ 123456bayer.com
                Author notes
                [* ]Correspondence: fable.zustovich@ 123456aulss1.veneto.it ; Tel.: +39-0437-516512
                Article
                ijms-19-00074
                10.3390/ijms19010074
                5796024
                29283383
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                Categories
                Review

                Molecular biology

                radium 223, tumour cell dormancy, prostate cancer, breast cancer, bone metastases

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