Biological and clinical effects of abiraterone on anti-resorptive and anabolic activity in bone microenvironment

Iuliani, Michele; Pantano, Francesco; Buttigliero, Consuelo; Fioramonti, Marco; Bertaglia, Valentina; Vincenzi, Bruno; Zoccoli, Alice; Ribelli, Giulia; Tucci, Marco; Vignani, Francesca; Berruti, Alfredo; Scagliotti, Giorgio Vittorio; Tonini, Giuseppe; Santini, Daniele

doi:10.18632/oncotarget.3724

Cited by 49 publications

(39 citation statements)

References 23 publications

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“…Although these secondary androgen suppression agents show high efficacy in Phase III trials (5–8), their impact on bone microenvironment remains largely unknown. One report has suggested that CYP17 inhibition with abiraterone has direct effects on bone anabolic and anti-resorptive activity (9). …”

Section: Introductionmentioning

confidence: 99%

Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models

Suominen

Fagerlund

Rissanen

et al. 2017

Clinical Cancer Research

142

118

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Purpose Radium-223 dichloride (radium-223, Xofigo®), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models. Experimental Design Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized to groups (n = 12–17) based on lesion grade and/or serum PSA level and administered with radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals. X-rays and serum samples were obtained biweekly. Soft tissue tumors were observed macroscopically at sacrifice. Tibiae were analyzed by gamma counter, micro-CT, autoradiography and histology. Results Radium-223 inhibited tumor-induced osteoblastic bone growth and protected normal bone architecture leading to reduced bone volume in LNCaP and abiraterone-resistant LuCaP 58 models. Furthermore, radium-223 resulted in lower PSA values and reduced total tissue and tumor areas, indicating that treatment constrains prostate cancer growth in bone. In addition, radium-223 suppressed abnormal bone metabolic activity as evidenced by decreased number of osteoblasts and osteoclasts and reduced level of the bone formation marker PINP. Mode-of-action studies revealed that radium-223 was deposited in the intratumoral bone matrix. DNA double-strand breaks were induced in cancer cells within 24 hours after radium-223 treatment and PSA levels were significantly lower 72 hours post treatment providing further evidence of the anti-tumor effects. Conclusion Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathological bone formation in tumor microenvironment in osseous CRPC growth in mice.

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Section: Introductionmentioning

confidence: 99%

Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models

Suominen

Fagerlund

Rissanen

et al. 2017

Clinical Cancer Research

142

118

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“…Androgen altered signalling is a validated therapeutic target in metastatic castration-resistant prostate cancer. Initially thought to target only prostate cancer cells, abiraterone acetate directly inhibits osteoclastogenesis and promotes osteoblastogenesis and bone matrix deposition [120]. The use of antiandrogens like abiraterone acetate increases OS and delays time to development of SRE in metastatic castration-resistant prostate cancer patients [121].…”

Section: Hormone Related Therapiesmentioning

confidence: 99%

Bone-Targeted Therapies in Cancer-Induced Bone Disease

Sousa

Clézardin

2017

Calcif Tissue Int

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Cancer-induced bone disease is a major source of morbidity and mortality in cancer patients. Thus, effective bone-targeted therapies are essential to improve disease-free, overall survival and quality of life of cancer patients with bone metastases. Depending of the cancer-type, bone metastases mainly involve the modulation of osteoclast and/or osteoblast activity by tumour cells. To inhibit metastatic bone disease effectively, it is imperative to understand its underlying mechanisms and identify the target cells for therapy. If the aim is to prevent bone metastasis, it is essential to target not only bone metastatic features in the tumour cells, but also tumour-nurturing bone microenvironment properties. The currently available bone-targeted agents mainly affect osteoclasts, inhibiting bone resorption (e.g. bisphosphonates, denosumab). Some agents targeting osteoblasts begin to emerge which target osteoblasts (e.g. romosozumab), activating bone formation. Moreover, certain drugs initially thought to target only osteoclasts are now known to have a dual action (activating osteoblasts and inhibiting osteoclasts, e.g. proteasome inhibitors). This review will focus on the evolution of bone-targeted therapies for the treatment of cancer-induced bone disease, summarizing preclinical and clinical findings obtained with anti-resorptive and bone anabolic therapies.

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“…The STAMPEDE study also demonstrated an unprecedented survival benefit in favor of the combination [95]. In another recent trial, abiraterone was shown to have direct bone antiresorptive and anabolic activity [96], and a randomized phase 3 trial is currently examining the survival benefit of abiraterone and ADT versus ADT plus a placebo in men with newly diagnosed mCRPC (NCT01715285). In comparison with bicalutamide, enzalutamide has proven to be a more potent AR blocker with no AR agonist activity in mPCa [97, 98].…”

Section: Potential Therapeutic Intervention Of Pca Metastasismentioning

confidence: 99%

Cellular determinants and microenvironmental regulation of prostate cancer metastasis

Rycaj

Zhou

et al. 2017

Seminars in Cancer Biology

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Metastasis causes more than 90% of cancer-related deaths and most prostate cancer (PCa) patients also die from metastasis. The ‘metastatic cascade’ is a complex biological process that encompasses tumor cell dissociation (from the primary tumor), local invasion, intravasation, transport in circulation, extravasation, colonization, and overt growth in end organs. It has become clear that successful metastasis not only involves many tumor cell-intrinsic properties but also depends on productive interactions between cancer cells and the tumor microenvironment. In this Review, we begin with a general summary on cancer metastasis and a specific discussion on PCa metastasis. We then discuss recent advances in our knowledge of the cellular determinants of PCa metastasis and the importance of tumor microenvironment, especially an immunosuppressive tumor microenvironment, in shaping metastatic propensities. We conclude with a presentation of current and future therapeutic options for patients with PCa metastasis, emphasizing the development of novel, mechanism-based combinatorial strategies for treating metastatic and castration-resistant PCa.

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Biological and clinical effects of abiraterone on anti-resorptive and anabolic activity in bone microenvironment

Cited by 49 publications

References 23 publications

Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models

Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models

Bone-Targeted Therapies in Cancer-Induced Bone Disease

Cellular determinants and microenvironmental regulation of prostate cancer metastasis

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