Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer

Michaelson, M. Dror; Kaufman, Donald S.; Kantoff, Philip W.; Oh, William K.; Smith, Matthew R.

doi:10.1002/cncr.22043

Cited by 40 publications

(22 citation statements)

References 21 publications

(27 reference statements)

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“…Atrasentan delays time to progression in prostate cancer in phase III clinical trials (Jimeno & Carducci 2005). A randomised phase II study of Atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer showed no evidence for additive or synergistic effects of combination therapy with Atrasentan and zoledronic acid on bone turnover markers (Michaelson et al 2006). However, ET-RA blockade enhances taxane effects in prostate cancer in vitro and in vivo (Akhavan et al 2006).…”

Section: Advances In Endothelin-based Therapeutic Strategies Prostatementioning

confidence: 99%

Endothelins and hypoxia-inducible factor in cancer

Grimshaw¹

2007

Endocr Relat Cancer

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The endothelin system is a family of three similar small peptides, two G-protein-coupled receptors and two proteinases. Endothelins have several physiological roles, notably in embryonic differentiation and vascular homeostasis. Numerous types of tumour express endothelins and their regulation is often aberrant when compared with the normal tissue from which the tumour arose. However, endothelin expression is tumour-type specific, and in some instances, expression of individual members of the endothelin system will be upregulated, while in other tumour types, they may be downregulated. Endothelins have numerous potential roles in tumours including modulating angiogenesis, inducing mitogenesis and invasion of tumour cells, and protecting cells from apoptosis. Expression of endothelins is controlled by the tumour microenvironment, whilst the endothelins themselves modify that environment; a case in point is that hypoxia stimulates endothelin expression via hypoxia-inducible factor (HIF)-1, while endothelins stabilise HIF-1 leading to expression of, for instance, vascular endothelial growth factor. This review highlights the potential roles of endothelins in various cancers and describes the pre-clinical and clinical progress that has been made in several tumour types -notably prostate, ovary, melanoma and breast cancer. The interactions between the endothelin network and HIF-1 are highlighted.

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Section: Advances In Endothelin-based Therapeutic Strategies Prostatementioning

confidence: 99%

Endothelins and hypoxia-inducible factor in cancer

Grimshaw¹

2007

Endocr Relat Cancer

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“…Also in combination strategies with conventional chemotherapy agents such as docetaxel in prostate cancer and carboplatin/paclitaxel in lung cancer, atransentan did not add any benefits in overall or progression-free survival (75,76). In the setting of bone metastasis of prostate cancer, atransentan and zoledronic acid did not prove synergistic in markers of bone metabolism (77). More extensive studies are required to assess the efficacy of endothelin Fig.…”

Section: Targeting Osteoblast Functionmentioning

confidence: 99%

Novel Bone-Targeted Strategies in Oncology

Vallet

Smith²

2010

Clinical Cancer Research

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Most patients with bone metastases experience skeletal complications, resulting in significant morbidity and increased risk of death. Although the use of bisphosphonates is a well-established form of supportive care treatment for bone metastasis, complications arising from long-term use require schedule optimization and a search for alternative strategies. Moreover, the scope of use of bone-targeted agents in oncology has widened to include therapy-induced bone loss and antitumor effects. Indeed, bone provides a permissive niche to tumor growth, and targeting the interactions within the bone microenvironment is a promising antitumor strategy. In addition, the pathogenesis of cancer-related bone disease has been partially unraveled with a focus on the anabolic bone compartment, and the rapid benchto-bedside translation has resulted in the identification of novel therapeutically amenable targets. This review focuses on studies optimizing bisphosphonate use and recent clinical data on denosumab in the treatment of bone disease. We also provide data on trials that have evaluated the antitumor effects of bisphosphonates and summarize the most recent discoveries on the role of the bone niche in cancer development, with insights into the preclinical rationale and clinical assessment of novel antiresorptive and anabolic bone-targeted agents. Clin Cancer Res; 16(16); 4084-93. ©2010 AACR. Scope of the ProblemBone involvement is a common feature in solid and hematologic cancers. Multiple myeloma localizes to the bone in nearly all patients, and the incidence of bone metastasis in solid cancers ranges between 20% and 75% (1, 2). Disease-related skeletal complications result in significant morbidity due to pain, pathologic fractures and spinal cord compression (3). In addition, the occurrence of pathologic fractures increases the risk of death by 20% to 40% (4). Not only is bone involvement due to metastatic disease of significance, but the increasing incidence of therapy-related bone loss has widened the scope of use of bone-targeted agents in oncology (5). In addition, recent preclinical and clinical studies have suggested that bone provides a permissive niche to tumor cell growth, and targeting the interactions within the bone milieu may represent an important strategy to suppress tumor development (6, 7). Therefore, restoring a balanced bone environment may not only positively impact bone disease but may also help reduce tumor burden.In this review, we provide an overview of novel, biologically based therapeutic strategies aimed at preventing and/or decreasing disease-related skeletal complications and discuss the evidence for antitumor effects from restored bone homeostasis. Biology of Bone Disease and MetastasisThe skeleton is a dynamic organ that undergoes extensive remodeling throughout life. Modest changes in the kinetics of bone resorption and formation result in dramatic net effects on bone architecture (8). In the cancer setting, the cross-talk between tumor and bone cells disrupts normal bone homeostasis...

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“…However, this trial failed to provide evidence for additive or synergistic effects of combination therapy with atrasentan and zoledronic acid on bone turnover markers. 22 Furthermore, a subsequent phase 3 trial, although showing evidence of biologic effects on PSA and bone markers, failed to delay disease progression in men with metastatic hormone refractory prostate cancer. 23 Another trial using the ET-1 receptor antagonist named zibotentan (ZD4054) failed to provide a significant clinical benefit in patients with prostate cancer when applied singularly and in combination with docetaxel.…”

Section: Endothelin-1mentioning

confidence: 99%

Cancer-targeted therapies and radiopharmaceuticals

Rachner¹,

Jakob

Hofbauer

2015

BoneKEy Reports

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The treatment of bone metastases remains a clinical challenge. Although a number of well-established agents, namely bisphosphonates and denosumab, are available to reduce the occurrence of skeletal-related events, additional cancer-targeted therapies are required to improve patients' prognosis and quality of life. This review focuses on novel targets and agents that are under clinical evaluation for the treatment of malignant bone diseases such as activin A, src and endothelin-1 inhibition or agents that are clinically approved and may positively influence bone, such as the mTOR inhibitor everolimus. In addition, the potential of alpharadin, a novel radiopharmaceutical approved for the treatment of prostatic bone disease, is discussed.

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Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer

Cited by 40 publications

References 21 publications

Endothelins and hypoxia-inducible factor in cancer

Endothelins and hypoxia-inducible factor in cancer

Novel Bone-Targeted Strategies in Oncology

Cancer-targeted therapies and radiopharmaceuticals

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