Anti-endothelin drugs in solid tumors

Russo, Antonio; Bronte, Giuseppe; Rizzo, Sérgio; Fanale, Daniele; Gaudio, Francesca Di; Gebbia, Nicola; Bazan, Viviana

doi:10.1517/14728210903571667

Cited by 19 publications

(12 citation statements)

References 76 publications

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“…In clinical studies (phase I -III) with ABT-627 in prostate cancer, pain was reduced, however, reduction of time to progression and overall survival has not been observed in clinical studies. With Zibotentan, another ET A R antagonist, comparable results were obtained [118]. In a phase II clinical trial using the ET A R antagonist ZD4054 time to progression (primary endpoint) was found not to be statistically different between treatment and placebo groups.…”

Section: The Et-1 Pathwaymentioning

confidence: 72%

“…Local ET-1 production by skeletal metastases enhances de novo bone formation via the ET A R leading, eventually, to osteoblastic metastases [28]. Atrasentan (ABT-627) is one of the most potent and selective ET A R antagonist [118]. In a preclinical model of breast cancer, treatment with ABT-627 resulted in significantly less osteoblastic bone metastases and a decrease in Fig.…”

Section: The Et-1 Pathwaymentioning

confidence: 99%

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Targeted Therapy Options for Treatment of Bone Metastases; Beyond Bisphosphonates

Buijs

Kuijpers²,

Pluijm³

2010

CPD

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Cancer is a major leading cause of death in the western world (following heart diseases). It poses an enormous burden on patients and society with a major impact on healthcare and economy. Once cancers have spread to the skeleton, treatment options are predominantly limited to palliation, treatment of hypercalcemia and prevention of pathological fractures. Despite the elaborate efforts of modern medicine to improve treatment, novel therapies for the treatment of solid tumors in patients with advanced disease, including metastatic bone disease, have generally failed to improve patient overall survival. Despite initial beneficial responses on metastatic tumor burden this is frequently followed by re-growth of therapy resistant, malignant metastatic bone lesions. Cancer relapse in bone coincides with devastating consequences and causes considerable morbidity. Bisphosphonates represent the current gold standard in bone metastasis therapies. Because of the progress made in our understanding of the pathogenesis of skeletal metastasis using preclinical models, newer and more efficacious compounds and therapies have been developed that are being evaluated (or will soon be) in clinical trails. In this chapter, we discuss novel therapeutic targets and strategies for the treatment of metastatic bone disease. Future, successful treatment of skeletal metastasis will rely on targeting critical molecular mediators/processes in both metastasis-initiating subpopulations of osteotropic cancers ("the seed") together with their supportive, cellular and extra-cellular surrounding bone/bone marrow stroma ("the soil").

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Section: The Et-1 Pathwaymentioning

confidence: 72%

Section: The Et-1 Pathwaymentioning

confidence: 99%

Targeted Therapy Options for Treatment of Bone Metastases; Beyond Bisphosphonates

Buijs

Kuijpers²,

Pluijm³

2010

CPD

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“…Since a role of ET-1 in cancer was first shown in prostate tumors and subsequent work implicated this molecule in prostate cancer bone metastasis, the clinical work was focused on this cancer type (Lalich et al, 2007;Russo et al, 2010). Following a promising Phase II program in advanced metastatic disease, both companies undertook similar Phase III trials which encompassed early metastatic disease, advanced metastatic disease and combination therapy with ET A antagonists and a taxane (the most effective chemotherapeutic in routine practice today).…”

Section: Outcomes Of Previous Clinical Trials In Cancer Patients Usinmentioning

confidence: 99%

Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

et al. 2012

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In the early 1990s, within three years of cloning of endothelin receptors, orally active endothelin receptor antagonists (ERAs) were tested in humans and the first clinical trial of ERA therapy in humans was published in 1995. ERAs were subsequently tested in clinical trials involving heart failure, pulmonary arterial hypertension, resistant arterial hypertension, stroke/subarachnoid hemorrhage and various forms of cancer. The results of most of these trials - except those for pulmonary arterial hypertension and scleroderma-related digital ulcers - were either negative or neutral. Problems with study design, patient selection, drug toxicity, and drug dosing have been used to explain or excuse failures. Currently, a number of pharmaceutical companies who had developed ERAs as drug candidates have discontinued clinical trials or further drug development. Given the problems with using ERAs in clinical medicine, at the Twelfth International Conference on Endothelin in Cambridge, UK, a panel discussion was held by clinicians actively involved in clinical development of ERA therapy in renal disease, systemic and pulmonary arterial hypertension, heart failure, and cancer. This article provides summaries from the panel discussion as well as personal perspectives of the panelists on how to proceed with further clinical testing of ERAs and guidance for researchers and decision makers in clinical drug development on where future research efforts might best be focused.

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“…In the next section, we provide an overview of therapeutic agents shown to slow the progression of prostate cancer-induced metastasis to the skeleton; detailed reviews may be found elsewhere (see Russo et al 2010; Saad and Lipton 2010b; Saylor et al 2013). As the analgesic efficacy for most of these agents in patients with PCIBP has not been reported on, this is a knowledge gap that remains to be addressed.…”

Section: Therapeutic Strategies For the Management Of Pcibpmentioning

confidence: 99%

Pathobiology and management of prostate cancer-induced bone pain: recent insights and future treatments

Muralidharan

Smith

2013

Inflammopharmacol

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Prostate cancer (PCa) has a high propensity for metastasis to bone. Despite the availability of multiple treatment options for relief of PCa-induced bone pain (PCIBP), satisfactory relief of intractable pain in patients with advanced bony metastases is challenging for the clinicians because currently available analgesic drugs are often limited by poor efficacy and/or dose-limiting side effects. Rodent models developed in the past decade show that the pathobiology of PCIBP comprises elements of inflammatory, neuropathic and ischemic pain arising from ectopic sprouting and sensitization of sensory nerve fibres within PCa-invaded bones. In addition, at the cellular level, PCIBP is underpinned by dynamic cross talk between metastatic PCa cells, cellular components of the bone matrix, factors associated with the bone microenvironment as well as peripheral components of the somatosensory system. These insights are aligned with the clinical management of PCIBP involving use of a multimodal treatment approach comprising analgesic agents (opioids, NSAIDs), radiotherapy, radioisotopes, cancer chemotherapy agents and bisphosphonates. However, a major drawback of most rodent models of PCIBP is their short-term applicability due to ethical concerns. Thus, it has been difficult to gain insight into the mal(adaptive) neuroplastic changes occurring at multiple levels of the somatosensory system that likely contribute to intractable pain at the advanced stages of metastatic disease. Specifically, the functional responsiveness of noxious circuitry as well as the neurochemical signature of a broad array of pro-hyperalgesic mediators in the dorsal root ganglia and spinal cord of rodent models of PCIBP is relatively poorly characterized. Hence, recent work from our laboratory to develop a protocol for an optimized rat model of PCIBP will enable these knowledge gaps to be addressed as well as identification of novel targets for drug discovery programs aimed at producing new analgesics for the improved relief of intractable PCIBP.

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Anti-endothelin drugs in solid tumors

Abstract: Atrasentan seems to be active in CRPC, although strong scientific evidence is still to be found. Interesting clinical findings regard zibotentan.

Cited by 19 publications

References 76 publications

Targeted Therapy Options for Treatment of Bone Metastases; Beyond Bisphosphonates

Targeted Therapy Options for Treatment of Bone Metastases; Beyond Bisphosphonates

Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

Pathobiology and management of prostate cancer-induced bone pain: recent insights and future treatments

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