zibotentan and Neoplasm-Metastasis

Prostate cancer is the most common malignancy in men in Western countries. Until the last decade, the main available therapeutic options were based on hormonal therapy. For castration-refractory prostate carcinoma, from 2004, the combination of chemotherapy with docetaxel and prednisone has shown to improve survival in this subset of patients. Many agents have been tested either alone or in combination with this standard therapy, trying to find synergistic effects between drugs, and to target specific pathways that influence tumor growth, invasiveness, angiogenesis, and the development of distant metastasis. Endothelin antagonists have been recently studied, as they can get involved in many of these oncogenic pathways, and results are encouraging; nevertheless, the right setting to use them, whether to use them in monotherapy or in combination with other agents, and if they really improve the survival of our patients, are questions that remain to be addressed. In this review, we summarize the role of endothelins in tumoral biology and specifically in prostate carcinoma natural history, and the results obtained in the clinical trials involving this new therapeutic group.

Topics: Atrasentan; Bone and Bones; Carcinoma; Cell Proliferation; Clinical Trials as Topic; Endothelins; Gene Expression Regulation, Neoplastic; Humans; Male; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; Prostatic Neoplasms; Pyrrolidines

Understanding the extent of disease in asymptomatic patients with castration resistant prostate cancer is important when making treatment decisions and designing clinical trials. The ENTHUSE M0 (ENdoTHelin A USE) trial (NCT00626548) was a large phase III study comparing the endothelin A receptor antagonist zibotentan with placebo in patients with nonmetastatic, castration resistant prostate cancer. The study was stopped prematurely after early efficacy review indicated that it was unlikely to meet its co-primary objectives of improved overall and progression-free survival vs placebo. Screening failed in an unexpectedly high number of patients. We investigated this screening failure rate to promote better classification of patients thought to have nonmetastatic castration resistant prostate cancer and inform the design of future clinical trials in this setting.. The number of patients enrolled in and subsequently excluded from study was analyzed by geographic region and by the specialty of the investigating clinician (oncology or urology) who enrolled the study patients.. Of 2,577 patients enrolled in a total of 350 hospital based centers in 39 countries screening failed in 1,155 (45%). The most common reason for screening failure was the detection of metastatic disease in 32% of all screened patients and in 71% of those in whom screening failed. The leading reasons for failed screening did not differ between investigator specialties overall or by geographic region.. The high frequency of asymptomatic metastasis in men thought to have nonmetastatic, castration resistant prostate cancer highlights the importance of periodic staging assessments for the condition. Optimal treatment modalities may differ for metastatic and nonmetastatic disease.

Topics: Adult; Aged; Aged, 80 and over; Disease Progression; Disease-Free Survival; Dose-Response Relationship, Drug; Double-Blind Method; Endothelin A Receptor Antagonists; Follow-Up Studies; Humans; Male; Mass Screening; Middle Aged; Neoplasm Metastasis; Orchiectomy; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Pyrrolidines; Survival Rate

To assess the maximum well-tolerated dose (MWTD), dose limiting toxicity (DLT), pharmacokinetics (PK) and pharmacodynamics of zibotentan, a novel specific endothelin-A receptor antagonist, in patients with metastatic prostate cancer.. Patients with metastatic, castrate-resistant prostate cancer (CRPC) were treated with escalating doses of oral zibotentan (ZD4054) 10-200 mg once daily. The initial cohort received 28 daily doses (Period 1). Patients who had evidence of clinical benefit and who had not met any of the criteria for withdrawal were allowed to receive zibotentan at their current dose level until they no longer derived clinical benefit (Period 2). PK of zibotentan and changes in prostate-specific antigen and bone markers were also assessed.. Sixteen patients were evaluable for the safety and single-dose PK analyses. Eleven patients completed Period 1, and nine patients proceeded to Period 2. DLTs were encountered at 22.5 mg; one patient had grade 3 dyspnea and peripheral edema and a second patient had grade 3 headache and intraventricular hemorrhage. Enrollment was expanded at the 15 mg dose level to further determine the safety and tolerability of zibotentan. No DLTs were seen at 15 mg, and the most frequent adverse events were headache, peripheral edema, fatigue, nasal congestion and nausea.. The MWTD for zibotentan was 15 mg orally daily. The predominant adverse events observed were consistent with those reported for this class of drugs, and prolonged stable disease was noted in some patients. Phase III studies with zibotentan in men with metastatic CRPC are ongoing.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Castration; Dose-Response Relationship, Drug; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Pyrrolidines; Time Factors; Treatment Outcome

This study evaluated overall survival (OS) of patients with advanced non-squamous NSCLC following treatment with the specific endothelin A receptor antagonist, zibotentan in combination with pemetrexed compared with pemetrexed monotherapy.. In this double-blinded, placebo-controlled study, patients with advanced NSCLC with non-squamous histology who had failed first-line platinum-based chemotherapy were randomized to receive either once-daily zibotentan 10 mg in combination with 3-weekly pemetrexed 500 mg/m(2) or placebo plus 3-weekly pemetrexed 500 mg/m(2). OS was calculated as the interval from date of randomization to date of death from any cause. Safety and tolerability were evaluated by recording the incidence of adverse events (AE) according to Common Toxicity Criteria for AE (CTCAE).. Sixty-six patients were randomized and completed the study (zibotentan plus pemetrexed, n = 30; placebo plus pemetrexed, n = 36). At the data cutoff, a total of 44 deaths had occurred, 20 and 24 in the zibotentan and placebo groups, respectively. No significant difference in OS was observed between the zibotentan and placebo treatment groups (HR, 1.13; 80% CI 0.77, 1.67; P = 0.69). The majority of AE were of CTCAE grade 1 or 2, and the most commonly reported AE in both treatment groups was anemia (23 and 25% of patients in the zibotentan and placebo groups, respectively).. There was no survival signal in patients with NSCLC following treatment with zibotentan in combination with pemetrexed. No new issues related to safety for either zibotentan or pemetrexed were identified.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Double-Blind Method; Glutamates; Guanine; Humans; Lung Neoplasms; Neoplasm Metastasis; Pemetrexed; Pyrrolidines; Survival Rate

Endothelin A receptor (ET(A)R) and epidermal growth factor receptor (EGFR) cross-talk enhances the metastatic potential of epithelial ovarian cancer (EOC) cells activating different pathways, including β-catenin signalling. Here, we evaluated β-catenin as one of ET(A)R/EGFR downstream pathway in the invasive behaviour of EOC cells and their therapeutic potential to co-target ET(A)R and EGFR.. The phosphorylation status and interactions of different proteins were analysed by immunoblotting and immunoprecipitation. Reporter activity and RT-PCR was used for evaluation of β-catenin transcriptional activity and gene expression. Functional effects were evaluated by gelatin zymography and cell invasion assays. An orthotopic model of metastatic human EOC in mice was used for in vivo studies.. In EOC cell lines, ET-1 induced Src-dependent EGFR transactivation, causing tyrosine (Y) phosphorylation of β-catenin at the residue Y654, its dissociation from E-cadherin complexes and the accumulation as an active form. This pool of Tyr-β-catenin relocalised to the nucleus promoting its transcriptional activity, and the expression of its target genes, such as MMP-2. At functional level, ET-1 and EGFR circuits enhanced protease activity and cell invasion. All these effects were significantly inhibited by the ET(A)R antagonist, zibotentan, or EGFR inhibitor, gefitinib, and are completely blocked by co-addition of both drugs. In vivo, zibotentan treatment significantly inhibited metastases, associated with reduced expression and activation of MMPs and active β-catenin, especially when combined with gefitinib.. Altogether these findings provide additional support to the potential use of ET(A)R and EGFR blockade as a new therapeutic opportunity for EOC treatment.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; beta Catenin; Cell Line, Tumor; ErbB Receptors; Female; Gefitinib; Humans; Matrix Metalloproteinases; Mice; Mice, Nude; Neoplasm Metastasis; Ovarian Neoplasms; Phosphorylation; Pyrrolidines; Quinazolines; Receptor, Endothelin A; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction