Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma

Abstract

The endothelin A receptor (ET A R) autocrine pathway is overexpressed in many malignancies, including nasopharyngeal carcinoma (NPC). In this tumor, ET A R expression is an independent determinant of survival and a robust independent predictor of distant metastasis. To evaluate whether ET A R represents a new target in NPC treatment, we tested the therapeutic role of ET A R in NPC. N asopharyngeal carcinoma is common in Southern China, with an annual incidence of 15-50 cases per 100 000 people.(1) NPC is distinct from other epithelial malignancies in the head and neck region in that it affects a relatively young population and has a propensity for distant metastases.(2) NPC is a radiosensitive tumor for which there is a high local control rate after radical radiotherapy. However, for patients with locoregionally advanced disease, the rate of distant metastasis is high and the 5-year overall survival rate is poor.(3) Randomized trials have confirmed that chemotherapy improves the distant metastasis control rate in patients with locoregionally advanced NPC; however, approximately 20% or more of the patients still have distant metastasis develop despite intensive chemotherapy.(4,5) These findings underscore the need to develop novel strategies in the management of patients with advanced NPC.The family of ET, including ET-1, ET-2 and ET-3, are 21-amino acid peptides exerting many biological effects.(6) Two major receptor subtypes belonging to the G protein-coupled family of receptors mediate ET signals: ET A R, which binds ET-1 and ET-2 with high affinity and ET-3 with low affinity; and ET B R, which binds all ET isopeptides with equal affinity.(7) ET-1, which is the most common circulating form of ET, is produced by many epithelial tumors.(8) ET-1 induces cell proliferation directly or synergistically with other growth factors that are relevant in cancer progression. Engagement of ET A R by ET-1 triggers activation of tumor proliferation, (9-13) VEGF-induced angiogenesis, (14,15) invasiveness (16) and inhibition of apoptosis. (17,18) The ET-1-ET A R autocrine pathway has a key role in the development and progression of prostatic, ovarian and cervical cancers.(9) The major relevance of ET A R in tumor development has led to an extensive search of highly selective antagonists. ABT-627 (Atrasentan), one such antagonist, is orally bioavailable and has suitable pharmacokinetic and toxicity profiles for clinical use. (19,20) ABT-627 has been given to cancer patients in phase II trials for prostate cancer and delayed the time to clinical and prostate-specific antigen progression.(21) Two pivotal randomized, double-blind, placebo-controlled, multinational phase III trials are ongoing in patients with hormone-refractory prostate cancer to verify these findings.We reported previously that patients with advanced-stage NPC had elevated plasma big ET-1 levels compared with the levels in healthy control participants; high pretreatment plasma big ET-1 levels are generally associated with post-treatment distant failure.(22) Our pr...

Endothelin-2 Differential Expression in Normal and Early-Stages of Colon Cancer Development

“…The ETB receptor plays a critical role in angiogenesis and the inhibition of anti-tumor immune cell recruitment [25]. In this work, ETA receptor underwent an overexpression both in proximal and distal segments; this behavior was reported several times in many kinds of tumors [26][27][28][29][30][31][32], including colorectal cancer [9]. Recent evidence showed that ETA receptor is expressed on CD133+ cancer stem cells in both cell lines and primary human tumor cells [25] and that CD133 expression exhibit enhanced tumorigenicity over CD133-negative (CD133-) cells, thus the former would be a more malignant phenotype than the latter [33].…”

Expression of endothelin receptor subtypes in bronchial tumors

“…In this study, pretreatment with the ET B R agonist IRL 1620 induced the delivery of increased amounts of paclitaxel to the tumor by increasing the blood flow, which caused a significant reduction in tumor volume and in some cases complete remission. Similarly, in a model of nude mice with nasopharyngeal carcinoma cell xenografts, ET A R blockade by atrasentan inhibited the growth of tumor cells, and combined treatment of ABT-627 with the cytotoxic drug cisplatin or 5-fluorouracil produced additive antitumor effects (46). However, a phase I/phase II clinical trial on the effect of atrasentan plus carboplatin and paclitaxel in NSCLC demonstrated the treatment is safe, but has no significant benefit on efficacy and survival (47).…”

Polymorphisms in the Endothelin-1 and Endothelin A Receptor Genes and Survival in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma

“…First, from the evidence to date, it appears that ET-1 and ETAR play a predominant role in malignancies (43). Our previous studies found that the ET-1/ETAR axis is closely associated with progression and prognosis of NPC (15)(16)(17). Second, the ET-1/ETAR axis is related to resistance to chemotherapy or radiotherapy.…”

“…Our study also showed that ETAR was overexpressed in 73.9% of NPC, and ETAR expression was an independent determinant of survival and a robust independent predictor of distant metastasis (16). Experimental study has shown that the ETAR antagonist ABT-627 can inhibit the growth and metastasis of NPC cells and increase sensitivity to chemotherapy (17).…”