Therapies for cancer targeting endothelin receptors

The endothelin (ET) axis, which includes ET-1, ET-2, ET-3 and the ET receptors, ET_A and ET_B, plays an important physiological role in normal tissue, acting as a modulator of vasomotor tone, tissue differentiation and development, cell proliferation and hormone production. Recent investigations into the role of the ET axis in mitogenesis, apoptosis inhibition, bone remodeling, invasiveness and angiogenesis have provided evidence of the importance of ET-1 in cancer. Data suggest that ET-1 plays a significant role in the growth and progression of a variety of tumors. Development of ET-1 receptor antagonists has provided a better understanding of the ET axis in cancer pathogenesis and suggests an important role for these antagonists in novel therapeutic interventions. The increasing evidence that the ET_A receptor plays a role in the progression of human cancer has led to an extensive search for antagonists that selectively block the ET _A receptor. Atrasentan is one such antagonist that is orally bioavailable and has suitable pharmacokinetic and toxicity profiles for clinical use. Preliminary data from clinical trials of atrasentan in patients with prostate cancer are encouraging. The role of the ET axis and the therapeutic relevance of ET-1 receptor antagonists in a range of malignancies requires further investigation.