Role of Endothelin Axis in Oral Cancer Invasion and Pain

Objectives: Oral cancer patients suffer from clinically intractable pain leading to poor quality of life; oral cancer is a capricious disease with unpredictable metastasis. We have shown in our previous studies that oral cancer pain and metastasis are processes controlled by the endothelin axis, which is a gene pathway comprised of the endothelin A and B receptors (ETAR and ETBR). We hypothesize that ETAR and ETBR play dichotomous roles in oral SCC metastasis and pain, such that ETAR activation and silenced ETBR expression result in increased metastasis and pain. In this study we explore the effect of inhibiting ETAR and re-expressing the ETBR gene on oral cancer metastasis, proliferation, and pain. Methods: Our treatment strategy involves antagonizing ETAR with macitentan, a new orally available drug, and re-expressing EDNRB with adenovirus gene transduction, a gene therapy technique we had developed previously. We hypothesize that this treatment strategy inhibits cancer invasion (i.e., metastasis) and pain. We employ in vitro and in vivo models, and the newly available pharmacologic agent macitentan, to test our hypothesis. Results: Our collective in vitro and in vivo results demonstrate that the combination of macitentan and EDNRB gene therapy produces an antinociceptive effect through inhibition of endothelin-1 mediated neuronal activation (i.e., calcium influx quantified by real-time calcium imaging). Conclusions: Furthermore, while the combination therapy does not significantly reduce proliferation, it inhibits invasion and metastasis both in cell culture and in a mouse model of tongue cancer. Lastly, we demonstrate that the endothelin axis genes are methylated and dysregulated in cancer tissue of patients. Grant support: Oral and Maxillofacial Surgery Foundatio