Telotristat ethyl showed significant antitumor activity in several cholangiocarcinoma xenograft models, according to a new study presented at the Cholangiocarcinoma Foundation Annual Conference. It also enhanced the effects of chemotherapy agents including cisplatin and nab-paclitaxel.
The researchers concluded that combination regimens with telotristat ethyl plus chemotherapy may also improve clinical outcomes in patients with advanced cholangiocarcinoma.
Cholangiocarcinoma is a highly aggressive type of cancer and the 5-year survival rate remains very low at only 5 to 15% even with chemotherapy. Previous research has shown that increased secretion of serotonin may support the oncogenic activity of cholangiocarcinoma.
In the present study, a team of researchers led by Roderich E. Schwartz, MD, from the Roswell Park Comprehensive Cancer Center in Buffalo, New York investigated the potential role of the serotonin biosynthesis inhibitor telotristat ethyl on cholangiocarcinoma. They conducted tumor growth inhibition studies using human intrahepatic, perihilar, and distal cholangiocarcinoma cells grown in culture as well as cells derived from patients grafted under the skin of mice.
Read more about the prognosis of cholangiocarcinoma
Ten days after the injection of tumor cells, the researchers treated the animals for 2 weeks with either telotristat ethyl only, cisplatin only, nab-paclitaxel only, telotristat ethyl plus cisplatin, telotristat ethyl plus nab-paclitaxel, or a saline solution as a control. They then measured the size of the tumor twice a week. They also conducted survival studies in some of the animals.
The results showed that telotristat ethyl and cisplatin alone inhibited the growth of intrahepatic cholangiocarcinoma cells by 53%. Nab-paclitaxel, on the other hand, inhibited tumor growth by 69%. In distal cholangiocarcinoma xenografts, telotristat ethyl reduced tumor growth by 51%, nab-paclitaxel by 56%, and cisplatin by 37%.
Finally, in perihilar cholangiocarcinoma xenografts, telotristat ethyl reduced tumor growth by 41% while nab-paclitaxel and cisplatin reduced it by 67% and 58% respectively. In all 3 cell types, the combination of telotristat ethyl with chemotherapy had an additive effect in terms of tumor growth inhibition. In xenografts derived from patients, telotristat ethyl markedly inhibited tumor growth and its effect increased when combined with chemotherapy.
Animal survival studies have shown that nab-paclitaxel improved survival by 60% while this ratio remained low for telotristat ethyl (11%) and cisplatin (9%). However, combining telotristat ethyl with nab-paclitaxel increased survival by 68%, and combining it with cisplatin increased survival by 26%.
Awashti N, Schwartz MA, Schwartz RE. Inhibition of serotonin biosynthesis by telotristat ethyl augments chemotherapy effects in cholangiocarcinoma. Poster presented at: Cholangiocarcinoma Foundation Annual Conference: February 23-25, 2022; Salt Lake City, Utah.