Posted: Monday, April 17, 2023
To improve outcomes in patients with cholangiocarcinoma, investigators are exploring whether the addition of telotristat ethyl—an inhibitor of tryptophan hydroxylase 1 (TPH1)—to several different standard chemotherapies might be of benefit. In fact, Niranjan Awasthi, MSc, PhD, of Indiana University School of Medicine, South Bend, and colleagues found that in several preclinical models, the addition of telotristat ethyl enhanced response to chemotherapy with the combination of gemcitabine plus cisplatin as well as with nanoparticle albumin-bound (nab)-paclitaxel. Their early research findings were presented at the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract 480/11).
“Combination therapies with telotristat ethyl have the potential to improve clinical cholangiocarcinoma therapy,” the investigators predicted.
Dr. Awasthi and colleagues focused on human CCLP-1 cells (iCCA), TFK-1 cells (dCCA), SNU-1196 cells (pCCA) in NOD/SCID mice, and in patient-derived xenografts in NSG mice to perform their tumor growth study in subcutaneous cell-derived xenografts. They used immunohistochemistry to determine intratumoral proliferation and serotonin levels.
In peritoneal dissemination xenografts, the authors reported, animal survival was enhanced by nab-paclitaxel (60%), whereas telotristat ethyl (11%) or gemcitabine/cisplatin (9%) had a marginal effect. However, the combination of telotristat ethyl with gemcitabine/cisplatin (26%) or nab-paclitaxel (68%) yielded a further increase in animal survival.
In iCCA xenografts, tumor growth inhibition by telotristat ethyl was 53%, and nab-paclitaxel (69%) caused greater inhibition than gemcitabine/cisplatin (53%). In dCCA xenografts, tumor growth inhibition by telotristat ethyl was 51%, and nab-paclitaxel seemed to be more effective than gemcitabine/cisplatin (56% vs. 37%). In pCCA xenografts, tumor growth reduction by telotristat ethyl, nab-paclitaxel, and gemcitabine/cisplatin was 41%, 67%, and 58%, respectively.
In all three cell-derived xenografts, the combination of telotristat ethyl and chemotherapy yielded an improved tumor growth inhibition effect (range, 67%–90%). In patient-derived xenografts, the investigators observed an additive effect with the combination of telotristat ethyl and chemotherapy.
Disclosure: Dr. Awasthi has received grant support from TerSera Therapeutics, the company developing telotristat ethyl.