Abstract
Abstract LB465: Inhibition of serotonin biosynthesis and tyrosine kinases suppresses tumor growth of neuroendocrine neoplasm
Cancer research (Chicago, Ill.), Vol.85(8_Supplement_2), pp.LB465-LB465
04/25/2025
DOI: 10.1158/1538-7445.AM2025-LB465
Abstract
Small bowel neuroendocrine tumors (SBNETs) originate from enterochromaffin cells in the intestine which synthesize and secrete serotonin. SBNETs express high levels of tryptophan hydroxylase 1 (Tph1), a key enzyme in serotonin biosynthesis. Patients with high serotonin level may develop carcinoid syndrome, which can be treated with somatostatin analogues and the Tph1 inhibitor telotristat ethyl (TE) in severe cases. Although the active drug TE can efficiently reduce serotonin levels, its effect on tumor growth is unclear. This study determined the effect of serotonin inhibition on tumor growth in vitro and in vivo. The levels of Tph1 in various neuroendocrine neoplasms (NENs) were determined and the biological effects of Tph1 inhibition using genetic and pharmacologic approaches was tested. Gene and protein expression analyses were performed on patient tumors and cancer cell lines. shRNAs targeting TPH1 were used to create stable knockdown in BON cells. Control and knockdown lines were assessed for their growth rates in vitro and in vivo, angiogenesis potential, serotonin levels, endothelial cell tube formation, tumor weight, and tumor vascularity. TPH1 is highly expressed in SBNETs and many cancer types. TPH1 knockdown cells and TE treated cells showed similar growth rates as control cells in vitro. However, TPH1 knockdown cells formed smaller tumors in vivo and tumors were less vascularized. Although Tph1 inhibition with TE showed no effect on tumor cell growth in vitro, Tph1 inhibition reduced tumor formation in vivo. The combination of TE andcabozantinib, an effective tyrosine kinase inhibitor for NET, showed further improvement of tumor inhibition. Serotonin inhibition in combination with other therapies is a promising new avenue for targeting metabolic vulnerabilities in NENs.
Details
- Title: Subtitle
- Abstract LB465: Inhibition of serotonin biosynthesis and tyrosine kinases suppresses tumor growth of neuroendocrine neoplasm
- Creators
- Dane H. TowMaclain RidderCatherine G. TranGuiying LiCourtney A. KaemmerAswanth H. MahalingamAnguraj SadanandamDouglas R. SpitzChandrikha ChandrasekaranCarlos H.F. ChanJoseph S. DillonDawn E. QuelleAndrew M. BellizziJames R. HowePo H. Ear
- Resource Type
- Abstract
- Publication Details
- Cancer research (Chicago, Ill.), Vol.85(8_Supplement_2), pp.LB465-LB465
- Publisher
- AMER ASSOC CANCER RESEARCH
- DOI
- 10.1158/1538-7445.AM2025-LB465
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 04/25/2025
- Academic Unit
- Pathology; Surgery; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984821350602771
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