Activity of pemetrexed in pre-clinical chordoma models and humans.

Autor: Kesari S; Department of Translational Neurosciences, Pacific Neuroscience Institute, Santa Monica, CA, USA. Santosh.Kesari@providence.org.; Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA. Santosh.Kesari@providence.org., Wang F; Department of Medical Oncology, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan, Chengdu, China. wangfeng5024@126.com., Juarez T; Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA., Ashili S; CureScience, San Diego, CA, USA., Patro CPK; CureScience, San Diego, CA, USA.; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Carrillo J; Department of Translational Neurosciences, Pacific Neuroscience Institute, Santa Monica, CA, USA.; Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA., Nguyen M; Department of Translational Neurosciences, Pacific Neuroscience Institute, Santa Monica, CA, USA.; Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA., Truong J; Department of Translational Neurosciences, Pacific Neuroscience Institute, Santa Monica, CA, USA.; Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA., Levy J; Chordoma Foundation, Durham, NC, USA., Sommer J; Chordoma Foundation, Durham, NC, USA., Freed DM; Chordoma Foundation, Durham, NC, USA., Xiu J; CARIS Life Sciences, Phoenix, AZ, USA., Takasumi Y; Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA., Bouffet E; The Hospital for Sick Children (SickKids), University of Toronto, Toronto, Canada., Gill JM; Department of Translational Neurosciences, Pacific Neuroscience Institute, Santa Monica, CA, USA.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 May 05; Vol. 13 (1), pp. 7317. Date of Electronic Publication: 2023 May 05.
DOI: 10.1038/s41598-023-34404-4
Abstrakt: Chordomas are rare slow growing tumors, arising from embryonic remnants of notochord with a close predilection for the axial skeleton. Recurrence is common and no effective standard medical therapy exists. Thymidylate synthase (TS), an intracellular enzyme, is a key rate-limiting enzyme of DNA biosynthesis and repair which is primarily active in proliferating and metabolically active cells. Eighty-four percent of chordoma samples had loss of TS expression which may predict response to anti-folates. Pemetrexed suppresses tumor growth by inhibiting enzymes involved in folate metabolism, resulting in decreased availability of thymidine which is necessary for DNA synthesis. Pemetrexed inhibited growth in a preclinical mouse xenograft model of human chordoma. We report three cases of metastatic chordoma that had been heavily treated previously with a variety of standard therapies with poor response. In two cases, pemetrexed was added and objective responses were observed on imaging with one patient on continuous treatment for > 2 years with continued shrinkage. One case demonstrated tumor growth after treatment with pemetrexed. The two cases which had a favorable response had a loss of TS expression, whereas the one case with progressive disease had TS present. These results demonstrate the activity of pemetrexed in recurrent chordoma and warrant a prospective clinical trial which is ongoing (NCT03955042).
(© 2023. The Author(s).)
Databáze: MEDLINE
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