Activity of pemetrexed in pre-clinical chordoma models and humans.
Publication Title
Sci Rep
Document Type
Article
Publication Date
5-5-2023
Keywords
california; santa monica; pni; sjhc; Humans; Animals; Mice; Pemetrexed; Chordoma; Prospective Studies; Guanine; Glutamates; Neoplasm Recurrence, Local; DNA; Thymidylate Synthase
Abstract
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).
Area of Special Interest
Cancer
Specialty/Research Institute
Oncology
Specialty/Research Institute
Pharmacy
DOI
10.1038/s41598-023-34404-4
