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Activity of pemetrexed in pre-clinical chordoma models and humans

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机构： [1]Department of Translational Neurosciences, Pacific Neuroscience Institute, Santa Monica, CA, USA. [2]Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA, USA. [3]Department of Medical Oncology, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan, Chengdu, China. [4]CureScience, San Diego, CA, USA. [5]Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. [6]Chordoma Foundation, Durham, NC, USA. [7]CARIS Life Sciences, Phoenix, AZ, USA. [8]The Hospital for Sick Children (SickKids), University of Toronto, Toronto, Canada.

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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).

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出版当年[2023]版：

大类 | 2 区综合性期刊

小类 | 2 区综合性期刊

最新[2023]版：

大类 | 2 区综合性期刊

小类 | 2 区综合性期刊

第一作者：

第一作者机构： [1]Department of Translational Neurosciences, Pacific Neuroscience Institute, Santa Monica, CA, USA. [2]Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA, USA.

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通讯作者：

通讯机构： [1]Department of Translational Neurosciences, Pacific Neuroscience Institute, Santa Monica, CA, USA. [2]Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA, USA.

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