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Activity of pemetrexed in pre-clinical chordoma models and humans
Santosh Kesari1,2, Feng Wang3, Tiffany Juarez4
1Department of Translational Neurosciences, Pacific Neuroscience Institute, Santa Monica, CA, USA. Santosh.Kesari@providence.org.
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).
Insights
Pemetrexed shows promise in treating recurrent chordoma, a rare bone cancer. Patients with low thymidylate synthase expression responded well to this chemotherapy, suggesting it may be an effective treatment option.
Area of Science:
- Oncology
- Medical Research
Background:
- Chordomas are rare, slow-growing tumors originating from notochord remnants, primarily affecting the axial skeleton.
- Recurrence is frequent, and effective standard medical therapies are lacking.
- Thymidylate synthase (TS) is crucial for DNA synthesis and repair, and its expression may predict response to antifolate drugs.
Purpose of the Study:
- To evaluate the efficacy of pemetrexed in patients with heavily pre-treated metastatic chordoma.
- To investigate the correlation between thymidylate synthase (TS) expression and response to pemetrexed therapy.
Main Methods:
- Case series of three patients with metastatic chordoma previously treated with various therapies.
- Pemetrexed was administered to two patients.
- Tumor response was assessed via imaging, and TS expression levels were analyzed.
Main Results:
- Two of the three patients showed objective responses to pemetrexed, with one experiencing sustained tumor shrinkage for over two years.
- The responding patients had a loss of TS expression, while the patient with progressive disease had detectable TS.
- Pemetrexed demonstrated preclinical activity in a human chordoma xenograft model.
Conclusions:
- Pemetrexed exhibits activity in recurrent chordoma, particularly in tumors with low or absent thymidylate synthase expression.
- These findings support further investigation of pemetrexed in chordoma, with a prospective clinical trial currently underway.
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