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.
Sci Rep. 2023 May 5;13(1):7317. doi: 10.1038/s41598-023-34404-4.
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).
脊索瘤是一种罕见的生长缓慢的肿瘤，起源于脊索的胚胎残余物，与轴性骨骼密切相关。复发很常见，目前尚无有效的标准医学治疗方法。胸苷酸合成酶（TS）是一种细胞内酶，是 DNA 生物合成和修复的关键限速酶，主要在增殖和代谢活跃的细胞中发挥作用。84%的脊索瘤样本存在 TS 表达缺失，这可能预示着对抗叶酸药物的反应。培美曲塞通过抑制叶酸代谢相关酶的活性来抑制肿瘤生长，导致胸苷的可用性降低，而胸苷是 DNA 合成所必需的。培美曲塞抑制了人类脊索瘤的临床前小鼠异种移植模型中的肿瘤生长。我们报告了 3 例转移性脊索瘤病例，这些病例先前已接受过多种标准治疗，疗效不佳。在 2 例病例中添加了培美曲塞，影像学检查显示有客观缓解，1 例患者持续治疗>2 年，肿瘤持续缩小。1 例病例在使用培美曲塞治疗后肿瘤生长。2 例有良好反应的病例存在 TS 表达缺失，而 1 例进展性疾病的病例存在 TS。这些结果表明培美曲塞在复发性脊索瘤中的活性，并需要进行正在进行的前瞻性临床试验（NCT03955042）。
