DataSheet_1_Erwinia asparaginase (crisantaspase) increases plasma levels of serine and glycine.pdf

The impact of asparaginases on plasma asparagine and glutamine is well established. However, the effect of asparaginases, particularly those derived from Erwinia chrysanthemi (also called crisantaspase), on circulating levels of other amino acids is unknown. We examined comprehensive plasma amino acid panel measurements in healthy immunodeficient/immunocompetent mice as well as in preclinical mouse models of acute myeloid leukemia (AML) and pancreatic ductal adenocarcinoma (PDAC) using long-acting crisantaspase, and in an AML clinical study (NCT02283190) using short-acting crisantaspase. In addition to the expected decrease of plasma glutamine and asparagine, we observed a significant increase in plasma serine and glycine post-crisantaspase. In PDAC tumors, crisantaspase treatment significantly increased expression of serine biosynthesis enzymes. We then systematically reviewed clinical studies using asparaginase products to determine the extent of plasma amino acid reporting and found that only plasma levels of glutamine/glutamate and asparagine/aspartate were reported, without measuring other amino acid changes post-asparaginase. To the best of our knowledge, we are the first to report comprehensive plasma amino acid changes in mice and humans treated with asparaginase. As dysregulated serine metabolism has been implicated in tumor development, our findings offer insights into how leukemia/cancer cells may potentially overcome glutamine/asparagine restriction, which can be used to design future synergistic therapeutic approaches.

天冬酰胺酶（asparaginase）对血浆中天冬酰胺与谷氨酰胺的影响已得到充分证实。然而，天冬酰胺酶，尤其是源自菊欧文氏菌（Erwinia chrysanthemi，又称crisantaspase）的天冬酰胺酶，对循环系统中其他氨基酸水平的影响尚不明确。我们采用长效crisantaspase，对健康免疫缺陷/免疫功能正常小鼠，以及急性髓系白血病（AML）和胰腺导管腺癌（PDAC）的临床前小鼠模型开展了全面血浆氨基酸谱检测；同时在一项急性髓系白血病临床研究（NCT02283190）中使用短效crisantaspase进行了相关检测。除了预期的血浆谷氨酰胺与天冬酰胺水平下降外，我们还观察到crisantaspase给药后血浆丝氨酸与甘氨酸水平显著升高。在胰腺导管腺癌肿瘤组织中，crisantaspase治疗可显著上调丝氨酸生物合成酶的表达。随后我们系统回顾了使用天冬酰胺酶类产品的临床研究，以明确血浆氨基酸的报告范围，结果发现现有研究仅报道了谷氨酰胺/谷氨酸以及天冬酰胺/天冬氨酸的血浆水平，未检测天冬酰胺酶给药后其他氨基酸的变化。据我们所知，本研究首次报道了接受天冬酰胺酶治疗的小鼠与人类体内全面的血浆氨基酸变化情况。鉴于丝氨酸代谢失调已被证实与肿瘤发生相关，我们的研究结果为白血病/肿瘤细胞如何潜在克服谷氨酰胺/天冬酰胺营养限制提供了新见解，可用于设计未来的协同治疗策略。