Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
Semin Hematol. 2021 Jan;58(1):35-44. doi: 10.1053/j.seminhematol.2020.11.008. Epub 2020 Dec 14.
One mechanism by which lymphoid malignancies resist standard apoptosis-intending (cytotoxic) treatments is genetic attenuation of the p53/p16-CDKN2A apoptosis axis. Depletion of the epigenetic protein DNA methyltransferase 1 (DNMT1) using the deoxycytidine analog decitabine is a validated approach to cytoreduce malignancy independent of p53/p16. In vivo decitabine activity, however, is restricted by rapid catabolism by cytidine deaminase (CDA). We, therefore, combined decitabine with the CDA-inhibitor tetrahydrouridine and conducted a pilot clinical trial in patients with relapsed lymphoid malignancies: the doses of tetrahydrouridine/decitabine used (∼10/0.2 mg/kg orally (PO) 2×/week) were selected for the molecular pharmacodynamic objective of non-cytotoxic, S-phase dependent, DNMT1-depletion, guided by previous Phase 1 studies. Patients with relapsed/refractory B- or T-cell malignancies (n = 7) were treated for up to 18 weeks. Neutropenia without concurrent thrombocytopenia is an expected toxicity of DNMT1-depletion and occurred in all patients (Grade 3/4). Subjective and objective clinical improvements occurred in 4 of 7 patients, but these responses were lost upon treatment interruptions and reductions to manage neutropenia. We thus performed parallel experiments in a preclinical in vivo model of lymphoma to identify regimen refinements that might sustain DNMT1-targeting in malignant cells but limit neutropenia. We found that timed-alternation of decitabine with the related molecule 5-azacytidine, and combination with inhibitors of CDA and de novo pyrimidine synthesis could leverage feedback responses of pyrimidine metabolism to substantially increase lymphoma cytoreduction but with less neutropenia. In sum, regimen innovations beyond incorporation of a CDA-inhibitor are needed to sustain decitabine DNMT1-targeting and efficacy against chemo-resistant lymphoid malignancy. Such potential solutions were explored in preclinical in vivo studies.
一种使淋巴恶性肿瘤抵抗标准凋亡诱导（细胞毒性）治疗的机制是遗传减弱 p53/p16-CDKN2A 凋亡轴。使用去氧胞苷类似物地西他滨耗竭表观遗传蛋白 DNA 甲基转移酶 1（DNMT1）是一种独立于 p53/p16 减少恶性肿瘤的已验证方法。然而，体内地西他滨活性受到胞苷脱氨酶（CDA）的快速代谢限制。因此，我们将地西他滨与 CDA 抑制剂四氢尿苷结合，并在复发的淋巴恶性肿瘤患者中进行了一项试点临床试验：使用的四氢尿苷/地西他滨剂量（约 10/0.2mg/kg 口服（PO）2×/周）是根据以前的 I 期研究选择的，用于非细胞毒性、S 期依赖性、DNMT1 耗竭的分子药效学目标，该目标由先前的 I 期研究指导。患有复发/难治性 B 或 T 细胞恶性肿瘤的患者（n=7）接受了长达 18 周的治疗。中性粒细胞减少而无血小板减少是 DNMT1 耗竭的预期毒性，所有患者均出现（3/4 级）。7 例患者中有 4 例出现主观和客观的临床改善，但这些反应在中性粒细胞减少症的治疗中断和减少时丢失。因此，我们在淋巴瘤的临床前体内模型中进行了平行实验，以确定可能在恶性细胞中维持 DNMT1 靶向但限制中性粒细胞减少的方案改进。我们发现，地西他滨与相关分子 5-氮杂胞苷的定时交替，以及与 CDA 和从头嘧啶合成抑制剂的联合使用，可以利用嘧啶代谢的反馈反应，大大减少淋巴瘤细胞减少，但中性粒细胞减少较少。总之，需要超越包含 CDA 抑制剂的方案创新来维持地西他滨对 DNMT1 的靶向作用和对抗化疗耐药性淋巴恶性肿瘤的疗效。在临床前体内研究中探索了这种潜在的解决方案。
