A pilot clinical trial of oral tetrahydrouridine/decitabine for noncytotoxic epigenetic therapy of chemoresistant lymphoid malignancies.
A pilot clinical trial of oral tetrahydrouridine/decitabine for noncytotoxic epigenetic therapy of chemoresistant lymphoid malignancies.
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DOI：
10.1053/j.seminhematol.2020.11.008
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发表时间：
2021-01
影响因子：
3.6
通讯作者：
Saunthararajah Y
中科院分区：
文献类型：
--
作者：
Hill B;Jagadeesh D;Pohlman B;Dean R;Parameswaran N;Chen J;Radivoyevitch T;Morrison A;Fada S;Dever M;Robinson S;Lindner D;Smith M;Saunthararajah Y
淋巴恶性肿瘤抵抗标准的细胞毒性治疗的一种机制是p53/p16-CDKN 2A凋亡轴的遗传衰减。使用脱氧胞苷类似物地西他滨消耗表观遗传蛋白DNA甲基转移酶1（DNMT 1）是一种有效的方法，可以不依赖于p53/p16而减少恶性肿瘤的发生。然而，地西他滨的体内活性受到胞苷脱氨酶（CDA）的快速催化作用的限制。因此，我们将地西他滨与CDA抑制剂四氢尿苷（THU）联合使用，并在复发性淋巴系统恶性肿瘤患者中进行了一项初步临床试验：根据先前I期研究的指导，选择THU/地西他滨的剂量（约10/0.2 mg/kg口服（PO）2X/周），以实现非细胞毒性、S期依赖性、DNMT 1耗竭的分子药效学目标。复发性/难治性B或T细胞恶性肿瘤患者（n=7）接受长达18周的治疗。中性粒细胞减少而不并发血小板减少是DNMT 1耗竭的预期毒性，发生在所有患者中（3/4级）。7例患者中有4例出现主观和客观临床改善，但这些缓解在治疗中断和减少以管理中性粒细胞减少后消失。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DNMT 1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组合，可以利用嘧啶代谢的反馈反应，以显著增加淋巴瘤细胞减少，但减少中性粒细胞减少。总之，除了加入CDA抑制剂之外，还需要方案创新来维持地西他滨DNMT 1靶向和对化疗耐药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。
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 (THU) and conducted a pilot clinical trial in patients with relapsed lymphoid malignancies: the doses of THU/decitabine used (~10/0.2 mg/kg orally (PO) 2X/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 pre-clinical 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 pre-clinical in vivo studies.
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影响因子：
20.3
作者：
Kalac, Matko;Scotto, Luigi;O'Connor, Owen A.
通讯作者：
O'Connor, Owen A.
罗米地辛治疗复发/难治性外周 T 细胞淋巴瘤：关键研究更新表明持久反应。
影响因子：
28.5
作者：
Coiffier B;Pro B;Prince HM;Foss F;Sokol L;Greenwood M;Caballero D;Morschhauser F;Wilhelm M;Pinter-Brown L;Padmanabhan Iyer S;Shustov A;Nielsen T;Nichols J;Wolfson J;Balser B;Horwitz S
通讯作者：
Horwitz S
影响因子：
--
作者：
Ebrahem Q;Mahfouz RZ;Ng KP;Saunthararajah Y
通讯作者：
Saunthararajah Y
影响因子：
28.2
作者：
Clozel T;Yang S;Elstrom RL;Tam W;Martin P;Kormaksson M;Banerjee S;Vasanthakumar A;Culjkovic B;Scott DW;Wyman S;Leser M;Shaknovich R;Chadburn A;Tabbo F;Godley LA;Gascoyne RD;Borden KL;Inghirami G;Leonard JP;Melnick A;Cerchietti L
通讯作者：
Cerchietti L
在复发/难治性急性淋巴细胞性白血病中，有或没有超vad的5-aza-2'-脱氧胞苷（去替替啶）的安全性和临床活性。
影响因子：
6.5
作者：
Benton CB;Thomas DA;Yang H;Ravandi F;Rytting M;O'Brien S;Franklin AR;Borthakur G;Dara S;Kwari M;Pierce SR;Jabbour E;Kantarjian H;Garcia-Manero G
通讯作者：
Garcia-Manero G