Optimizing decitabine regimen + formulation for nonDNA damaging DNMT1 depletion

优化地西他滨方案配方以消除非 DNA 损伤性 DNMT1

• 批准号: 8477003
• 负责人: Yogen Saunthararajah
• 金额: $ 30.02万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8477003
• 关键词: Aberrant DNA Methylation; Adjuvant; Biological Availability; Cancer Histology; Cell Survival; Cells; Chronic; Clinical; Clinical effectiveness; Cytarabine; Cytidine Deaminase; Cytidine Deaminase Inhibitor; DNA; DNA Damage; Decitabine; Dose; Drug Formulations; Drug Kinetics; Dysmyelopoietic Syndromes; Elderly; Ensure; Enzymes; FDA approved; Future; Genes; Health; Hematopoietic stem cells; Individual; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular Target; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Normal tissue morphology; Oral; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Prevention; Procedures; Quantum Dots; Recruitment Activity; Regimen; Relapse; Request for Proposals; Resistance; Sickle Cell Anemia; Stem cells; Tetrahydrouridine; Therapeutic Index; Toxic effect; Transferase; Translating; United States National Institutes of Health; Variant; base; cancer cell; cancer prevention; chemotherapy; clinical effect; clinical practice; cytosine analog; gene repression; improved; killings; leukemia; leukemic stem cell; methylome; neoplastic; nucleoside analog; phase 1 study; prevent; resistance mechanism; response; self-renewal; treatment duration; tumor

DESCRIPTION (provided by applicant): Most chemotherapy for leukemia is limited by its toxicity to both leukemia cells and normal tissue. Ideally, therapy would target bio-molecules which are essential for leukemia stem-cell (LSC) but not normal hematopoietic stem-cell (HSC) survival. We demonstrate that the DNA methyl-transferase enzyme DNMT1 constitutes such an ideal molecular target; in HSC, DNMT1 is necessary for the self-renewal gene repression that must precede lineage-specific differentiation. In contrast, in LSC, DNMT1 is aberrantly recruited to repress pro-differentiation genes, prevent terminal differentiation and maintain dysregulated proliferation. Therefore, intermittent depletion of DNMT1 with non-DNA damaging doses of the cytosine analogue decitabine terminally differentiates LSC but increases self-renewal of HSC. This constitutes a very favorable therapeutic index. In the first aim of this proposal, we translate these observations into clinical practice. Decitabine was originally developed as a DNA-damaging agent. Doses were escalated to maximum tolerated levels in traditional phase I studies. Current regimens of decitabine still employ relatively high doses and drug administration is cycled to allow the patient to recover from toxicity. However, we show that effective DNMT1 depletion can be produced with levels of decitabine that do not damage DNA. Therefore, we propose lowering the dose of decitabine to minimize/avoid DNA damage and toxicity while maintaining DNMT1 depletion. The lack of toxicity will allow weekly, multi-year therapy to sustain the differential effect on LSC and HSC and introduces the possibility of adjuvant, maintenance or cancer prevention applications. We have demonstrated the remarkable clinical effectiveness and tolerability of using decitabine in this way in the treatment of severe sickle cell disease, where decitabine is administered 1-3X/week for multi-year treatment durations 2,3 4. In Specific Aim 1 of this proposal, we seek proof of concept of this regimen in treating malignancy. We believe the effort described in Aim 1 will be a significant advance in the treatment of malignancy. However, obstacles to realizing the full clinical potential of DNMT1 depletion by decitabine remain: (i) pharmacogenomic variation in cytidine deaminase (CDA), the enzyme which breaks-down decitabine, produces significant inter-individual variation in pharmacokinetics (PK) and pharmacodynamics (PD), compromising the ability to predict clinical effects in response to a specific dose; (ii) because of CDA- mediated drug destruction, decitabine has limited oral bioavailability, a significant impediment to the proposed treatment paradigm of multi-year, chronic therapy; (iii) we show that the major tumor stratagem for resistance to decitabine is CDA-mediated destruction of the drug. Such resistance may be especially likely in the intended chronic low-dose application of decitabine. In Specific Aim 2, we propose to surmount all three obstacles by combining decitabine with the CDA inhibitor tetrahydrouridine (THU) in a single oral formulation.

描述（由申请人提供）：大多数白血病化疗因其对白血病细胞和正常组织的毒性而受到限制。理想情况下，治疗应该针对白血病干细胞（LSC）而非正常造血干细胞（HSC）生存所必需的生物分子。我们证明DNA甲基转移酶DNMT1构成了这样一个理想的分子靶标；在HSC中，DNMT1是自我更新基因抑制所必需的，而自我更新基因抑制必须先于谱系特异性分化。相反，在LSC中，DNMT1被异常募集来抑制分化前基因，阻止终末分化并维持增殖失调。因此，用非dna损伤剂量的胞嘧啶类似物地西他滨间歇性消耗DNMT1最终分化LSC，但增加HSC的自我更新。这是一个非常有利的治疗指标。在这个建议的第一个目标，我们将这些观察转化为临床实践。地西他滨最初是作为dna损伤剂开发的。在传统的I期研究中，剂量增加到最大耐受水平。目前的地西他滨治疗方案仍然使用相对较高的剂量，并且药物给药是循环的，以使患者从毒性中恢复。然而，我们表明，在不损害DNA的情况下，地西他滨的水平可以产生有效的DNMT1消耗。因此，我们建议降低地西他滨的剂量，以尽量减少/避免DNA损伤和毒性，同时保持DNMT1的消耗。缺乏毒性将允许每周、多年的治疗来维持对LSC和HSC的不同效果，并引入辅助、维持或癌症预防应用的可能性。我们已经证明了以这种方式使用地西他滨治疗严重镰状细胞病的显着临床有效性和耐受性，其中地西他滨给予1-3次/周，持续多年治疗2,34。在本提案的具体目标1中，我们寻求该方案在治疗恶性肿瘤中的概念证明。我们相信在Aim 1中描述的努力将是恶性肿瘤治疗的重大进展。然而，实现地西他滨消耗DNMT1的全部临床潜力的障碍仍然存在：(i)胞苷脱氨酶（CDA）的药物基因组学差异，分解地西他滨的酶在药代动力学（PK）和药效学（PD）方面产生显着的个体间差异，损害了预测特定剂量临床效果的能力；（ii）由于CDA介导的药物破坏，地西他滨具有有限的口服生物利用度，这是拟议的多年慢性治疗模式的重大障碍；（iii）我们表明，对地西他滨耐药的主要肿瘤策略是cda介导的药物破坏。这种耐药性在慢性低剂量地西他滨应用中尤其可能发生。在具体目标2中，我们建议通过将地西他滨与CDA抑制剂四氢吡啶（THU）联合制成单一口服制剂来克服这三个障碍。

项目成果

Modelling c-Abl Signalling in Activated Neutrophils: the Anti-inflammatory Effect of Seliciclib.

• DOI: 10.7750/biodiscovery.2013.7.4
• 发表时间: 2013-03-01
• 期刊: BioDiscovery
• 作者: Jackson RC;Radivoyevitch T
• 通讯作者: Radivoyevitch T

Why is there so much therapy-related AML and MDS and so little therapy-related CML?

为什么治疗相关的 AML 和 MDS 如此之多，而与治疗相关的 CML 如此之少？

• DOI: 10.1016/j.leukres.2014.08.002
• 发表时间: 2014
• 期刊: Leukemia research
• 影响因子: 2.7
• 作者: Gale,RobertPeter;Hlatky,Lynn;Sachs,RainerK;Radivoyevitch,Tomas
• 通讯作者: Radivoyevitch,Tomas

Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy.

男性中 CDA 表达/活性增加会导致胞苷类似物半衰期缩短，并可能导致 5-氮杂胞苷或地西他滨治疗的结果更差。

• DOI: 10.1158/1078-0432.ccr-12-1722
• 发表时间: 2013-02-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Mahfouz RZ;Jankowska A;Ebrahem Q;Gu X;Visconte V;Tabarroki A;Terse P;Covey J;Chan K;Ling Y;Engelke KJ;Sekeres MA;Tiu R;Maciejewski J;Radivoyevitch T;Saunthararajah Y
• 通讯作者: Saunthararajah Y