Operationalizing DNMT1-Targeting to Treat Chemorefractory Pancreatic Cancer

运用 DNMT1 靶向治疗化学难治性胰腺癌

基本信息

批准号：
10579306
负责人：
Yogen Saunthararajah
金额：
$ 22.13万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2024-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10579306
关键词：
Apoptosis Apoptosis Regulation Gene Azacitidine Biochemical Pathway Cell Cycle Cell Death Cells Clinic Clinical Clinical Research Clinical Trials Combination Drug Therapy Combined Modality Therapy Correlative Study Cytidine Deaminase Cytidine Deaminase Inhibitor DNA DNA Modification Methylases Data Decitabine Disease Dose Enzymes Epigenetic Process Epithelium Failure Fluorouracil Genetic Harvest Homeostasis Induction of Apoptosis Laboratories Malignant Neoplasms Malignant neoplasm of pancreas Measures Metabolic Methods Modality Modeling Modification Molecular Target Mutation Myeloproliferative disease Nucleotides Oral Paclitaxel Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pharmacodynamics Prodrugs Publishing Pyrimidine Pyrimidine Nucleosides Refractory Regimen Resistance S phase Schedule Solid Solid Neoplasm TP53 gene Testing Therapeutic Index Tissues Toxic effect Translating Translations Treatment Failure Tumor Burden Up-Regulation Xenograft Model alternative treatment analog cancer cell cell suicide chemotherapy clinical translation cytotoxic cytotoxicity design gemcitabine improved in vivo in vivo Model inhibitor irinotecan molecular targeted therapies non-genetic novel nucleobase nucleoside analog oxaliplatin pancreatic ductal adenocarcinoma cell pre-clinical preclinical study pyrimidine metabolism resistance mechanism response standard care targeted treatment treatment response tumor

项目摘要

Pancreatic ductal adenocarcinoma (PDAC) is a recalcitrant, deadly problem. Most PDAC patients receive aggressive multi-agent chemotherapy but median overall survivals remain at <1 year. A well-established basis for limited chemotherapy response is mutation and deletion of the master regulator of apoptosis p53 in most PDAC. Thus, alternative treatment modalities that do not rely on p53 are needed. The key epigenetic regulator DNA methyltransferase 1 (DNMT1) is a scientifically validated molecular target to cytoreduce chemo-refractory malignancies including PDAC, since it effects cancer cell cycling exits by p53-independent epithelialization. DNMT1 can be inhibited/ depleted by the pyrimidine nucleoside analog pro-drugs decitabine (Dec) or 5- azacytidine (5Aza), approved to treat myeloid malignancies. However, results from several completed clinical trials using Dec, 5Aza, or analogs to treat PDAC and other solid tumors have disappointed. A reason for this was suggested by correlative studies that revealed failure of Dec to elicit DNMT1-inhibiting pharmacodynamic effect in >75% of solid cancer tissues. We explored reasons for this further, in both pre-clinical and clinical studies we found inherent and adaptive configurations of pyrimidine metabolism in PDAC cells that forestall Dec or 5Aza processing into DNMT1-depleting nucleotide. Fortunately, there are practical modifications to therapy that can counter these mechanisms of resistance to DNMT1-targeting by Dec/5Aza. Specifically, we hypothesize that resistance to Dec, 5Aza emerges from adaptive responses of pyrimidine metabolism that can be anticipated and exploited using alternative schedules, and by combination with non-toxic modifiers of pyrimidine metabolism. Aim 1: Evaluate schedules of Dec and 5Aza administration designed to exploit peaks/troughs in pyrimidine metabolism adaptation and increase S-phase dependent DNMT1-depletion. Our prelim data indicates that scheduling Dec/5Aza administration to exploit reactive peaks and troughs in key pyrimidine metabolism enzymes, and frequent, distributed administration to increase overlap between malignant cell S-phase entries and treatment exposures, adds substantial benefit in vivo – we will extend this data to guide mechanistically-rational, readily implementable schedule improvements to clinical therapy. Aim 2: Enhance non-cytotoxic DNMT1-targeting by combining Dec and 5Aza with non-cytotoxic modifiers of pyrimidine metabolism. We have found that auto-upregulation of cytidine deaminase (CDA) that rapidly catabolizes Dec/5Aza, and of de novo pyrimidine synthesis that competes with Dec/5Aza for incorporation into DNA, contributes critically to resistance. We will therefore combine Dec/5Aza with clinical non-cytotoxic inhibitors of catabolic and de novo pyrimidine metabolism pathways, to identify combinations that increase DNMT1-targeting, response rates and durations. The treatment concepts we evaluate here are practical for clinical translation, e.g., we have developed into the clinic oral forms of CDA-inhibitor+Dec/5Aza that are readily combined with clinical inhibitors of de novo pyrimidine synthesis, to rapidly translate pre-clinical proof-of-principle into clinical therapy.

胰腺导管腺癌 (PDAC) 是一种顽固且致命的疾病，大多数 PDAC 患者都会出现这种情况。积极的多药化疗，但中位总生存期仍低于 1 年。有限的化疗反应是大多数细胞凋亡主调节因子 p53 的突变和缺失因此，需要不依赖 p53 的替代治疗方式。 DNA 甲基转移酶 1 (DNMT1) 是经过科学验证的分子靶标，可减少化疗耐药性包括 PDAC 在内的恶性肿瘤，因为它通过不依赖 p53 的上皮化作用影响癌细胞周期。 DNMT1 可以被嘧啶核苷类似物前药地西他滨 (Dec) 或 5- 抑制/耗尽氮胞苷 (5Aza)，已被批准用于治疗骨髓恶性肿瘤。然而，来自多个已完成临床的结果。使用 Dec、5Aza 或类似物治疗 PDAC 和其他实体瘤的试验令人失望。相关研究表明 Dec 未能引发 DNMT1 抑制药效学我们在临床前和临床研究中进一步探讨了这一现象的原因。我们发现 PDAC 细胞中嘧啶代谢的固有和适应性配置可以阻止 Dec 或 5Aza 幸运的是，有一些实用的治疗方法可以修改。通过 Dec/5Aza 对抗这些针对 DNMT1 靶向的抵抗机制。对 Dec、5Aza 的耐药性源于嘧啶代谢的适应性反应，可以预见和使用替代方案并与嘧啶代谢的无毒调节剂结合使用。目标 1：评估旨在利用高峰/低谷的 12 月和 5Aza 管理计划嘧啶代谢适应并增加 S 期依赖性 DNMT1 消耗。表明安排 Dec/5Aza 给药以利用关键嘧啶中的反应峰和谷代谢酶以及频繁的分布式给药以增加恶性细胞 S 期进入和治疗暴露之间的重叠，增加了体内的实质性益处——我们将扩展这些数据来指导机械合理、易于实施的临床治疗时间表改进。通过将 Dec 和 5Aza 与嘧啶的非细胞毒性修饰剂相结合，实现非细胞毒性 DNMT1 靶向我们发现胞苷脱氨酶（CDA）的自动上调可快速分解代谢。 Dec/5Aza，以及与 Dec/5Aza 竞争掺入 DNA 的从头合成嘧啶，因此，我们将 Dec/5Aza 与临床非细胞毒性抑制剂结合起来。分解代谢和从头嘧啶代谢途径，以确定增加 DNMT1 靶向的组合，我们在这里评估的治疗概念对于临床转化来说是实用的，例如，我们已经开发出CDA抑制剂+Dec/5Aza的临床口服剂型，易于与临床结合嘧啶从头合成抑制剂，可快速将临床前原理验证转化为临床治疗。