Novel RNA-Directed Therapy for the Treatment of Acute Myeloid Leukemia

治疗急性髓系白血病的新型 RNA 导向疗法

• 批准号: 9243226
• 负责人: STEVEN Terry ROSEN
• 金额: $ 46.35万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243226
• 关键词: Acute Myelocytic Leukemia; Adenosine; Adult; Adult Acute Myeloblastic Leukemia; Affect; Allogenic; Alpha Cell; Animal Model; Animals; Antineoplastic Agents; Apoptosis; Blast Cell; Bone Marrow; Cell Death; Cell Survival; Cells; Chemotherapy-Oncologic Procedure; Chronic; Chronic Lymphocytic Leukemia; City of Hope Comprehensive Cancer Center; Clinical; Clinical Trials; Collaborations; Comorbidity; Correlative Study; Critical Pathways; Cytogenetics; Data; Disease; Disease remission; Dose; Drug Kinetics; Drug resistance; Economic Factors; Effectiveness; Energy-Generating Resources; Enrollment; Epigenetic Process; Exposure to; FLT3 gene; Failure; Gene Expression Profiling; Gene Mutation; Genes; Genetic; Genetic Transcription; Growth; Hematologic Neoplasms; Hematopoietic System; Hematopoietic stem cells; Human; In Vitro; Leukemic Hematopoietic Stem Cell; Malignant - descriptor; Maximum Tolerated Dose; Measures; Messenger RNA; MicroRNAs; Molecular; Morbidity - disease rate; Mutation; Neoadjuvant Therapy; Normal Cell; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Production; Property; RNA; Recurrence; Refractory; Relapse; Research; Resistance development; Resolution; Ribonucleosides; Ribose; Risk; Risk stratification; Route; Safety; Signal Pathway; Solid; Stem cell transplant; Stem cells; Subgroup; TP53 gene; Tern; Texas; Toxic effect; Translations; Transplantation; Universities; adverse outcome; analog; base; cancer cell; cancer survival; cellular targeting; chemotherapy; clinical development; cytotoxic; cytotoxicity; design; drug candidate; genomic profiles; high risk; in vivo; leukemia; leukemic stem cell; molecular targeted therapies; multidisciplinary; neoplastic cell; novel; novel therapeutics; nucleoside analog; outcome forecast; outcome prediction; pre-clinical; prevent; public health relevance; relapse patients; response; socioeconomics; sugar; transcriptome sequencing; treatment strategy; tripolyphosphate

 DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is associated with a poor prognosis. Despite progress made in implementing risk-adapted treatment strategies for AML and the design and clinical development of novel molecular-targeted therapeutics, the majority of patients will still die from this disease. Therefore, there is an urgent need to develo novel and potent anticancer drugs that have different mechanisms of action than traditional chemotherapeutics. The current application focuses on the clinical implementation of a novel halogenated ATP analog, 8-chloro-adenosine (8-Cl-Ado), which has a unique mode of action. In cells, 8-Cl-Ado is metabolized into the active, cytotoxic metabolite 8-Cl-ATP, which accumulates at high micromolar concentrations. 8-Cl-ATP incorporates predominantly into mRNA and inhibits ATP synthase activity, thus diminishing intracellular ATP pools. As a consequence, 8-Cl-Ado/8-Cl-ATP attacks cancer cells through multiple routes by interfering with transcription and translation, cellular bioenergy production, and signaling pathways critical for survival. Cancer cells, including AML cells, are more sensitive to growth and survival inhibition by 8-Cl-Ado than normal cells and frequently undergo apoptosis or autophagic cell death upon exposure to 8-Cl-Ado. 8-Cl-Ado may also help overcome another challenge in AML, that the disease is cytogenetically and molecularly very diverse, and so recurrent genetic or epigenetic aberrations have been used for risk-stratification, treatment guidance and prediction of outcome. For example, about 20 to 30% of AML patients carry an internal tandem duplication in the FLT3 gene (FLT3/ITD), which is associated with poor clinical outcome. 8-Cl-Ado has particularly high efficacy against AML cells that carry the FLT3 gene mutation, further suggesting it as an ideal drug candidate for AML. In addition, 8-Cl-Ado was extremely potent in vitro against a variety of solid and hematologic cancers and had favorable pharmacokinetic and pharmacodynamic properties in preclinical animal studies as well as in a phase I clinical trial in chronic lymphocyic leukemia (CLL). Moreover, in animal models, 8-Cl-Ado shows in vivo antitumor activity but minimal or non-detectable toxicity. Based on these previous studies, promising preliminary studies evaluating 8-Cl-Ado in AML, and encouraging results from the phase I clinical trial in CLL patients that support a favorable pharmacokinetic profile in humans, we now propose to advance 8-Cl-Ado to a phase I/II clinical trial in relapsed/refractory AML. In Aim 1, we will determine the safety and efficacy of 8-Cl- Ado in a phase I/II clinical trial in relapsed/refractor adult AML. In Aim 2, we will determine intracellular accumulation of 8-Cl-ATP and its effect on cellular ATP pools. In Aim 3, we will determine the cytotoxicity of 8- Cl-Ado toward leukemic hematopoietic stem cells and generate a preliminary mRNA/miRNA signature associated with response to 8-Cl-Ado treatment. Successful completion of these studies could identify 8-Cl- Ado as a novel therapeutic drug with potential to substantially reduce or eliminate relapse of patients with AML.

 描述（由申请人提供）：急性髓性白血病（AML）与不良预后相关。尽管在实施AML的风险适应性治疗策略以及新型分子靶向疗法的设计和临床开发方面取得了进展，但大多数患者仍将死于这种疾病。因此，迫切需要开发新的和有效的抗癌药物，其具有与传统化疗药物不同的作用机制。目前的申请集中在一种新的卤代ATP类似物，8-氯-腺苷（8-Cl-Ado），它具有独特的作用模式的临床实施。在细胞中，8-Cl-Ado被代谢成活性的细胞毒性代谢物8-Cl-ATP，其以高微摩尔浓度积累。8-Cl-ATP主要掺入mRNA并抑制ATP合酶活性，从而减少细胞内ATP库。因此，8-Cl-Ado/8-Cl-ATP通过干扰转录和翻译、细胞生物能量产生和对生存至关重要的信号传导途径，通过多种途径攻击癌细胞。癌细胞，包括AML细胞，比正常细胞对8-Cl-Ado的生长和存活抑制更敏感，并且在暴露于8-Cl-Ado时经常经历凋亡或自噬性细胞死亡。8-Cl-Ado还可以帮助克服AML中的另一个挑战，即该疾病在细胞遗传学和分子学上非常多样化，因此复发性遗传或表观遗传畸变已用于风险分层、治疗指导和结果预测。例如，约20%至30%的AML患者在FLT 3基因中携带内部串联重复（FLT 3/ITD），这与不良临床结果相关。8-Cl-Ado对携带FLT 3基因突变的AML细胞具有特别高的疗效，进一步表明它是AML的理想候选药物。此外，8-Cl-Ado在体外对各种实体和血液癌症非常有效，并且在临床前动物研究以及慢性淋巴细胞白血病（CLL）的I期临床试验中具有有利的药代动力学和药效学特性。此外，在动物模型中，8-Cl-Ado显示出体内抗肿瘤活性，但毒性极小或不可检测。基于这些先前的研究，评估AML中8-Cl-Ado的有希望的初步研究，以及来自CLL患者中的I期临床试验的令人鼓舞的结果（其支持在人类中有利的药代动力学特征），我们现在提议将8-Cl-Ado推进到复发性/难治性AML中的I/II期临床试验。在目标1中，我们将在复发/难治性成人AML的I/II期临床试验中确定8-Cl-Ado的安全性和有效性。在目标2中，我们将确定8-Cl-ATP的细胞内积累及其对细胞ATP库的影响。在目标3中，我们将确定8- Cl-Ado对白血病造血干细胞的细胞毒性，并产生与对8-Cl-Ado处理的响应相关的初步mRNA/miRNA签名。这些研究的成功完成可以确定8-Cl-Ado作为一种新的治疗药物，有可能大大减少或消除患者的复发 在AML