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: 9458707
• 负责人: STEVEN Terry ROSEN
• 金额: $ 48万
• 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/9458707
• 关键词: Acute Myelocytic Leukemia; Adenosine; Adult; Adult Acute Myeloblastic Leukemia; Affect; Allogenic; Animal Model; Animals; Antineoplastic Agents; Apoptosis; Blast Cell; Bone Marrow; Cell Death; 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; TP53 gene; Tern; Texas; Toxic effect; Translations; Transplantation; Universities; adverse outcome; analog; base; cancer cell; cancer survival; cellular targeting; chemotherapy; clinical development; clinical implementation; cytotoxic; cytotoxicity; design; drug candidate; genomic profiles; high risk; in vivo; leukemia; leukemic stem cell; miRNA expression profiling; molecular targeted therapies; multidisciplinary; neoplastic cell; novel; novel therapeutics; nucleoside analog; outcome forecast; outcome prediction; patient subsets; 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（由适用提供）：急性髓细胞性白血病（AML）与预后不良有关。尽管在针对AML实施风险的治疗策略以及新型分子靶向治疗的设计和临床发展方面取得了进展，但大多数患者仍将死于这种疾病。因此，迫切需要开发与传统化学治疗药具有不同作用机理的新颖和潜在的抗癌药物。当前的应用集中于新型卤代ATP类似物，8-氯 - 腺苷（8-CL-ADO）的临床实施，该盐具有独特的作用方式。在细胞中，将8-CL-ADO代谢成活性的细胞毒性代谢物8-CL-ATP，该代谢物8-CL-ATP以高的微摩尔浓度积累。 8-CL-ATP主要融合到mRNA中，并抑制ATP合酶活性，从而减少细胞内ATP池。结果，8-CL-ADO/8-CL-ATP通过干扰转录和翻译，细胞生物能源产生以及对生存至关重要的信号通路，通过多种途径攻击癌细胞。包括AML细胞在内的癌细胞对8-CL-ADO的生长和生存抑制更为敏感，并且暴露于8-CL-ADO后经常发生凋亡或自噬细胞死亡。 8-CL-ADO也可能有助于克服AML的另一个挑战，即该疾病在细胞遗传学和分子上非常多样化，因此已将复发性的遗传或表观遗传畸变用于风险分层，治疗指导和预测结果。例如，大约20％至30％的AML患者在FLT3基因（FLT3/ITD）中携带内部串联重复，这与临床不良结果有关。 8-CL-ADO对携带FLT3基因突变的AML细胞具有特别高的效率，进一步表明它是AML的理想药物候选者。此外，在临床前动物研究中以及在慢性淋巴细胞性白血病（CLL）的I期临床试验中，在各种固体和血液学癌症中对各种固体和血液学癌症具有极大的体外潜力。此外，在动物模型中，8-CL-ADO在体内抗肿瘤活性中显示，但最小或非可检测的毒性。基于这些先前的研究，有望评估AML中8-CL-ADO的有希望的初步研究，并鼓励CLL患者I期临床试验的结果，这些临床试验支持人类的有利的药代动力学特征，我们现在建议将8-CL-ADO推进到中继/降低/降低症状AML的I/II期临床试验。在AIM 1中，我们将在接力/难治性成人AML中的I/II期临床试验中确定8-CL-ADO的安全性和效率。在AIM 2中，我们将确定8-CL-ATP的细胞内积累及其对细胞ATP池的影响。在AIM 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治疗的反应有关的初步mRNA/miRNA签名。这些研究的成功完成可以鉴定8-CL-ADO是一种新型的治疗药物，有可能大大减少或消除患者的继电器 与AML。