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: 9107212
• 负责人: STEVEN Terry ROSEN
• 金额: $ 49.94万
• 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/9107212
• 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; Data; Development; 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; Genetic; Genetic Transcription; Growth; Hematologic Neoplasms; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Human; In Vitro; Leukemic Hematopoietic Stem Cell; Malignant - descriptor; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Messenger RNA; MicroRNAs; 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; Route; Safety; Signal Pathway; Signaling Protein; Solid; Staging; Stem cell transplant; Stem cells; Subgroup; TP53 gene; Texas; Toxic effect; Translations; Transplantation; Universities; adverse outcome; analog; base; cancer cell; cellular targeting; chemotherapy; cytotoxic; cytotoxicity; design; drug candidate; genomic profiles; high risk; in vivo; leukemia; leukemic stem cell; molecular targeted therapies; neoplastic cell; novel; novel therapeutics; nucleoside analog; outcome forecast; outcome prediction; pre-clinical; prevent; progenitor; public health relevance; relapse patients; response; socioeconomics; sugar; transcriptome sequencing; treatment strategy; treatment stratification; 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(申请人提供)：急性髓系白血病(AML)与预后不良有关。尽管在实施急性髓细胞白血病的风险适应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，迫切需要开发具有不同于传统化疗药物作用机制的新型有效抗癌药物。目前的应用主要集中在一种新型的卤代ATP类似物8-氯腺苷(8-Cl-ADO)的临床应用上，它具有独特的作用模式。在细胞中，8-氯-腺苷被代谢成活性的、细胞毒性的代谢物8-氯-三磷酸腺苷，在较高的微摩尔浓度下积累。8-氯-三磷酸腺苷主要结合到信使核糖核酸中，抑制三磷酸腺苷合成酶的活性，从而减少细胞内的三磷酸腺苷库。因此，8-氯-腺苷/8-氯-三磷酸腺苷通过干扰转录和翻译、细胞生物能量的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。癌细胞，包括急性髓系白血病细胞，对8-氯-腺苷的生长和存活抑制比正常细胞更敏感，并且在暴露于8-氯-腺苷后经常发生凋亡或自噬细胞死亡。8-氯-腺苷还可能有助于克服AML的另一个挑战，即这种疾病在细胞遗传学和分子水平上是非常多样化的，因此反复发生的遗传或表观遗传学异常已被用于风险分层、治疗指导和预后预测。例如，大约20%到30%的AML患者携带Flt3基因的内部串联重复(Flt3/ITD)，这与不良的临床结果有关。8-氯-腺苷对携带Flt3基因突变的AML细胞具有特别高的疗效，进一步表明它是治疗AML的理想候选药物。此外，8-氯-腺苷在体外对多种实体和血液学癌症非常有效，在临床前动物试验和慢性淋巴细胞白血病(CLL)的I期临床试验中具有良好的药代动力学和药效学特性。此外，在动物模型中，8-氯-腺苷显示出体内抗肿瘤活性，但毒性很小或检测不到。在这些先前研究的基础上，我们建议将8-Cl-ADO推进到复发/难治性AML的I/II期临床试验。在这些研究的基础上，有希望的初步研究评估8-Cl-ADO在急性髓细胞白血病中的应用，并从CLL患者的I期临床试验中令人鼓舞的结果支持在人类中具有良好的药代动力学特征。在目标1中，我们将在I/II期临床试验中确定8-氯-腺苷治疗复发/难治性成人急性髓细胞白血病的安全性和有效性。在目标2中，我们将确定8-氯-三磷酸腺苷在细胞内的积累及其对细胞三磷酸腺苷库的影响。在目标3中，我们将确定8-氯-腺苷对白血病造血干细胞的细胞毒性，并产生与8-氯-腺苷治疗反应相关的初步的mRNA/miRNA信号。这些研究的成功完成可能确定8-氯-腺苷为一种新的治疗药物，具有显著减少或消除患者复发的潜力 急性髓系白血病。