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

基本信息

批准号：
9900748
负责人：
STEVEN Terry ROSEN
金额：
$ 43.05万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900748
关键词：
Acute Myelocytic Leukemia Adenosine Adult Adult Acute Myeloblastic Leukemia Affect Allogenic Animal Model Animals Antineoplastic Agents Apoptosis Bone Marrow Cell Death Cells Chemotherapy-Oncologic Procedure Chronic Chronic Lymphocytic Leukemia City of Hope Comprehensive Cancer Center Clinical Collaborations 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 Phase Phase I Clinical Trials Phase I/II Clinical Trial Production Property RNA Recurrence Refractory Relapse Research Resistance development Resolution Ribonucleosides Ribose Risk Risk stratification Route Safety Signal Pathway Solid Stem cell transplant TP53 gene Tern Texas Toxic effect Translations Transplantation Universities acute myeloid leukemia cell adverse outcome analog base cancer cell cancer survival cellular targeting chemotherapy clinical development clinical implementation comorbidity 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 pharmacokinetics and pharmacodynamics pre-clinical prevent public health relevance relapse patients response socioeconomics stem cells sugar transcriptome sequencing treatment strategy tripolyphosphate

项目摘要

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，尽管在实施针对 AML 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，但大多数患者仍会面临预后不良的问题。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。卤化 ATP 类似物 8-氯-腺苷 (8-Cl-Ado)，具有独特的作用模式在细胞中，8-Cl-Ado 代谢为活性细胞毒性代谢物 8-Cl-ATP，并在高微摩尔浓度的 8-Cl-ATP 主要掺入 mRNA 中并抑制 ATP 合酶活性，从而减少细胞内 ATP 库。 8-Cl-Ado/8-Cl-ATP 通过干扰转录和翻译、细胞生物能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，对生长和生存抑制更加敏感。 8-Cl-Ado 比正常细胞更容易发生细胞凋亡或自噬性细胞死亡，这也可能有助于克服 AML 中的另一个挑战，即该疾病在细胞遗传学和分子水平上非常重要。例如，大约 20% 至 30% 的 AML 患者携带 FLT3 基因（FLT3/ITD）内部串联重复。 8-Cl-Ado 对携带 FLT3 基因突变的 AML 细胞具有特别高的功效，这进一步表明它是治疗 AML 的理想药物。 8-Cl-Ado 在体外对多种实体癌和血液癌非常有效，并且在临床前动物研究以及慢性淋巴细胞白血病 (CLL) 模型的 I 期临床试验中具有良好的药代动力学和药效学特性，8-。 Cl-Ado 显示出体内抗肿瘤活性，但毒性很小或不可检测。基于这些先前的研究，评估 8-Cl-Ado 在 AML 中的初步研究很有前景，并且该阶段的结果令人鼓舞。 I 在 CLL 患者中进行的临床试验支持了良好的人体药代动力学特征，我们现在建议将 8-Cl-Ado 推进到复发/难治性 AML 的 I/II 期临床试验中，我们将确定其安全性和有效性。在复发/难治性成人 AML 的 I/II 期临床试验中使用 8-Cl-Ado 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 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，并生成与 8-Cl-Ado 治疗反应相关的初步 mRNA/miRNA 特征。成功完成这些研究可以鉴定 8-Cl-Ado。 Cl-Ado 作为一种新型治疗药物，具有显着减少或消除患者复发的潜力与反洗钱。