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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：
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
项目类别：
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

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.