Novel differentiation therapy for AML

AML 的新型分化疗法

基本信息

批准号：
7480153
负责人：
Mukesh Kumar Agarwal
金额：
$ 12.82万
依托单位：
INVENIO THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2009-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7480153
关键词：
6-benzylthioinosine Acute Acute Myelocytic Leukemia Acute Promyelocytic Leukemia Adult Age Alternative Therapies Benign Biological Assay Biological Models Biology Bone Marrow Cell Surface Proteins Cells Cessation of life Clinical Clinical Trials Collaborations Cultured Cells Data Development Differentiation Therapy Disease Drug Delivery Systems Drug Formulations Drug Kinetics Elderly Engraftment Ensure Exhibits Familiarity Goals Hematopathology Hematopoietic In Vitro Individual International Lead Leukemic Cell Life Malignant - descriptor Malignant Neoplasms Marketing Measures Modeling Mus Myeloid Cells Natural regeneration Nonprofit Organizations Outcome Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Population Preclinical Drug Development Preclinical Drug Evaluation Preparation Proliferating Public Health Range Receptor Signaling Reporting Research Sampling Source Standards of Weights and Measures Therapeutic Thinking Toll-like receptors Toxic effect Treatment Protocols Tretinoin Work Xenograft Model Xenograft procedure age group cancer cell cell growth chemotherapy cytotoxicity drug development experience improved in vivo leukemia member mouse model novel novel therapeutics nucleoside analog older patient pre-clinical programs research study stem success technological innovation

项目摘要

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is one of the most common forms of leukemia in adults and despite advances in treatment the 5 year survival is less than 20-50% in adults and significantly lower in the elderly. The remarkable success in treating one relatively uncommon subset of AML, acute promyelocytic leukemia, with all trans-retinoic acid (ATRA) illustrates the great promise for agents with greater efficacy and less toxicity. Utilizing ATRA, the presumed cure of 75-85% of patients is possible. ATRA's remarkable success stems from the fact that AML is a disease characterized by the arrest of differentiation of immature myeloid cells. ATRA overcomes this block in differentiation by forcing leukemic cells to mature. After leukemic cells undergo terminal differentiation, they lose their ability to proliferate. The aim of this phase I project is to demonstrate the promise of a novel nucleoside analogue with potent differentiation-inducing activity for the treatment of AML. This compound will be evaluated for differentiation activity using primary patient samples in both cell culture and bone marrow engraftment mouse xenograft experiments. In addition, this promising compound will be analyzed for potential toxicities, particularly myelotoxicity. As differentiation therapies are able to treat leukemia without the necessity for overt cytotoxicity, this work has the potential to lead to a more efficacious, less toxic, and better tolerated therapy for patients with AML. PUBLIC HEALTH RELEVANCE: This project is highly relevant to public health as its main objective is to develop a novel therapy for patients with Acute Myeloid Leukemia that is both efficacious and has low toxicity. As the current AML therapeutics have low efficacy and high toxicities, there is a significant need for new therapies for AML.

描述（由申请人提供）：急性髓系白血病 (AML) 是成人最常见的白血病形式之一，尽管治疗取得了进步，但成人的 5 年生存率仍低于 20-50%，老年人的生存率明显更低。使用全反式视黄酸 (ATRA) 治疗一种相对罕见的 AML 亚型——急性早幼粒细胞白血病，取得了显着的成功，这说明了具有更高疗效和更低毒性的药物的巨大前景。利用 ATRA，预计可以治愈 75-85% 的患者。 ATRA 的显着成功源于以下事实：AML 是一种以未成熟骨髓细胞分化停滞为特征的疾病。 ATRA 通过迫使白血病细胞成熟来克服这种分化障碍。白血病细胞经历终末分化后，就会失去增殖能力。该一期项目的目的是展示一种具有有效分化诱导活性的新型核苷类似物治疗 AML 的前景。将在细胞培养和骨髓移植小鼠异种移植实验中使用原始患者样品评估该化合物的分化活性。此外，还将分析这种有前途的化合物的潜在毒性，特别是骨髓毒性。由于分化疗法能够治疗白血病而无需明显的细胞毒性，因此这项工作有可能为 AML 患者提供更有效、毒性更小、耐受性更好的治疗方法。公共健康相关性：该项目与公共健康高度相关，因为其主要目标是为急性髓系白血病患者开发一种有效且低毒的新疗法。由于目前的 AML 治疗方法疗效低且毒性高，因此迫切需要针对 AML 的新疗法。