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）：急性髓细胞性白血病（AML）是成年人最常见的白血病形式之一，尽管治疗的进步在成人的5年生存期少于20-50％，而老年人的生存率却显着降低。在治疗一个相对罕见的AML，急性前临床白血病的子集中取得了显着的成功，所有反视网膜酸（ATRA）表明了对具有更大功效和毒性较小的药物的巨大希望。利用ATRA，可能可以治愈75-85％的患者。 ATRA的显着成功源于AML是一种疾病，其特征是暂停未成熟髓样细胞的分化。 ATRA通过强迫白血病细胞成熟来克服分化的块。白血病细胞经历末端分化后，它们失去了增殖的能力。该阶段I项目的目的是证明新型核苷类似物具有有效分化活性以治疗AML的希望。该化合物将在细胞培养和骨髓植入小鼠异种移植实验中使用原代患者样品进行分化活性。此外，将分析这种有希望的化合物的潜在毒性，尤其是骨髓毒性。由于分化疗法能够在无需明显的细胞毒性的情况下治疗白血病，因此这项工作有可能导致AML患者更有效，毒性较低且耐受性更好。公共卫生相关性：该项目与公共卫生高度相关，因为其主要目的是为急性髓细胞性白血病患者开发一种新颖的疗法，该疗法既有效且毒性低。由于当前的AML治疗疗法具有低疗效和高毒性，因此对AML的新疗法非常需要。