Natural product-derived differentiation agents for AML

天然产物衍生的 AML 分化剂

基本信息

批准号：
8338881
负责人：
Mukesh Kumar Agarwal
金额：
$ 41.05万
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：
2008-04-08 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8338881
关键词：
Acute Acute Myelocytic Leukemia Acute Promyelocytic Leukemia Adult Age Agonist Alkaloids Animals Biological Factors Biology Cell Differentiation process Cells Clinical Clinical Trials Development Differentiation Inducer Differentiation Therapy Disease Dose Drug Delivery Systems Drug Kinetics Elderly Ensure Exhibits Hematopoietic In Vitro Lead Letters Leukemic Cell Life Malignant - descriptor Malignant Neoplasms Modeling Mus Myeloid Cells Patients Pharmaceutical Chemistry Phase Plants Preclinical Drug Evaluation Proliferating Public Health Receptor Signaling Regimen Research Research Contracts Safety Sampling Staging Therapeutic Toll-like receptors Toxic effect Toxicology Tretinoin Work Xenograft Model age group analog animal efficacy chemotherapy commercialization cytotoxicity drug development experience human disease in vivo leukemia novel novel therapeutics older patient patient population preclinical efficacy preclinical toxicity research and development stem success

项目摘要

DESCRIPTION (provided by applicant): Though AML is one of the most common forms of leukemia in adults; the 5 year survival is less than 20-50% in adults and significantly lowers in the elderly. The remarkable success in treating one relatively uncommon subset of AML, acute promyelocytic leukemia (APL), with all trans- retinoic acid (ATRA) illustrates the great promise for differentiation therapy. Utilizing ATRA, the presumed cure of 75-85% of patients is possible but only for this rare AML subset. 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. We have recently found that a plant-derived alkaloid holds promise as an AML therapeutic for non-APL leukemia due to its ability to induce potent AML differentiation. The major aims of this phase II project are to perform preclinical efficacy and toxicity studies in order to develop our optimized form of this plant-derived alkaloid into a clinical agent. As differentiation therapies are able to treat leukemia without the necessity for overt cytotoxicity, this work has the potential to lead to much needed more efficacious, less toxic, and better tolerated therapy for patients with AML.

描述（由申请人提供）：尽管AML是成年人中最常见的白血病形式之一；成人的5年生存率不到20-50％，老年人的生存率显着降低。在治疗AML，急性前临床白血病（APL）的一个相对罕见的子集中，所有跨视黄酸（ATRA）取得了显着的成功，这表明了分化治疗的巨大希望。利用ATRA，可以预测的75-85％的患者可以治愈，但仅适用于这个罕见的AML子集。 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。我们最近发现，由于其能够诱导有效的AML分化的能力，植物来源的生物碱具有非APL白血病的AML治疗。该第二阶段项目的主要目的是进行临床前疗效和毒性研究，以便将我们优化的这种植物来源的生物碱形式开发为临床剂。由于分化疗法能够无需明显的细胞毒性治疗白血病，因此这项工作有可能导致非常有效，毒性且毒性较小且耐受疗法对AML患者的疗效更高。