Natural product-derived differentiation agents for AML

天然产物衍生的 AML 分化剂

• 批准号: 8915846
• 负责人: Mukesh Kumar Agarwal
• 金额: $ 14.25万
• 依托单位: INVENIO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 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/8915846
• 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 Kinetics; Drug Targeting; 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

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）：虽然AML是成人中最常见的白血病形式之一；成人5年生存率低于20-50%，老年人5年生存率更低。全反式维甲酸（ATRA）在治疗急性髓细胞白血病（APL）这一相对罕见的亚型上取得了显著的成功，说明了分化治疗的巨大前景。使用ATRA，可能治愈75-85%的患者，但仅针对这种罕见的AML亚群。ATRA的显著成功源于AML是一种以未成熟骨髓细胞分化受阻为特征的疾病。ATRA通过迫使白血病细胞成熟来克服这种分化障碍。白血病细胞经过终末分化后，就失去了增殖能力。我们最近发现一种植物源性生物碱因其诱导AML分化的能力而有望成为非apl白血病的AML治疗药物。该二期项目的主要目的是进行临床前疗效和毒性研究，以开发这种植物源生物碱的优化形式，使其成为临床药物。由于分化疗法能够治疗白血病而不需要明显的细胞毒性，这项工作有可能为AML患者带来更有效、毒性更小、耐受性更好的治疗方法。