Natural product-derived differentiation agents for AML

天然产物衍生的 AML 分化剂

• 批准号: 8201228
• 负责人: Mukesh Kumar Agarwal
• 金额: $ 43.45万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201228
• 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

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. PUBLIC HEALTH RELEVANCE: This project is highly relevant to public health as its main objective is to develop a novel therapeutic regimen for patients with Acute Myeloid Leukemia that is both efficacious and has low toxicity. As current AML therapeutics has poor efficacy and high toxicities, there is a significant need for new therapies and therapeutic approaches for AML.

描述（由申请人提供）：尽管 AML 是成人最常见的白血病形式之一；成人的 5 年生存率低于 20-50%，老年人的生存率显着降低。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 (APL) 取得了显着成功，这说明了分化治疗的巨大前景。利用 ATRA，预计治愈 75-85% 的患者是可能的，但仅限于这种罕见的 AML 亚型。 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。我们最近发现，一种植物来源的生物碱有望作为非 APL 白血病的 AML 治疗剂，因为它能够诱导有效的 AML 分化。该二期项目的主要目标是进行临床前功效和毒性研究，以便将这种植物源生物碱的优化形式开发成临床药物。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 患者带来急需的更有效、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型治疗方案。由于目前的AML治疗方法疗效差且毒性高，因此迫切需要针对AML的新疗法和治疗方法。