Targeting AML Mitochondria by Ceramide

通过神经酰胺靶向 AML 线粒体

• 批准号: 10546239
• 负责人: Besim Ogretmen
• 金额: $ 40万
• 依托单位: LIPO-IMMUNO TECH, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10546239
• 关键词: Acute Myelocytic Leukemia; Affect; Antineoplastic Agents; Apoptosis; BCL2 gene; Bone Marrow Cells; Cell Death; Cell Membrane Permeability; Ceramides; Charge; Clinical; Complex; Data; Defect; Development; Drug Kinetics; Drug Targeting; Drug resistance; Electrons; Event; Exhibits; Exposure to; FLT3 gene; Fatty Acids; Feasibility Studies; Functional disorder; Generations; Goals; Growth; Human; In Situ; In Vitro; Isocitrate Dehydrogenase; Lead; Legal patent; Length; Lipids; Malignant Neoplasms; Maximum Tolerated Dose; Mediating; Metabolism; Mitochondria; Modeling; Molecular; Mus; Names; Non-Malignant; Nucleotides; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Phase; Publishing; Receptor Activation; Receptor Protein-Tyrosine Kinases; Resistance; Signal Transduction; Sodium Selenite; Solubility; Sphingolipids; Stimulus; Stress; System; Therapeutic; Tissues; Toxic effect; Tumor Suppression; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; United States; Warburg Effect; Xenograft procedure; acute myeloid leukemia cell; analog; base; cancer cell; design; dihydroceramide desaturase; drug-sensitive; improved; in vivo; inhibitor; innovation; macromolecule; novel; pharmacokinetics and pharmacodynamics; preclinical study; reconstitution; response; survival outcome; targeted treatment; tool; tumor; uptake; water solubility

SUMMARY This proposal's long-term objective is to develop a mechanism-based therapeutic drug for the treatment of human acute myeloid leukemias (AML), which are among the deadliest cancers in the United States. Despite some advances in treatment, survival for AML has not improved significantly in decades, with rare exceptions for specific subclasses. While targeted therapies with FLT3, IDH, and Bcl-2 inhibitors have increased response rates significantly, survival has been extended only by several months. Thus, novel and innovative therapeutic drugs are needed to improve the survival outcomes of AML patients. The sphingolipid ceramide, an emerging tumor suppressor lipid, mediates anti-proliferative signaling events in response to various stress stimuli, including tyrosine kinase inhibitors (TKIs). Our published and unpublished data suggest that decreased levels of C18-ceramide might be critical in the pathophysiology, progression and drug-resistance of AML. These data also revealed that reconstitution of C18-ceramide by molecular and pharmacologic tools results in the suppression of AML growth, and help overcome drug resistance. Because of pharmacologic challenges of the conventional exogenous short-chain ceramides, we have developed novel mitochondrial targeted pyridinium- C18-ceramide (Pyr-Cer) analogs that induce cancer cell mitophagy and tumor suppression. These Pyr-Cer analogs exhibit increased water solubility, cell-membrane permeability, and cancer cell-selective mitochondrial uptake, compared to uncharged conventional ceramides. Pyr-Cer analog drugs, such as LCL461 (patented Class I) or LCL768 (Class II), contain a positive charge at a delocalized pi-electron system. This then results in preferential localization of the drug into highly negatively charged mitochondria in cancer cells/tissues due to the Warburg effect. The accumulation of Pyr-Cer in mitochondria results in cancer cell death via induction of mitophagy by reducing cellular energy generation and decreasing the synthesis of other vital macromolecules, such as nucleotides. This effect of Pyr-Cer on mitophagy induction is further increased when cancer cells are exposed to general ROS/RNS inducer sodium selenite that causes Drp1 activation and mitochondrial fission. Thus, we have generated a new (Class II) Pyr-Cer analog drugs conjugated with sodium selenite, named as SoSe-C18-Pyr-Cer (LCL768), which selectively induced mitophagy-dependent cell death in AML in situ and in vivo. Based on these data, our goal is to develop LCL768 as an anti-cancer drug for the treatment of AML. In these feasibility studies, we will: 1) Validate the mechanism by which Pyr-Cer drugs target AML mitochondria by mitophagy in vitro; and 2) Determine bioactivity, toxicity, pharmacokinetics and anti-AML activity of LCL768 in vivo. We will determine the possible off-target effects, maximum tolerated dose (MTD), pharmacokinetic/pharmacodynamic profiles and anti-AML effects of LCL768 in various models. These include drug sensitive versus resistant AML xenografts, AML PDXs, and primary AML blasts. This Phase I feasibility study will help the commercial development of LCL768 for a Phase II application.

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