Existing therapeutic agents for Acute Myeloid Leukemia (AML) are inadequate to due poor efficacy and severe side effects. This is especially a problem in adults where the 5 year survival is less than 20-50%. Differentaition therapy for AML holds significant promise in leading to more efficacious and less toxic therapies. AML is a disease characterized by the arrest of differentiation of immature myeloid cells. After leukemic cells undergo terminal differentiation, they lose their ability to proliferate. The potential of differentiation therapy has been demonstrated by the use of the differentiation agent, ATRA, for one relatively uncommon subset of AML, acute promyelocytic leukemia. With the use of ATRA 75-85% of acute promyelocytic leukemia patients can now be cured. We have recently identified a novel differentiation-inducing agent, CLT731, that exhibits potent in vitro leukemia differentiation-inducing activity and preliminary evidence of mouse in vivo activity. CLT731 is an analogue of ellipticine, an agent that has perviously been found to have anti-tumor activity but also exhibits high toxicity. As CLT731 has preferential activity on leukemic cells, it appears to have a significantly reduced toxicity profile. The aims of this phase I project are to 1) demonstrate the promise of a CLT731 in mouse AML model systems 2) demonstrate the activity of this compound on patient samples in vitro and 3) to assess its potential toxicities. Due to the enormous need for novel AML therapeutics, especially agents with reduced toxicity, this work has the potential to improve the quality of life 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.
Public Health Relevance Statement: Project Narrative 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.
Project Terms: (All-E)-3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic Acid; 21+ years old; 2H-Tetrazolium, 3,3'-(3,3'-dimethoxy(1,1'-biphenyl))-4,4'-diyl bis(2-(4-nitrophenyl))-5-phenyl-, dichloride; 5,11-dimethyl-6H-pyrido(4,3-b)carbazole; AML - Acute Myeloid Leukemia; ATRA; Acute; Acute Promyelocytic Leukemia; Address; Adult; Adverse effects; All-trans retinoic acid; Animals; Attention; Benign; Biological Models; Biology; Blood (Leukemia); Bone Marrow; Cancer of Breast; Cancers; Cell Death; Cell Line; Cell Lines, Strains; Cell Maturation; CellLine; Cells; Cellular Expansion; Cellular Growth; Colon Cancer; Colon Carcinoma; Colonic Carcinoma; Development; Differentiating Agents; Differentiation Agents; Differentiation Inducer; Differentiation Therapy; Disease; Disorder; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; Dysfunction; Ellipticines; Exhibits; Functional disorder; HL-60; HL60; Hematopoietic; Hemolysis; Human, Adult; IMPHENO; Immunophenotyping; In Vitro; LEUKCL; Leukemia, Granulocytic; Leukemia, Myelocytic, Acute; Leukemias, General; Leukemic Cell; Libraries; Life; Lymphocyte; Lymphocytic; Malignant; Malignant - descriptor; Malignant Cell; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Breast; Malignant neoplasm of breast; Mammals, Mice; Mice; Model System; Modeling; Models, Biologic; Morphology; Mother Cells; Murine; Mus; Myeloblastic Leukemia, Acute; Myelocytic Leukemia; Myelogenous; Myelogenous Leukemia; Myelogenous Leukemia, Acute; Myeloid; Myeloid Cells; Myeloid Leukemia; Myeloid Leukemia, Acute, M3; Natural regeneration; Nitro-BT; Nitroblue Tetrazolium; Nitrotetrazolium Blue; Non-Lymphoblastic Leukemia; Non-Lymphocytic Leukemia; Patients; Phase; Physiopathology; Progenitor Cells; Progranulocytic Leukemia; Proliferating; Protocols, Treatment; Public Health; QOL; Quality of life; RGM; Regeneration; Regimen; Reticuloendothelial System, Bone Marrow; Retinoic Acid; Safety; Sampling; Source; Stem cells; Subtyping, Immunologic; Subtypings, Immunologic; Therapeutic; Therapeutic Agents; Toxic effect; Toxicities; Trans Vitamin A Acid; Treatment Protocols; Treatment Regimen; Treatment Schedule; Treatment Side Effects; Tretinoin; Tretinoinum; Vitamin A Acid; Work; acute granulocytic leukemia; acute myeloid leukemia; acute nonlymphocytic leukemia; adult human (21+); all-trans-Retinoic Acid; all-trans-Vitamin A acid; analog; base; cancer cell; cell growth; chemotherapeutic agent; chemotherapy; cultured cell line; disease/disorder; ellipticine; immunophenotype; improved; in vivo; leukemia; lymph cell; malignancy; malignant breast neoplasm; mouse model; myeloid granulocytic leukemia; myelosis; necrocytosis; neoplasm/cancer; novel; pathophysiology; promyelocytic leukemia; public health medicine (field); public health relevance; regenerate; side effect; subcutaneous; therapy adverse effect; trans-Retinoic Acid; treatment adverse effect; tumor; tumor growth
