SBIR-STTR Award

Plant-derived compounds, particularly alkaloids, have historically been a successful source of currently used therapeutics. Recently, a plant-derived alkaloid was identified that is a potent acute myeloid leukemia (AML) differentiation-inducing compound. Differentiation therapy for AML holds significant promise in leading to more efficacious and less toxic therapies. 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 lower in the elderly. The remarkable success in treating one relatively uncommon subset of AML, acute promyelocytic leukemia, 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. 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. The aims of this phase I project are to 1) demonstrate the promise of a novel plant-derived alkaloid in a mouse xenograft model system 2) demonstrate the activity of this compound and its analogues in vitro and 3) to identify novel plant-derived alkaloids with potent AML differentiation activity. As differentiation therapies are able to treat leukemia without the necessity for overt cytotoxicity, this work has the potential to lead to a 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 identify and develop novel therapeutics for patients with Acute Myeloid Leukemia that are better tolerated and more efficacious. As the prognosis for most patients with AML is currently poor, there is a significant need for new therapies.

Thesaurus Terms:
There Are No Thesaurus Terms On File For This Project.

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.

Thesaurus Terms:
(All-E)-3,7-Dimethyl-9-(2,6,6-Trimethyl-1-Cyclohexen-1-Yl)-2,4,6,8-Nonatetraenoic Acid;21+ Years Old;Aml - Acute Myeloid Leukemia;Atra;Acute;Acute Myeloblastic Leukemia;Acute Myelogenous Leukemia;Acute Promyelocytic Leukemia;Adult;Adult Human;Age;Aged 65 And Over;Agonist;Alkaloids;All-Trans Retinoic Acid;Animals;Biologic Factor;Biological Factors;Biology;Blood (Leukemia);Cancers;Cell Differentiation;Cell Differentiation Process;Cells;Clinical;Clinical Trials;Development;Development And Research;Differentiating Agents;Differentiation Agents;Differentiation Inducer;Differentiation Therapy;Disease;Disorder;Dose;Drug Delivery;Drug Delivery Systems;Drug Kinetics;Drug Screening;Drug Targeting;Elderly;Ensure;Evaluation Studies, Drug, Pre-Clinical;Evaluation Studies, Drug, Preclinical;Exhibits;Hematopoietic;In Vitro;Leukcl;Lead;Letters;Leukemia, Myelocytic, Acute;Leukemic Cell;Life;Lytotoxicity;Malignant;Malignant - Descriptor;Malignant Neoplasms;Malignant Tumor;Medicinal Chemistry;Mice;Mice Mammals;Modeling;Murine;Mus;Myeloid Cells;Myeloid Leukemia, Acute, M3;Natural Products;Patients;Pb Element;Pharmaceutic Chemistry;Pharmaceutical Chemistry;Pharmacokinetics;Phase;Plants;Preclinical Drug Evaluation;Progranulocytic Leukemia;Proliferating;Public Health;R &D;R&D;Receptor Signaling;Regimen;Research;Research Contracts;Retinoic Acid;Safety;Sampling;Staging;Tlr Protein;Therapeutic;Toll-Like Receptors;Toxic Effect;Toxicities;Toxicology;Trans Vitamin A Acid;Tretinoin;Tretinoinum;Vitamin A Acid;Work;Xenograft Model;Acute Granulocytic Leukemia;Acute Myeloid Leukemia;Adult Human (21+);Adulthood;Advanced Age;Age Group;All-Trans-Retinoic Acid;All-Trans-Vitamin A Acid;Analog;Animal Efficacy;Chemotherapy;Clinical Investigation;Commercialization;Cytotoxicity;Developmental;Disease/Disorder;Drug Development;Elderly Patient;Elders;Experience;Geriatric;Heavy Metal Pb;Heavy Metal Lead;Human Disease;In Vivo;Late Life;Later Life;Leukemia;Malignancy;Neoplasm/Cancer;New Therapeutics;Next Generation Therapeutics;Novel;Novel Therapeutics;Older Adult;Older Patient;Older Person;Over 65 Elderly;Patient Population;Preclinical Efficacy;Preclinical Toxicity;Promyelocytic Leukemia;Public Health Medicine (Field);Research And Development;Senior Citizen;Stem;Success;Trans-Retinoic Acid