Hematological malignancies, specifically leukemias, are cancers affecting various types of blood cells. They are among the most common cancers worldwide and account for more than 10% of all new cancer diagnoses. One particularly challenging form of leukemia is Acute Myelogenous Leukemia (AML), which is the most common form of adult leukemia. AML is still very difficult to treat and typically associated with dramatically higher mortality rates, especially in older patients. Worldwide, AML affects roughly 1 million people per year and is responsible for >150,000 deaths per year, accounting for nearly 2% of all cancer-related deaths in the US. The cure rate of AML falls dramatically with age; 33% for patients under 60, falling to 10% for patients older than 60. Patients receiving no treatment, typically due to being too weak to tolerate therapy, have a life expectancy of less than one year. One of the more significant drugs developed for the treatment of lymphoid derived leukemias is the folate antimetabolite methotrexate (MTX). MTX exerts its activity primarily through targeting the essential enzyme dihydrofolate reductase (DHFR). DHFR is a key player in the de novo synthesis of both pyrimidine and purine building blocks crucial for the propagation of rapidly dividing cancer cells. However, this important class of antimetabolites has found very little clinical application in treating AML. MTX is a classical antifolate and an analog of folic acid, a highly negatively charged vitamin that must be actively transported into cells where it is polyglutamylated for maximum activity and cellular retention. The classical anticancer antifolates require the same transport and enzymatic machinery to achieve their therapeutic potential and, as such, these proteins become the key mechanisms through which cancer cells achieve resistance. Recently another antifolate, pemetrexed (PMX), has been shown to be a substantial improvement in the treatment of some solid tumors. It is theorized that PMXs improved efficacy is a consequence of incidental multi-targeting whereby other folate- dependent enzymes in associated metabolic pathways are also inhibited. In this application, we will pursue the development of new antifolates, designed for AML that mirror the multi-targeting nature of PMX while reducing the liabilities associated with classical antifolates like MTX and PMX. Our work has focused on non-classical antifolates, inhibitors that do not require folic acid active transport or enzymatic modification to achieve efficacy. Recently, we have begun to explore these compounds for anti-cancer application and discovered congeners in this series that display remarkable activity against hematological cell lines, including myeloid lines, while maintaining good selectivity over other tissues. This application focuses on (1) scale-up synthesis and profiling of the lead antifolate against a diverse panel of AML subtypes and (2) evaluation of pharmacokinetic profile and effectiveness in an animal model of AML.
Public Health Relevance Statement: Public Health Relevance: Myelogenous leukemias are cancers of the blood system affecting both children and adults. Despite significant advances in treatment, many patients do not respond to the current therapies and there is a compelling need to develop agents to address drug resistance and toxicity. Herein, we propose the development of a new class of antimetabolites designed to be effective in drug-resistant and relapsed forms of the disease.
Project Terms: Accounting; Active Biological Transport; Acute Myelocytic Leukemia; acute myeloid leukemia cell; Address; Adult; adult leukemia; Affect; Age; Allogenic; Animal Model; Animals; anti-cancer; Antimetabolites; antimicrobial; Ara-C; base; Blood Cells; cancer cell; Cancer cell line; cancer diagnosis; Cell Line; Cells; Cessation of life; Charge; Chemical Exposure; chemotherapy; Chemotherapy and/or radiation; Child; clinical application; Connecticut; Daunorubicin; design; Development; Dihydrofolate Reductase; Dihydrofolate Reductase Inhibitor; Disease; Dose; Dose-Limiting; drug disposition; Drug Kinetics; Drug resistance; Drug toxicity; Dysmyelopoietic Syndromes; Effectiveness; efficacy study; Elderly; Enzymes; Evaluation; falls; Folic Acid; Folic Acid Antagonists; Follow-Up Studies; Formulation; Foundations; Future; Goals; Growth; Hematologic Neoplasms; Hematology; Hematopoietic Neoplasms; hematopoietic tissue; HL-60 Cells; Human; Immunotherapy; improved; in vivo; in vivo evaluation; inhibitor/antagonist; Injections; interest; Interleukin-2; Joints; Lead; lead candidate; leukemia; Life Expectancy; Link; Lymphoid; Lymphoid Tissue; Malignant Neoplasms; Metabolic Pathway; metabolomics; Methotrexate; Modification; mortality; mouse model; Mus; Myelogenous; Myeloid Leukemia; Nature; Neoadjuvant Therapy; No-Observed-Adverse-Effect Level; older patient; Pancytopenia; Pathway interactions; Patients; Pemetrexed; Pharmaceutical Preparations; Phase; Population; Positioning Attribute; preclinical evaluation; prevent; Proteins; public health relevance; Purines; Pyrimidine; Radiation therapy; Relapse; Resistance; Route; scale up; screening panel; Series; Small Business Technology Transfer Research; Solid Neoplasm; Source; standard of care; stem; Stem cell transplant; Surveys; Survival Rate; System; Testing; Therapeutic; therapy design; Tissues; Toxic effect; Universities; Vitamins; Work; Xenograft Model
