TEAMEDON INTERNATIONAL, INC. — Department of Health and Human Services SBIR Phase I: 102

Description

DESCRIPTION provided by applicant We propose to develop ML a small molecule PKM M isoform of pyruvate kinase activator into a new targeted therapeutic for Acute Myeloid Leukemia AML The majority of AML cases is diagnosed in adults and incidence increases significantly among elderly population The outcomes for adults with AML are poor Although chemotherapy results in high rates of remission the majority of patients relapse with an overall year survival only for younger patients and a median overall survival less than year for older patients The persistence of leukemia stem cells LSCs following chemotherapy is a major factor contributing to clinical relapse Therefore there is an urgent need to develop novel therapeutics that specifically target LSCs in AML patients Pyruvate kinase catalyzes the last step of glycolysis Its M isoform PKM is highly expressed in tumors of all kinds including AML cells but with low pyruvate kinase activity PKM occurs in tetramer active and dimer inactive forms a high tetramer to dimer ratio leads to energy production while a low ratio channels metabolites into synthetic processes ML potently activates human PKM in vitro induces PKM tetramer formation and significantly reduces aerobic glycolysis in cancer cells In addition ML also increases reactive oxygen species ROS concentrations and induces oxidative stress in cancer cells PKM is abundantly expressed up to x of control in many AML cell lines and primary AML patient samples suggesting all subtypes of AML could benefit from ML treatment ROS is important for the maintenance of malignant LSCs in AML Significantly lower ROS level is observed in LSCs like CD cells compared to more mature CD cells In human primary AML samples ML increases ROS level and significantly reduces the colony formation of LSCs In AML transgenic MLL AF mouse model deletion of PKM with expression of PKM a situation similar to ML treatment reduces the levels of metabolic intermediates important for biosynthesis and impairs leukemic cells in blood and bone marrow without perturbing normal hematopoietic stem cells HSCs ML is well tolerated in repeat dose toxicity studies in mice suggesting a greater than X margin of safety based on an in vitro efficacious concentration in human primary AML samples Our SBIR Phase I goal is to establish the pre clinical proof of concept and demonstrate that ML selectively targets LSCs and complements standard therapy in AML patient derived xenograft PDX mouse The specific aims proposed in this proposal include Determine the optimal concentration of ML via in vitro viability assays At this concentration ML not only strongly reduces the survival of phenotypically described LSCs but is also well tolerated by normal HSCs We will investigate whether ML could selectively target LSCs using AML PDX model We will treat the AML PDX mice with ML for weeks followed by a secondary serial transplantation to validate killing of LSCs Using AML PDX mouse we will further determine whether ML could complement current standard induction chemotherapy and extend the life span of chemotherapy treated AML mouse We will treat the AML PDX mice with ML induction chemotherapy or ML in combination with induction chemotherapy The dosing of ML will last for weeks mice will be monitored for survival and signs of leukemia Demonstrating that ML selectively targets LSCs and complements standard therapy in AML will justify Phase II research and open development of a new way to attack one of worldandapos s most deadly cancers PUBLIC HEALTH RELEVANCE Acute Myeloid Leukemia AML is one of worldandapos s most deadly cancers among elderly patient population with a median overall survival less than year The persistence of leukemia stem cells LSCs following chemotherapy is a major factor contributing to clinical relapse of AML To address this unmet medical need we are developing a new small molecule therapeutic selectively targets LSCs in AML In this project we propose that our compound selectively targets LSCs and complements standard chemotherapy in AML patient derived xenograft PDX mouse