Dr. Arnon Lavie

This proposal focuses on testing a novel concept that combines two drugs, L-asparaginase and TRAIL on a single polypeptide, as a therapeutic for AML. My laboratory is studying the structure and function L-asparaginases with the ultimate goal of developing improved versions as drugs. Drug safety (in addition to drug efficacy) is major criteria guiding our drug development process. For L-asparaginases, their concomitant L-glutaminase activity has been implicated as the source of many of the observed toxic side effects. To remedy this problem, our strategy is to identify variants with no or diminished L-glutaminase activity (to reduce the toxicity) while fully maintaining the anti-cancer L-asparaginase activity. Our publications #1 to #8 below showcase our success towards this goal. In addition to L-asparaginase, we have been also testing TRAIL as a therapeutic, especially in combination with L-asparaginase. The rationale to combine these two drugs comes from the observation of synergy between the two drugs in glioblastoma. The high potency of our TRAIL+L-asparaginase combination comes from: (i) by being on a single polypeptide that codes three tandem TRAIL domains followed by an L-asparaginase domain (TR3-Asp), the trimeric nature of the TRAIL component is stabilized. This solves the low in vivo stability seen for dulanermin (single TRAIL domain currently in clinical trials). (ii) the tetrameric nature of L-asparaginase results in a molecule that present 4 TRAIL timers, increasing the ability of the drug to cluster death receptors. (iii). Asparagine depletion, caused by L-asparaginase, through activation of GCN2 which ultimately activates CHOP, results in higher expression of death receptor 5 (DR5). These factors explain how L-asparaginase can sensitize AML cells to TRAIL-induced apoptosis. We asked whether such a biologic could be effective against AML cells. Indeed, our cell culture studies demonstrate potent killing of the MV4;11 AML cell line by the TRAIL+L-asparaginase fusion, with the two drugs being synergistic. Moreover, this biologic showed remarkable efficacy in vivo. The goal of this proposal is to optimize the expression of this biologic molecule, identify predictive biomarkers to response in AML cells, and conduct a pre-clinical in vivo efficacy study of this novel TR3-Asp drug in PDX models of AML

Degree: PhD

Title: Professor

College:  College of Medicine at Chicago

Department: Biochemistry and Molecular Genetics

Program: Translational Oncology

Member Type:Research Member

PubMed: link

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