Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY Leukemia stem cells (LSCs) are at the apex of the acute myeloid leukemia (AML) cellular hierarchy. The quiescent fraction of LSCs provides a reservoir of self-renewing cells that sustain leukemia growth, prevent clonal exhaustion, and are treatment resistant; thus, eliminating LSCs is the `holy grail' of any anti-leukemia treatment. In previous studies, we showed that miR-126 is necessary to maintain a quiescent subfraction of LSCs that prevent clonal exhaustion. We demonstrated how SPRED1/miR-126 autoregulatory loop in LSCs and in BM endothelial cells (ECs) converge to increase miR-126 levels in LSCs, protect them and support leukemia growth. We showed that high miR-126 levels are due to both LSC autonomous mechanisms, resulting in enhanced endogenous production, and non-autonomous mechanisms, through exogenous miR-126 supply from ECs. To deplete miR-126 in LSCs and ECs, we designed a novel oligodeoxynucleotide anti-miR-126 inhibitor, called miRisten. Our data show that pharmacological miR-126 deprivation by miRisten significantly decreases LSC endogenous production of miR-126 and decreases the exogenous supply of endothelial miR-126. The net result is a significant decrease of miR-126 that damages the homeostasis and activity of LSCs, as demonstrated in serial transplant experiments. In addition, we now have evidence that miR-126 enhances mitochondrial metabolism (i.e., oxidative phosphorylation) and mitochondrial dynamics (i.e., mitochondrial fusion) in LSCs through SPRED1/ERK/p-BCL-2/NRF2 signaling. Accordingly, depletion of miR-126 by miRisten treatment significantly downregulates BCL-2 and disrupts mitochondrial metabolism, leading to increased levels of reactive oxygen species and apoptosis of LSCs. In addition, miRisten disrupts LSC mitochondrial function by upregulating the dynamin related protein 1 (DRP1), inducing mitochondrial fission, decreasing mitochondrial membrane potential, and inducing expression of mitophagy marker proteins. Since mitochondria-centered metabolism is the main metabolic energetic source for LSCs, we propose to dissect how miRisten exploits the mitochondrial metabolic vulnerability as a novel mechanism of action to eliminate LSCs. Furthermore, after conducting Investigational New Drug application (IND)-enabling pharmacokinetic, pharmacodynamic and toxicology studies, we will rapidly translate miRisten from bench to beside with a first-in-human phase 1 clinical trial of miRisten in patients with relapsed/refractory (r/r) AML. The central hypothesis of this proposal is that miRisten targets miR- 126-depended metabolic vulnerability of LSCs and will provide a novel therapeutic approach for LSC elimination in AML. We propose the following Specific Aims (SAs): SA#1: Determine the mechanisms of miRisten-induced mitochondrial metabolic vulnerability in LSCs. SA#2: Conduct pharmacokinetic, pharmacodynamic, efficacy and toxicology studies of miRisten to inform dose and schedule selection for human studies. SA#3: Conduct a first-in-human phase 1 trial of miRisten in patients with r/r AML. This project will translate novel discoveries on miR-126 into the clinic, by conducting preclincal studies that culminate in a first-in-human trial of miRisten.
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