FDA-approved drugs with previously unrecognized anti-leukemia activity could be rapidly repositioned for this new indication by leveraging the prior toxicology and pharmacology data on the compound. To identify drugs cytotoxic to leukemia cells and leukemia stem cells, we compiled a chemical library of on-patent and off-patent drugs with wide therapeutic windows and well-understood pharmacokinetics focused on anti-microbials and metabolic regulators. We then screened this library and identified the antimicrobial tigecycline. In preclinical studies, tigecycline induced cell death in leukemia cell lines and primary patient samples in vitro at pharmacologically achievable concentrations. Moreover, systemic treatment with tigecycline delayed tumor growth of leukemia cell lines and primary AML samples in mouse models. Mechanistically, our preliminary data suggest that tigecycline acts as an anti-leukemic agent by inhibiting mitochondrial protein synthesis and thereby disrupting mitochondrial membrane potential. In this application, we will determine the mechanism of action of tigecycline as an anti-leukemic agent and test our hypothesis that it acts by inhibiting mitochondrial protein synthesis inhibiting that results in disruption of oxidative phosphorylation, leading to activating the mitochondrial pathway of caspase activation. We will also define the dependence of leukemia cells on the oxidative phosphorylation for survival and the capacity of the oxidative phoshphorylation pathway in leukemia cell lines and primary samples. Here, we hypothesize that leukemia cell lines, primary AML cells, and leukemia stem cells can tolerate only small reductions in the activity of the respiratory complex before there is impairment of respiration, reduced oxygen consumption, loss of mitochondrial membrane potential and ultimately cell death. As such, we predict that these differences will explain sensitivity and insensitivity to tigecycline. Finally, we will leverage the prior toxicology and pharmacology with tigecycline to initiate a phase I clinical trial in patients with relapsed and refractory AML. In the context of this trial, we will conduct correlative studies and measure plasma and intracellular levels of tigecycline. We will also conduct pharmacodynamic studies to determine whether tigecycline decreases the expression of mitochondrially translated proteins in the primary leukemic blasts. Thus, through this work, we will develop a novel therapeutic strategy for the treatment of leukemia. In addition, we will rapidly translate findings from our lab to the clinic. Of note, this drug would be a first-in-class mitochondrial protein synthesis inhibitor used for the treatment of malignancy.
Drugs clinically used or tested for alternate indications that have unrecognized ability to kill leukemia cells and leukemia stem cells but not normal blood cells be rapidly re-purpositoned for the treatment of leukemia given their prior safety and toxicity testing. By screening a large chemical library of old drugs, we identified Tigecycline a drug used for treatment of serious infections that has unrecognized anti-leukemia activity. Here, we will determine the mechanism by which Tigecycline kills leukemia cells and advance this drug into clinical trial for patients with relapsed/refractory leukemia.
|Jitkova, Yulia; Gronda, Marcela; Hurren, Rose et al. (2014) A novel formulation of tigecycline has enhanced stability and sustained antibacterial and antileukemic activity. PLoS One 9:e95281|
|Mourtada, Rida; Fonseca, Sonali B; Wisnovsky, Simon P et al. (2013) Re-directing an alkylating agent to mitochondria alters drug target and cell death mechanism. PLoS One 8:e60253|
|Sukhai, Mahadeo A; Prabha, Swayam; Hurren, Rose et al. (2013) Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors. J Clin Invest 123:315-28|
|Jhas, Bozhena; Sriskanthadevan, Shrivani; Skrtic, Marko et al. (2013) Metabolic adaptation to chronic inhibition of mitochondrial protein synthesis in acute myeloid leukemia cells. PLoS One 8:e58367|
|Schimmer, Aaron D; Skrtic, Marko (2012) Therapeutic potential of mitochondrial translation inhibition for treatment of acute myeloid leukemia. Expert Rev Hematol 5:117-9|
|Skrtic, Marko; Sriskanthadevan, Shrivani; Jhas, Bozhena et al. (2011) Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell 20:674-88|