A team led by Boaz Tirosh, PhD, Co-leader of Case CCC's Molecular Oncology Program, have identified a promising new therapeutic strategy for acute myeloid leukemia (AML), including some of the disease’s most treatment-resistant forms.
Published in Molecular Cancer, the study describes AcTor, a first-of-its-kind small molecule designed to inhibit TSC2 and sustain mTOR signaling in leukemia cells. When combined with the oral proteasome inhibitor ixazomib, AcTor produced striking anti-leukemia activity across AML cell lines, primary patient samples, and patient-derived xenograft models.
The combination triggered what investigators describe as a “mitochondrial catastrophe” — a rapid collapse of mitochondrial respiration and energy production that drove oxidative stress and apoptosis in leukemia cells. Importantly, the therapy remained effective in TP53-mutant AML, a highly aggressive subtype associated with poor prognosis and limited treatment options.
The findings are especially notable because the approach appeared to eliminate not only AML blast cells, but also leukemic stem cells that can fuel relapse. In mouse models, the combination reduced disease burden, improved survival, and retained potency even after relapse, suggesting the strategy may overcome mechanisms of resistance that limit current therapies such as venetoclax-based regimens.
Beyond its therapeutic implications, the study highlights a broader shift toward targeting cancer metabolism and stress-response pathways rather than relying solely on DNA-damaging approaches. Investigators also identified ADM2 as a potential biomarker of treatment response, which could help guide future translational and clinical studies.
If validated in further preclinical and clinical development, the AcTor/ixazomib strategy could open a new avenue for patients with relapsed or refractory AML who currently face limited options and poor long-term outcomes. Case CCC members on the research team include Jordan Winter, MD, Co-leader, Developmental Therapeutics Program; Daniel Lindner, MD, PhD, Developmental Therapeutics Program; Jason Mears, PhD, Associate Director, Training and Education; and David Wald, MD, PhD, Co-leader, Immune Oncology Program.