Boaz Tirosh
Case Western Reserve University, OH·Pharmacology
Some cancers are hard to treat because their cells can slow down, adapt to drug stress, and wait out therapy. Acute myeloid leukemia (AML), a blood cancer that starts in the bone marrow, is one of them: the marrow environment helps leukemia cells survive and resist treatment.
- Fields
Pharmacology
Medicine & Clinical Research
Biochemistry
- Topics
acute myeloid leukemia
mTORC1
mTOR activator
- Grants
- 1 known grant, through Feb 2030
What they work on
- Map the specific defect in mitochondrial respiration that appears when AML cells are treated with the mTORC1 activator AcTor plus a proteasome inhibitor, a drug that blocks protein disposal.
- Determine why mitochondria in mTORC1-activated AML cells are prone to stress-induced shutdown, and test how this predisposition relates to drug resistance.
- Identify the protein-translation mechanisms by which mTORC1 activation pulls dormant (quiescent) AML cells back into the cell cycle and restores their sensitivity to chemotherapy.
- Evaluate the therapeutic value of mTORC1 hyperactivation as a chemotherapy sensitizer in cell-culture and animal models of AML.
More about the research
Proteasome inhibitors are drugs that block the cell's protein-disposal machinery. They work very well against multiple myeloma, a cancer of antibody-making plasma cells, but have had limited success elsewhere. This project asks whether AML can be made just as vulnerable by pushing its metabolism into a sudden crisis.
Why it matters
Patients with acute myeloid leukemia often relapse because some leukemia cells survive treatment, sheltered in the bone marrow or resting in a dormant state. If switching on mTORC1 makes these cells sensitive to proteasome inhibitors and chemotherapy, the approach could point to new drug combinations and new metabolic weak points to target in AML.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Xunlei Kang
University of Missouri-Columbia, MO·Medicine & Clinical Research
Determine how DPP4, a cell-surface enzyme, controls the location, survival and self-renewal of human AML stem cells, using colony-forming assays and mice carrying human AML cells.
Herman Sintim
University of Notre Dame, IN·Chemistry
Biochemically characterize second-generation 3H-pyrazolo[4,3-f]quinoline kinase inhibitors and use new chemistry to make third-generation compounds with better drug-like properties that target FLT3, CDK2, CDK12/13 or CDK18.
Senthil Kumar Radhakrishnan
Virginia Commonwealth University, VA·Biochemistry
Express and purify DDI2 protease and run high-throughput screens with a protein thermal shift assay, which detects binding by shifts in protein unfolding temperature, to find small molecules that bind DDI2.
The school
Case Western Reserve University: 34 labs on PI Pages, $643M a year on research, 213 research doctorates a year.
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