Paul W. Burridge
Northwestern University, IL·Pharmacology
Nilotinib is a highly effective pill for chronic myelogenous leukemia (CML), a blood cancer, but it carries a vascular cost. In a 10-year clinical trial, 97.3% of treated patients avoided progression to the acute phase of the disease, yet 23.5% developed some form of artery disease, sometimes severe enough to require amputation.
- Fields
Pharmacology
Medicine & Clinical Research
Genetics
- Topics
nilotinib
chronic myelogenous leukemia
tyrosine kinase inhibitor
- Grants
- 1 known grant, through Jul 2030
What they work on
- Test whether susceptibility to nilotinib-induced artery disease is intrinsic to patients' cells by generating induced pluripotent stem cell lines from 100 nilotinib-treated patients, differentiating them to endothelial cells, and comparing drug responses across six validated assays.
- Link drug response to genotype by correlating dose-dependent RNA-sequencing changes after nilotinib exposure with whole-genome sequence from the same patients to identify expression quantitative trait loci, DNA variants that tune gene responses.
- Replicate candidate risk variants in an independent 200-patient DNA-only cohort of nilotinib-treated patients using SNP array genotyping.
- Use CRISPR-based genome editing to introduce or correct candidate variants in stem cell-derived endothelial cells, then pharmacologically target the implicated pathways to test whether artery injury can be prevented.
More about the research
The side effect appears even in patients with no prior cardiovascular risk factors, and no test exists to predict who is vulnerable, so affected patients are identified only after irreversible complications.
Why it matters
Patients cured of chronic myelogenous leukemia sometimes must stop their best therapy because of drug-induced artery disease. This work could yield genetic markers that let oncologists choose the safest drug for each patient up front, a mechanistic explanation for the vascular injury, and candidate protective co-treatments identified in human cells that could be carried into clinical trials.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
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University of Utah, UT·Physiology·Early-career
Test whether a signaling chain from reactive oxygen species through the transcription factors FOXO1 and KLF5 to IL-18 and IL-1β drives endothelial dysfunction, using iPSC-derived endothelial cells and transgenic mice carrying the ALDH2*2 variant.
Henry Kranzler
University of Pennsylvania, PA·Genetics
Map alcohol-linked GWAS variants to the genes they control by combining ATAC-seq (open DNA maps) and Capture C (maps of DNA looping) data from iPSC-derived cortical, dopaminergic and other neurons.
Daniel Garry
University of Minnesota, MN·Medicine & Clinical Research
Test whether GFP-labeled pig stem cells with mismatched MHC immune genes can rescue pig embryos lacking the heart-building genes NKX2-5, TBX5 and HAND2, using blastocyst complementation.
The school
Northwestern University: 71 labs on PI Pages, $1.3B a year on research, 536 research doctorates a year.
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