# Mechanism of Ponatinib induced vascular toxicity

> **NIH NIH F30** · TUFTS UNIVERSITY BOSTON · 2024 · $44,724

## Abstract

PROJECT SUMMARY/ABSTRACT
The development of first generation Abl-tyrosine kinase inhibitor (Abl-TKI) imatinib (Im) to treat chronic
myelogenous leukemia (CML) in 2001 has changed this previously lethal cancer into a chronic illness. Despite
initial success, Im intolerance and resistance necessitates development of newer generation Abl-TKIs.
Ponatinib (Po), a newer Abl-TKI that is lifesaving for T315I mutation CML, is associated with a four-fold
increased risk of acute arterial occlusive events, including life-threatening heart attack or stroke, compared to
Im, which has nullified any cancer survival benefit. With a rapidly growing prevalence of over 100,000 survivors
and 10,000 new cases annually in the US alone, there exists an urgent need to determine the mechanism of
Abl-TKI toxicity to improve CML outcomes. Previous published studies assessing direct effects of Po on
platelets and clotting are inconclusive. Because CML patients present with high prevalence of cardiovascular
risk factors and underlying atherosclerotic disease, we introduce the novel hypothesis that Po acts to instead
inflame pre-existing atherosclerotic plaques and prime them for rupture and subsequent thrombosis.
Endothelial cells (ECs) lining the vasculature are anti-inflammatory but become proinflammatory in the setting
of injury, expressing adhesion molecules that induce leukocyte trafficking and subsequent plaque
inflammation. As these patients also exhibit elevated serum proinflammatory cytokine TNFa despite remission,
this proposal also tests the hypothesis that Po sensitizes ECs to TNFa signaling via increased expression of
TNF receptor (TNFR) on cell surface, resulting in increased adhesion molecule expression on human ECs in
vitro, increased leukocyte trafficking into vessels in vivo, and thus more inflamed atherosclerotic plaques in
vivo. Preliminary data confirms that Po: 1) induces expression of adhesion molecules in ECs in vitro and that
this increase is prevented by a TNFR inhibitor, 2) increases leukocyte trafficking by intravital microscopy in
vivo, and 3) increases plaque leukocyte content, a marker of plaque inflammation, measured by flow cytometry
in atherogenic mice (ApoE-KO). This proposal tests this hypothesis for Im, Po, and asciminib which is recently
approved but vascular safety is unknown. Aim 1 explores the mechanism by which Po induces EC adhesion
molecule expression and the role of EC TNFR signaling in vitro using genetic and pharmacologic approaches
to block TNFR. Aim 2 examines the impact of Po on leukocyte trafficking and plaque inflammation in vivo via
intravital microscopy in EC-TNFR1-KO mice and on plaque inflammation in ApoE-KO mice by aortic arch flow
cytometry. Successful completion of these aims will test a recently approved Abl-TKI for toxicity and provide
novel insight into Po’s mechanism of vascular toxicity, which can lead to support for an EC protective strategy
that will prevent arterial thrombosis and improve CML outcomes. The det...

## Key facts

- **NIH application ID:** 10900243
- **Project number:** 1F30HL170641-01A1
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Alec Stepanian
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,724
- **Award type:** 1
- **Project period:** 2024-09-16 → 2026-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900243

## Citation

> US National Institutes of Health, RePORTER application 10900243, Mechanism of Ponatinib induced vascular toxicity (1F30HL170641-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10900243. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*