# Ponatinib Induces Vascular Events in CML-Mechanisms and Correction

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $179,067

## Abstract

Project Abstract
Management of Chronic Myelogenous Leukemia (CML) has improved greatly since the advent of oral
tyrosine kinase inhibitors (TKIs). However, as the use of these agents has been adopted widely, it has
become increasingly clear that different polymorphisms of ABL1 kinase influence the effectiveness of the
TKI. One mutation in ABL1 kinase is the T315I positive CML that is resistant to most tyrosine TKIs.
Ponatinib (Iclusig, Ariad Pharmaceuticals) uniquely targets the T315I mutation in the BCR-ABL protein.
This TKI has a wider range of kinase targets than other agents and has been effective in salvage therapy in
patients who have failed other treatments. However, it is not without consequences. In the PACE trial, data
indicate that when the sum of cardiovascular (CV) events (myocardial infarction, stroke, limb ischemia,
coronary artery stenosis, and occlusions of brain and peripheral circulation) were obtained in the ponatinib-
treated patients, ~29% of patients had a negative outcome. It was not clear from the clinical trial what were
the conditions in these patients that were associated with the negative CV outcomes.
We created a murine model to determine if ponatinib treatment is distinct from imatinib or nilotinib in terms
of increasing thrombosis risk. In mice treated with the various TKIs under steady-state conditions,
ponatinib, unlike imatinib or nilotinib, increased risk for arterial thrombosis. Further we observed that
ponatinib-treated mice have increased reactive oxygen species and apoptosis in vessel wall and hyper-
responsive platelets – two features that contribute to heightened clinical thrombosis. These effects in vivo
are mechanistically related. Treatment of mice with pioglitazone is able to correct vessel wall injury, correct
platelet hyperactivity, and correct arterial thrombosis times to normal.
The overall hypothesis that guides this application is that ponatinib's pharmacologic inhibition of vascular
ABL1 kinase and platelet p-Lyn results in reduced antithrombotic vascular function and hyperactive
platelets, leading to heightened arterial thrombosis. Our data indicate that ponatinib increases risk for
thrombosis by blocking vasculo-protective mechanisms and activating platelets.
The specific aims of this proposal are: 1) Characterize the mechanism(s) by which ponatinib reduces the
antithrombotic nature of the vascular wall; 2) Characterize the mechanism(s) by which ponatinib treatment
creates platelet hyperactivity and 3) Determine what classes of agents have potential to nullify the negative
effects of ponatinib.
These investigations will determine the mechanism(s) for ponatinib-associated cardiovascular events. They
will provide a mechanistic basis for recognition of therapies to protect patients from the risk of increased
adverse cardiovascular events while receiving ponatinib treatment. We will demonstrate how to ameliorate
the negative cardiovascular effects of ponatinib with conjoint use of certain medicat...

## Key facts

- **NIH application ID:** 9851882
- **Project number:** 5R21CA223301-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** ALVIN H SCHMAIER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $179,067
- **Award type:** 5
- **Project period:** 2019-01-18 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851882

## Citation

> US National Institutes of Health, RePORTER application 9851882, Ponatinib Induces Vascular Events in CML-Mechanisms and Correction (5R21CA223301-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9851882. Licensed CC0.

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