# Credentialing a Cross-Species Platform to Investigate Cancer Therapy-Associated Cardiovascular Toxicity

> **NIH NIH R01** · TUFTS MEDICAL CENTER · 2021 · $614,697

## Abstract

As survival improves with advances in cancer care, cardiovascular (CV) complications associated with treatment
have become more prevalent. Effects of traditional chemotherapeutics are generally well known, but
incorporation of small molecule inhibitors and immunotherapeutics has led to the emergence of new and
unexpected toxicities. The mechanistic drivers underlying many of these have not been well characterized,
undermining both appropriate monitoring and effective intervention. This is further complicated by reliance upon
models of CV toxicity that do not fully recapitulate the complicated landscape of human cancer. While in vitro
studies permit dissection of cellular and molecular alterations in response to drug exposure, they lack context of
the whole organism that contributes to pathogenesis. Rodent models have been instrumental in defining
fundamental characteristics of treatment induced CV complications, but, there are significant differences in
duration of exposure to therapeutics and an absence of co-morbidities that likely influence outcome. Moreover,
their small size and short lifespan limit instrumentation, longitudinal analysis, and repeated sampling. Pet dogs
with spontaneous cancer are routinely treated with anti-cancer agents known to produce CV toxicity including
doxorubicin, tyrosine kinase inhibitors, and more recently immune checkpoint inhibitors and may thus provide
an opportunity for mechanistic interrogation in a more clinically relevant context to bridge the gap from cells and
mice to humans. Their larger size and longer lifespan permit the use of prospective study designs in the setting
of standard cancer treatment that more closely represent the human experience, thereby overcoming some
limitations of rodent models. As such, the fundamental premise underlying this proposal is that no single
model system of cancer treatment-induced CV toxicity is sufficient to effectively interrogate mechanistic
drivers and assess approaches to therapeutic intervention. Instead, a coordinated, integrated effort across
the landscape of multiple in vitro and in vivo model systems is required to efficiently identify and validate
biomarkers for early intervention, evaluate novel treatments to address complications, and ultimately develop
algorithms for predicting potential CV toxicity in the setting of combination therapy. We therefore propose that
inclusion of data generated from dogs with spontaneous cancer treated with agents known to induce
CV toxicity will permit a more accurate characterization and confirmation of key mechanistic drivers and
therapeutic intervention strategies critical for advancing human outcomes. To accomplish this, we created
a non-reductionist, multi-species framework for analyzing data generated in the laboratory, mouse models, dogs
with spontaneous cancer, and human patients. The studies in this proposal will credential and optimize this
novel platform using two established yet unique CV toxicities that constrain...

## Key facts

- **NIH application ID:** 10242677
- **Project number:** 5R01CA243542-03
- **Recipient organization:** TUFTS MEDICAL CENTER
- **Principal Investigator:** Iris Z Jaffe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $614,697
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242677

## Citation

> US National Institutes of Health, RePORTER application 10242677, Credentialing a Cross-Species Platform to Investigate Cancer Therapy-Associated Cardiovascular Toxicity (5R01CA243542-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10242677. Licensed CC0.

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