Retinoic Acid Agonists for Attenuation of Doxorubicin-Induced Cardiotoxicity

SHORT DESCRIPTION

A method for preventing cardiotoxicity in patients undergoing anthracycline-based chemotherapy using retinoic acid receptor gamma (RARG) agonists.

INVENTORS

• Paul W Burridge*, PhD
  • Associate Professor, Pharmacology, Northwestern University Feinberg School of Medicine

* Principal Investigator

NU Tech ID: 2017-174

 

IP STATUS

Issued US patent 11,135,236

 

DEVELOPMENT STAGE

TRL-5 Prototype Validated in Relevant Environment: The technology showed robust performance in both in vitro cardiomyocyte assays and an in vivo doxorubicin mouse model.

BACKGROUND

Anthracycline chemotherapeutic agents like doxorubicin are widely used for treating various cancers but have well-established dose-dependent cardiotoxicity. Current treatment regimens are dose-limited to prevent heart failure, but may still fail to adequately protect cardiac tissue during therapy. This unmet clinical need calls for a novel approach that safeguards cardiac function while preserving anticancer efficacy.

Magdy et al. use a rs2229774 doxorubicin-induced cardiotoxicity patient-specific model to functionally validate the role of this RARG variant as predictive of patients experiencing cardiotoxicity. They go on to demonstrate that RARG agonists attenuate doxorubicin-induced cardiotoxicity in human and mouse models.

ABSTRACT

This technology arises from a key discovery that identified common variants in RARG that leaves patients more susceptible to doxorubicin-induced cardiotoxicity. Thus, selective retinoic acid receptor agonists that activate RARG signaling were found to protect cardiomyocytes from doxorubicin-induced toxicity. In vitro, treatment with the RARG agonists increased the half-maximal lethal dose of doxorubicin by approximately 7-fold. In vivo, co-administration of RARG agonists with doxorubicin maintained significantly higher cardiac function in mice compared with vehicle controls. Importantly, the treatment did not compromise doxorubicin’s anticancer efficacy and even enhanced its effects in certain breast cancer cell lines.

APPLICATIONS

• Cardiotoxicity Mitigation: Protects heart function during anthracycline chemotherapy, particularly in pediatric populations who are especially vulnerable.
• Combination Therapy: RARG agonists administered before, during, or after anthracycline chemotherapy to prevent or treat developing cardiotoxicity.
• Enhanced Chemotherapy Regimen: Enables higher cumulative doses of anthracycline chemotherapy for enhanced anticancer treatment.

ADVANTAGES

• Enhances Cell Viability: Increases LD50 by approximately 7-fold in cardiomyocytes.
• Protects Cardiac Function: Demonstrates significant improvement in cardiac performance in preclinical models.
• Preserved Anticancer Efficacy: Does not reduce and may even enhance doxorubicin effectiveness.

PUBLICATIONS

• Magdy et al., RARG variant predictive of doxorubicin-induced cardiotoxicity identifies a cardioprotective therapy, Cell Stem Cell, 2021 Dec 2, 28(12): 2076-2089.