NU 2018-028
INVENTORS Paul Burridge* Tarek Magdy
SHORT DESCRIPTION The use of desipramine to protect against doxorubicine-induced cardiotoxitiy
BACKGROUND Doxorubicin, a cytotoxic anthracycline antibiotic, is a common anti–cancer agent used to treat a wide variety of adult and childhood cancers. The cardiotoxicity of anthracyclines, however, has been documented to occur in 9% of treated adult patients typically within 3.5 months of the last chemotherapy dose, and the majority of patients experience cardiotoxicity within the first year, leading to dose limitations or discontinued use. While the cardiotoxicity of doxorubicin is well–understood to be dose–dependent and associated with a decline in left ventricular ejection fraction (LVEF), cardiotoxicity persists despite attempts to limit cumulative dosing. Some pharmacogenomic research has discovered predictive DNA biomarkers for anthracycline–induced cardiotoxicity (AIC) and has so far identified about 75 AIC–associated loci. However, the true connection between these loci and cardiotoxicity is far from proven, as the vast majority of AIC pharmacogenomic studies lack functional validation of the identified associations. As a result, there are currently no FDA–approved genetic biomarkers being used in routine clinical practice to predict AIC, and only a single on–market drug, dexrazoxane is approved to decrease the incidence of AIC.
ABSTRACT Northwestern reseachers have discovered the important role of the an SLC transporter in the uptake of doxorubicin in cardiomyocytes. In an hiPSC-CM model, they found that the downregulation of this transporter can reduce doxorubicin transport into cardiomyocytes, thereby offering a suitable cardioprotective mechanism capable of attenuating sensitivity to doxorubicin. Downregulation of the SLC transporter may be introduced either by the insertion of a long non-coding RNA (SLC28A3-AS1) or by competitive inhibition with desipramine, a common antidepressant. Using Nanopore-based fine-mapping and base editing, they identified a novel cardioprotective single nucleotide polymorphism, rs11140490, in the SLC28A3 locus; its effect is exerted via regulation of an antisense long noncoding RNA (SLC28A3-AS1) that overlaps with SLC28A3. Using high-throughput drug screening in patient-derived cardiomyocytes and whole organism validation in mice, they also identified the SLC competitive inhibitor desipramine as protective against DIC.
APPLICATIONS
ADVANTAGES
IP STATUS A provisional application has been filed. PUBLICATION Magdy T, Jouni M, Kuo H, Weddle C, Lyra-Leite D, Fonoudi H, Romero-Tejeda M, Gharid M, Javed H, Fajardo G, Ross C, Carleton B, Berstein D and Burridge P (2022) Identification of Drug Transporter Genomic Variants and Inhibitors that Protect Against Doxorubicin-Induced Cardiotoxicity. Circulation. 145: 279-297.