A Path to Heart-Safe Chemotherapy
Cedars-Sinai Investigators Create and Test a New Version of a Standard Cancer-Killing Therapy Called Doxorubicin, Showing It Is Safer for the Heart Than the Current Formulation
Investigators from the Cedars-Sinai Board of Governors Regenerative Medicine Institute and Cedars-Sinai Cancer have collaborated to co-develop and test a new version of the chemotherapy workhorse doxorubicin. Their study, published in the peer-reviewed journal Stem Cell Reports, concluded that the reformulated version is less toxic to the heart than the version in wide use since the 1960s.
“Our lab tested this new version of doxorubicin on heart cells that we created from induced pluripotent stem cells—skin or blood cells that have been sent back in time to become stem cells that we can then use to generate any cell type in the human body,” said Arun Sharma, PhD, research scientist in the Board of Governors Regenerative Medicine Institute, the Smidt Heart Institute, Cedars-Sinai Cancer and the Department of Biomedical Sciences at Cedars-Sinai, and co-senior author of the study. “We found that this reformulation is much less toxic to the heart than the original version of the drug, and that could be good news for many cancer patients.”
Early-phase clinical trials of the new formulation have received a green light from the Food and Drug Administration and will soon be underway, Sharma said.
Doxorubicin is a common chemotherapy drug and used to treat breast, bladder and several other cancers, but can cause serious heart damage. To help protect the heart while preserving the drug’s cancer-killing benefits, Xiaojiang Cui, PhD, professor of Surgery at Cedars-Sinai, researcher at Cedars-Sinai Cancer and co-senior author of the study, encapsulated the drug in a protein called albumin.
“Albumin is one of the most common proteins found in the bloodstream, and tumor cells take up a lot of albumin as a nutrient,” Cui said. “We hypothesized that by encapsulating doxorubicin in albumin, more of the drug would be rapidly taken up by tumor cells and less would make its way to the heart.”
Tests of this new version of the drug—called single-protein encapsulated doxorubicin, or SPEDOX-6—showed that human cancer cells robustly took in the encapsulated medication and that it killed the cells efficiently.
Sharma and his team then tested the heart safety of the new formulation.
The team first exposed different cell types within the heart, generated in a dish from stem cells, to traditional doxorubicin and SPEDOX-6, and found that SPEDOX-6 killed fewer of the cells. They also found that human stem cell-derived cardiomyocytes—heart muscle cells that beat even in the laboratory dish—kept beating if exposed to SPEDOX-6 but lost function if exposed to traditional doxorubicin.
SPEDOX-6 also proved less heart toxic when tested on a new laboratory model called 3D cardiac spheroids, previously developed by the Sharma Lab.
“These are 3D spheres made up of fewer than 100,000 heart muscle cells, heart blood vessel cells and other cell types found in the heart,” Sharma said. “They are all grown from stem cells. You can barely see the spheres with the naked eye, but they allow us to rapidly and accurately test the heart toxicity of various substances.”
The team also created stem cell-derived heart cell models from individual cancer patients who had experienced heart damage from doxorubicin treatment—indicating that their hearts were especially vulnerable to the effects of the drug. Again, SPEDOX-6 caused significantly less damage to the cells than the original doxorubicin formulation did.
Going forward, the teams plan to encapsulate other chemotherapy drugs in albumin in the hope of improving both their cancer-killing efficiency and their safety for the heart.
“Widespread use of doxorubicin and other cardiotoxic chemotherapies demonstrates the urgent need to identify effective anti-cancer treatments that are safer for the heart,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai. “These human stem cell-derived models offer a path to identify such treatments and, because of the ability to create patient-specific testing models, also could provide future developments in precision medicine for both cardiology and oncology.”
Other Cedars-Sinai co-authors of this study include first authors Madelyn Arzt and Bowen Gao, as well as Maedeh Mozneb, Stephany Pohlman, Qizhi Liu, Yi Zhang, Xuemo Fan, Amelia Jenkins and Armando Giuliano.
Funding: The study was funded by American Heart Association Career Development Award number 856987; National Institutes of Health grant number 2R01CA151610; Department of Defense grant number W81XWH-18-1-0067; the Uretsky BRCA Research Fund; the Samuel Oschin Comprehensive Cancer Institute Research Development Fund; the Cedars-Sinai Cancer Center; the Fashion Footwear Charitable Foundation of New York, Inc.; the Margie and Robert E. Petersen Foundation; the Linda and Jim Lippman Fund; the Board of Governors Regenerative Medicine Institute at Cedars-Sinai; a NASA In-Space Production Award; the Donna and Jesse Garber Award for Cancer Research; and a California Institute for Regenerative Medicine Bridges Award.
Read more on the Cedars-Sinai Blog: What Are Induced Pluripotent Stem Cells?