Memorial Sloan Kettering Cancer Center (MSK) researchers have discovered that innate immune signaling drives late cardiac toxicity after DNA-damaging cancer therapies. Their results, published in the Journal of Experimental Medicine on March 6, 2023, identify a targetable mechanism for one of the most challenging treatment-related late toxicities in cancer survivors. (1)
Using mouse models and human biospecimens, the investigators found that activation of cytosolic cyclic GMP-AMP synthase (cGAS)- and stimulator of interferon genes (STING)-dependent type 1 interferon signaling (cGAS-STING pathway) induced delayed cardiac inflammation after radiation and anthracycline chemotherapy. Further, they found that suppressing this signaling pathway with an experimental STING antagonist effectively prevented cardiac toxicity in mouse models. The researchers also identified the chemokine CXCL10 in circulating blood as a novel biomarker for radiation-induced cardiac toxicity. (1)
“At MSK, radiation oncologists, medical oncologists, and cardiologists are dedicated to finding new ways to prevent, detect, and treat long-term cardiac disease resulting from cancer treatment,” says radiation oncologist Adam Schmitt, MD, senior author of the paper. “Our novel findings suggest there is a window of opportunity to predict and prevent late cardiac toxicity — after cancer therapy is completed and without undermining its efficacy.”
DNA-Damaging Cancer Therapies and Late Cardiac Toxicity
Radiation therapy and anthracycline chemotherapeutics cause double-stranded breaks in DNA. “DNA-damaging therapies are essential in treatment regimens for several cancers, such as breast and lung cancers and Hodgkin and non-Hodgkin lymphomas,” says cardiologist Anthony Yu, MD, MS, a co-author on the paper and a member of MSK’s Cardiology Service within the Division of Subspeciality Medicine. “However, the survival gains conferred from these effective treatments may be offset by long-term cardiotoxic effects in cancer survivors seen months and years later, including heart failure, coronary artery disease, valvular heart disease, arrhythmias, and cardiovascular-specific mortality.”
Other studies have quantified the risk of cardiac toxicity following cancer treatment as follows:
- Radiation therapy-induced cardiotoxicity after treatment for breast cancer doubles with every gray of mean dose to the heart. (2)
- Radiation-induced cardiotoxicity occurs in 8% of long-term survivors of Hodgkin lymphoma, five times higher than in the general population. (3)
- The risk of late cardiac toxicity after anthracycline treatment is greater than 35% with cumulative doxorubicin doses more than 600 mg/m. (2) , (4)
Exactly how DNA damage leads to tissue remodeling and late cardiac toxicity has not been well understood.
Novel Insights From Lab Studies
Dr. Schmitt’s lab studies how DNA damage stresses cells; how they respond by deciding to die, differentiate, or even survive and adapt; and the various signaling pathways that determine whether affected tissues maintain a healthy state or maladapt and develop toxicity over time.
“For this study, we used an unbiased discovery approach to identify the molecular signaling that drives late toxicity. This study utilized our expertise in molecular mechanisms of cellular stress response signaling and animal genetics to dissect the signaling pathways that remodel the heart over time after DNA-damaging therapy,” he says.
First, Dr. Schmitt and colleagues developed mouse models of late cardiac toxicity and identified that type 1 interferon signaling is activated in cardiac fibroblasts in a delayed manner following DNA damage from radiation therapy or anthracycline doxorubicin. (1)
Using advanced imaging techniques, they identified that an increase in cytosolic cGAS foci in cardiac fibroblasts after radiation therapy activated the cGAS-STING pathway and downstream interferon signaling. Physician-scientist Samuel Bakhoum, MD, PhD, a member of MSK’s Human Oncology and Pathogenesis Program, provided the imaging expertise. His lab studies innate immune signaling pathways caused by cytosolic DNA, and he has previously published findings on cGAS-STING signaling inside cancer cells. (1)
Genetically engineered mice deficient in cGAS-STING signaling showed no DNA damage-induced cardiac toxicity and did not experience late cardiac functional decline after treatment with radiation or doxorubicin. Additionally, treatment with the experimental STING inhibitor H-151 effectively prevented a drop in left ventricle ejection fraction (LVEF) in wild-type mice after radiation therapy and prevented LVEF and left ventricle dilation in wild-type mice treated with doxorubicin. (1)
Wild-type mice treated with radiation therapy also had significantly higher circulating levels of CXCL10 than control mice. (1) “CXCL10 is a classic interferon-stimulated gene and one of the more potent cytokines or chemokines associated with cGAS-STING signaling,” says Dr. Schmitt. “But to our knowledge, we are the first to show its potential as a biomarker for cardiac toxicity after cancer therapy.”
Notably, the investigators examined blood samples from 80 patients with HER2-positive breast cancer enrolled in an MSK clinical trial led by co-author Dr. Yu. CXCL10 levels were significantly higher among patients who experienced decreases in global longitudinal strain, an early imaging biomarker of cardiac toxicity that can precede cardiac functional decline. (1)
Future Research Directions
“Ultimately, our goal is to conduct a clinical trial in patients. But first, more research is required to confirm our findings,” Dr. Schmitt says. He and his colleagues continue to investigate the cGAS-STING pathway in additional cohorts of patients receiving anthracyclines for breast cancer or thoracic radiation to further define the predictive validity of CXCL10 as a biomarker of cardiac toxicity.
“We think there is a therapeutic window after cancer therapy to intervene to prevent toxicity. We are currently working to determine the precise timeline when the cGAS-STING pathway is activated after cancer treatment — before cardiac toxicity develops — in order to guide potential future clinical trials,” Dr. Schmitt says.
This study contributes further to MSK’s longstanding program to understand and manage the adverse cardiac outcomes of cancer therapy. Cardiologist Angel Chan, MD, PhD, who was also a co-author of the study, is conducting a pilot study generating cardiomyocytes from induced pluripotent stem cells of patients with HER2-positive breast cancer treated at MSK to gain further insight into the molecular mechanisms of cardiotoxicity from doxorubicin and HER2-targeted therapy. Study co-author Dr. Yu is the principal investigator of an upcoming National Cancer Institute-funded clinical trial that will evaluate whether intensive blood pressure control can reduce the cardiotoxic effects of anthracycline-based treatment for breast cancer. In collaboration with Dr. Schmitt, Dr. Yu’s study will also examine the effects of intensive blood pressure control on biomarkers of cardiotoxicity, including CXCL10.
Multidisciplinary Research Collaboration
Four different teams of experts across several divisions and departments at MSK contributed to this study, including the Division of Translational Oncology (Department of Radiation Oncology), the Human Oncology and Pathogenesis Program, the Breast Medicine Service (Department of Medicine), the Clinical Chemistry Service (Department of Pathology and Laboratory Medicine), the Cardiology Service (Division of Subspecialty Medicine), and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology.
“Many thanks to all of the collaborators that made this research possible, including physician-scientist Suchit Patel, MD, a former MSK resident in radiation oncology and co-lead author on the paper,” Dr. Schmitt says. “He was especially interested in studying the adverse effects of radiation on the heart and was the initial catalyst for pulling our team together.”
The study was supported by the Department of Defense Discovery Award W81XWH1910002, the National Institutes of Health GM 124909, an MSK Imaging and Radiation Sciences grant, an MSK Chanel Endowment for Survivorship Research Grant, and an MSK Support Grant P30 CA 008748. Dr. Schmitt reports his spouse is an employee of Regeneron Pharmaceuticals. Please refer to the paper to read disclosures from other study authors.
