Periodic Reporting for period 4 - MATRIX (Novel mitochondria-targeted therapies for cancer treatment-induced cardiotoxicity)
Período documentado: 2024-03-01 hasta 2025-05-31
Every year, more that 4 million European are diagnosed with cancer, and 80% of them receive anthracyclines as part of the chemotherapy regimes. Cancer Therapy-induced CardioToxicity (CTiCT) is a major health issue. Cardiac mitochondrial damage is now recognized at the center of CTiCT. More than 30% of cancer survivors treated with anthracyclines develop some form of CTiCT, with severe heart failure occurring in around 6%. An estimated one million Europeans currently live with severe heart failure as a consequence of CTiCT. This represents a substantial burden for patients, families, and healthcare systems.
Identifying new mitochondria-targeted preventive and therapeutic strategies would have significant societal impact, improving long-term quality of life for cancer survivors.
There are 3 main challenges in the field:
(1) better understanding of the mechanisms leading to CTiCT,
(2) improve early diagnosis of CTiCT, and
(3) identify therapeutic targets to develop preventive/curative therapies for CTiCT.
MATRIX´s objectives are:
1) Study mitochondrial dynamics and substrate utilization in the context of CTiCT and test therapies aimed at reversing metabolic reprogramming.
2) Refine early diagnosis of CTiCT by exploiting the versatility of cardiac magnetic resonance and coronary physiology evaluation.
3) Study the best methodology for efficient mitochondrial transplantation to cardiomyocytes.
4) Evaluate mitochondrial transplantation as a therapy to rescue metabolic reprogramming and treat and/or prevent CTiCT.
Identifying new mitochondria-targeted preventive and therapeutic strategies would have significant societal impact, improving long-term quality of life for cancer survivors.
There are 3 main challenges in the field:
(1) better understanding of the mechanisms leading to CTiCT,
(2) improve early diagnosis of CTiCT, and
(3) identify therapeutic targets to develop preventive/curative therapies for CTiCT.
MATRIX´s objectives are:
1) Study mitochondrial dynamics and substrate utilization in the context of CTiCT and test therapies aimed at reversing metabolic reprogramming.
2) Refine early diagnosis of CTiCT by exploiting the versatility of cardiac magnetic resonance and coronary physiology evaluation.
3) Study the best methodology for efficient mitochondrial transplantation to cardiomyocytes.
4) Evaluate mitochondrial transplantation as a therapy to rescue metabolic reprogramming and treat and/or prevent CTiCT.
We have comprehensively characterized the progression of anthracycline-induced cardiotoxicity in mouse and pig models from anatomical, functional, molecular, and metabolic perspectives. These studies have enabled the identification of early and reversible mitochondrial abnormalities, establishing mitochondrial fragmentation and metabolic dysfunction as central hallmarks of CTiCT.We demonstrated how pressure overload and anthracycline exposure synergistically induce cardiotoxicity, providing mechanistic support for the “dual-hit” concept. We also used novel gene therapy approaches to explore gain- and loss-of-function of key regulators of mitochondrial dynamics, revealing new biological roles for classical mitochondrial proteases. Complementary nutritional strategies—such as high-protein diet—were identified as means to reverse cardiac atrophy and metabolic derangement.
In humans, MATRIX study, have prospectively assessed the incidence, temporal evolution, and predictors of antracyclines related cardiac dysfunction through comprehensive multimodality imaging and biomarker monitoring in lymphoma patients. The results are currently under review for publication.
One of the most relevant outputs of MATRIX is the identification of Remote Ischemic Conditioning (RIPC) as the first mitochondria-targeted, translatable therapy for CTiCT. After demonstrating its strong protective effect in preclinical models and human imaging studies, this intervention was tested in patients in a multicenter clinical trial.
We have developed novel CMR methodologies—including the ultrafast 3D sequence ESSOS—to better detect tissue changes during CTiCT and to make cardiac MRI more accessible to vulnerable oncology populations.
We have optimized protocols to preserve functional mitochondria ex vivo prior to transplantation and have completed a large-animal preclinical trial in pigs demonstrating that intracoronary mitochondrial transplantation after chronic doxorubicin injury leads to cardiac engraftment and functional left ventricular improvement.
Dissemination: Between 2019 and 2025, CNIC’s cardio-oncology research achieved remarkable media visibility at both national and international levels. The dissemination focused on advances in preventing and treating cardiotoxicity associated with cancer therapies, highlighting projects such as MATRIX and RESILENCE, and featuring CNIC’s leadership in European collaborative research. Overall, the coverage reached an estimated audience of several tens of millions, consolidating CNIC’s position as a key reference in cardiovascular research and translational medicine.
A total of approximately 95 media pieces were identified between 2019 and 2025, covering CNIC’s research on cardio-oncology and related topics.
In humans, MATRIX study, have prospectively assessed the incidence, temporal evolution, and predictors of antracyclines related cardiac dysfunction through comprehensive multimodality imaging and biomarker monitoring in lymphoma patients. The results are currently under review for publication.
One of the most relevant outputs of MATRIX is the identification of Remote Ischemic Conditioning (RIPC) as the first mitochondria-targeted, translatable therapy for CTiCT. After demonstrating its strong protective effect in preclinical models and human imaging studies, this intervention was tested in patients in a multicenter clinical trial.
We have developed novel CMR methodologies—including the ultrafast 3D sequence ESSOS—to better detect tissue changes during CTiCT and to make cardiac MRI more accessible to vulnerable oncology populations.
We have optimized protocols to preserve functional mitochondria ex vivo prior to transplantation and have completed a large-animal preclinical trial in pigs demonstrating that intracoronary mitochondrial transplantation after chronic doxorubicin injury leads to cardiac engraftment and functional left ventricular improvement.
Dissemination: Between 2019 and 2025, CNIC’s cardio-oncology research achieved remarkable media visibility at both national and international levels. The dissemination focused on advances in preventing and treating cardiotoxicity associated with cancer therapies, highlighting projects such as MATRIX and RESILENCE, and featuring CNIC’s leadership in European collaborative research. Overall, the coverage reached an estimated audience of several tens of millions, consolidating CNIC’s position as a key reference in cardiovascular research and translational medicine.
A total of approximately 95 media pieces were identified between 2019 and 2025, covering CNIC’s research on cardio-oncology and related topics.
To date, MATRIX has achieved all major objectives and has validated its central hypotheses. Several advances—such as the discovery of RIPC as a mitochondria-targeted therapy and the first demonstration of autologous mitochondrial transplantation in a large-animal cardiotoxicity model—go beyond the original proposal.All results to date strongly support that the remaining objectives will be completed on time, including full mechanistic integration, final optimization of mitochondrial transplantation protocols, and translation of advanced imaging biomarkers and therapeutic strategies into clinical practice.