Periodic Reporting for period 3 - MATRIX (Novel mitochondria-targeted therapies for cancer treatment-induced cardiotoxicity)
Reporting period: 2022-09-01 to 2024-02-29
Every year, more that 4 million European are diagnosed with cancer, and 80% of them receive anthracyclines as part of the chemotherapy combination. Cancer Therapy-induced CardioToxicity (CTiCT) is a major health issue. Up to 30% of cancer survivors develop chronic heart failure as a side effect of anthracycline chemotherapy. Cardiac mitochondrial damage is at the center of CTiCT.
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.
More than 30% of cancer survivors who received anthracyclines develop CTiCT, being in the form of severe heart failure in 6%. It is estimated that approximately 1 millio Europeans live with severe heart failure as a consequence of CTiCT. This represents a huge burden both for individuals and for healthcare systems. The possibility of identifying new therapies (based on improved knowledge) that can prevent this problem will represent a major advance for European citizens.
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.
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.
More than 30% of cancer survivors who received anthracyclines develop CTiCT, being in the form of severe heart failure in 6%. It is estimated that approximately 1 millio Europeans live with severe heart failure as a consequence of CTiCT. This represents a huge burden both for individuals and for healthcare systems. The possibility of identifying new therapies (based on improved knowledge) that can prevent this problem will represent a major advance for European citizens.
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 deeply phenotyped the course of pig and mouse models anthracycline-induced cardiotoxicity from the anatomical, functional, molecular, and metabolic perspectives. Discoveries made have served to identify novel mitochondria-targeted therapies for this condition.
We have identified how pressure overload and exposure to anthracyclines cooperate to induce cardiotoxicity.
We are using novel gene therapy means to study the gain and loss of function of key players involved in mitochondrial dynamics in the context of anthracycline-induced cardiotoxicity.
We have identified novel biological functions of classical mitochondrial proteases and identified nutritional approaches that can revert heart associated with loss of function of these.
One of the most relevant outputs of the project so far is the identification of the first translatable mitochondria-targeted therapy: Remote Ischemic Conditioning. After the demonstration of its strong protective effect, we are now testing this intervention in patients.
We have developed novel Cardiac Magnetic Resonance imaging methodologies for the better study of tissue changes occurring during anthracycline cardiotoxicity to be able to track the process in vivo. We also developed a method to make cardiac magnetic resonance more accessible to vulnerable populations.
We have refined the best methodology for keeping mitochondria alive in culture while awaiting for their transplantation into subjects at risk of with overt cardiotoxicity.
We finished the preclinical trial in pigs testing the rescue effect of mitochondrial transplantation in vivo after 5 doses of the intracoronary doxorubicin approach
We have identified how pressure overload and exposure to anthracyclines cooperate to induce cardiotoxicity.
We are using novel gene therapy means to study the gain and loss of function of key players involved in mitochondrial dynamics in the context of anthracycline-induced cardiotoxicity.
We have identified novel biological functions of classical mitochondrial proteases and identified nutritional approaches that can revert heart associated with loss of function of these.
One of the most relevant outputs of the project so far is the identification of the first translatable mitochondria-targeted therapy: Remote Ischemic Conditioning. After the demonstration of its strong protective effect, we are now testing this intervention in patients.
We have developed novel Cardiac Magnetic Resonance imaging methodologies for the better study of tissue changes occurring during anthracycline cardiotoxicity to be able to track the process in vivo. We also developed a method to make cardiac magnetic resonance more accessible to vulnerable populations.
We have refined the best methodology for keeping mitochondria alive in culture while awaiting for their transplantation into subjects at risk of with overt cardiotoxicity.
We finished the preclinical trial in pigs testing the rescue effect of mitochondrial transplantation in vivo after 5 doses of the intracoronary doxorubicin approach
Until now, we have accomplished the objectives proposed. All the results and hypotheses have been validated and we also performed some additional experiments beyond the original objectives (such as the preclinical trial involving remote ischemic preconditioning to prevent CTiCT). All the advances achieved by date predict that all the adjectives of the project will be developed on time as previously described in the application.