Radiotherapy (RT) is an established adjuvant therapy for approximately 50% of cancer patients with a significant increase in cancer survival. However, radiation treatment to the thoracic cavity leads to increase in cardiac diseases due to acute and delayed cardiac injury. Even with improved radiation techniques, RT-induced cardiac complications are common. This is likely due to high dose exposure to a small portion of the heart or low dose exposure to the whole heart. Ionizing radiation induces endothelial damage, cardiomyocyte loss, peri-myocardial inflammation with excess macrophage and mast cell infiltration. This leads to fibrosis, and consequent loss of cardiac function. There is an urgent need to identify novel therapeutic strategies to prevent and mitigate these devastating effects. Based on previously published reports and our preliminary data, it is evident that an endogenous tetrapeptide N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), produced from thymosin-?4, has robust anti-inflammatory and anti-fibrotic effects. This peptide exerts anti-inflammatory effects by inhibiting mast cell and macrophage activity. Ac-SDKP also inhibits the expression of a potent pro-fibrotic molecule galectin-3, initially identified as an IgE binding protein. This could act as a potential unifying mechanism that relates inflammation and fibrosis. Despite strong evidence on the protective role of Ac-SDKP in cardiac remodeling, there are no conclusive data on whether this novel peptide can be used therapeutically to prevent the detrimental effects of radiotherapy-induced cardiac damage. Since Ac-SDKP has a plasma half-life of 80-minutes, therapeutic use of this peptide has been challenging. Novel approaches to design a stable compound and inflammatory cell-directed delivery of this peptide are expected to bridge these translational gaps and enhance success. In this multidisciplinary explorative study, we hypothesize that delivery of a newly developed Ac-SDKP- liposomal compound to injured myocardium can prevent RT-induced cardiac injury, namely coronary vascular, pericardial, and myocardial inflammation and fibrosis, and that these effects are mediated by inhibition of galectin-3, a strong pro-fibrotic molecule. To test this hypothesis, we will utilize comprehensive in vitro and in vivo approaches in a transdisciplinary set-up that includes experts from cardiovascular medicine, cardio-oncology, advanced cardiac MR imaging, laboratory medicine, and thoracic radiation oncology. We anticipate that these studies will have important therapeutic implications for patients with radiation-induced cardiotoxicity.
Despite increasing cancer survival rates after thoracic radiation, t he prognosis of radiation-induced cardiomyopathy remains poor. This interdisciplinary project will utilize comprehensive in vitro and in vivo strategies to examine the therapeutic efficacy of a novel liposomal peptide in a rodent model of radiation- induced cardiomyopathy. We anticipate these studies will have important therapeutic implications for patients with radiation-induced cardiotoxicity.
| Sharma, Umesh C; Sonkawade, Swati D; Spernyak, Joseph A et al. (2018) A Small Peptide Ac-SDKP Inhibits Radiation-Induced Cardiomyopathy. Circ Heart Fail 11:e004867 |
