Sunday, May 18, 2025
5/18/2025
CSP7 inhibits toxicity of ionizing radiation to the lung - Radiation therapy is the mainstay in the treatment of lung, breast and esophageal cancers, types of lymphoma and tumors that metastasize to the lungs. Each year in the US, there are an estimated 252,950 new cases of lung cancer and 313,510 cases of breast cancer. Acute and chronic lung injury, due to radiation of normal lung tissue, occurs during cancer treatment. The resulting tissue damage is a major cause of morbidity and occasional mortality. Lung injury and consequent pulmonary fibrosis (PF), resulting from lung irradiation is one of the major causes of impaired quality of life after cancer treatment. While every effort is made to minimize the radiation dose to areas of the lung which do not contain cancer, some normal lung damage ultimately occurs. Although a variety of medications have been evaluated in animal models to mitigate radiation-induced lung toxicity, none have been sufficiently compelling to gain FDA approval. Ionizing radiation induces alveolar epithelial cell (AEC) damage leading to radiation-induced lung injury (RILI). This results in lung tissue barrier dysfunction, secretion of various pro-inflammatory and pro-fibrotic cytokines. This in turn leads to activation and differentiation of lung fibroblasts to activated myofibroblasts or fibrotic lung fibroblasts (fLfs), resulting in excessive extracellular matrix (ECM) deposition. These changes promote radiation-induced PF (RIPF). Increased p53 levels occur in damaged AECs and induce senescence and apoptosis. p53 is reciprocally suppressed with increasing proliferation and resistance to apoptosis of fLfs. A Cav1 scaffolding domain 7-mer peptide (CSP7) suppresses p53 in injured AECs, preventing senescence and apoptosis, and restores baseline p53 expression in fLfs from IPF lungs, reversing established PF. CSP7 is well-tolerated in mice, rats, and dogs, and completed phase 1a human safety, tolerability, and PK testing without adverse effects (NCT04233814) and currently going through safety and limited efficacy (phase 1b) testing in patients with IPF (NCT05954988) in U.S. and Europe. Thus, our work provides robust proof of rigor and reproducibility and validates development of targeted intervention. Our objective is to test the beneficial effects of CSP7 that confer protection against RILI and RIPF and develop a novel peptide intervention for cancer patients undergoing thoracic radiation. We hypothesize that CSP7 will inhibit lung injury and resolve PF caused by ionizing radiation. We will test our hypothesis in two Specific Aims: 1) determine the ability of CSP7 to inhibit radiation-induced lung injury (RILI) and prevent development of PF in mice and 2) assess if CSP7 resolves radiation-induced established pulmonary fibrosis (RIPF) in mice. The RILI destroys functional units of lung and worsens function, which is already marginal in many lung cancer patients, leading to less physical activity, increased breathing medications, supplemental oxygen, and/or mechanical ventilation. The preventive effect of CSP7, if proven by the proposed project, provides a novel p53-targeted therapy for RILI and RIPF. The findings from this project are essential to determine whether CSP7 can provide a more reliable and effective intervention that can be further developed for cancer patients with RILI and/or RIPF.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).