This proposal entitled "A dual acting drug for enhancing radiotherapeutic benefit" is designed to provide proof of concept evidence that the novel compound EWA001 can protect normal lung tissue from radiation-induced damage within an in vivo model without appreciably protecting neoplastic tissue. The protection of radiation induced lung toxicity from ionizing radiation and in particular, radiation induced pneumonitis and fibrosis, is an unmet need that may benefit thousands of patients considering that more than two thirds will receive radiation therapy during the course of their treatment for cancer with such complications limiting treatment or even resulting in death.
In aim 1, we will examine the effect of EWA001 in tumor LLC and human tumor xenografts in vitro and in vivo in conjunction with radiation.
In aim 2, we will investigate EWA001's efficacy at protecting against and mitigating radiation induced lung injury in mice. Currently, there is no drug available that would minimize radiation toxicity to normal tissue without interfering with its anti-tumor effect and this data is designed to lead to a successful phase II application where we will further develop the pre-clinical data towards an effective drug to treat radiation induced lung toxicity and pneumonitis.
Radiation is an extremely important therapeutic modality in the management of cancer and in particular, the treatment of the tumors within the thoracic region. This, at times, inevitably encompasses radiation to the remaining normal lung tissue. For patients treated with any type of intrathoracic malignancies, the lung receives a range of doses. For conventional delivery, a dose of around 70 Gy may be prescribed but this is limited by the normal tissue volume, so that no more than 30% of the lung receives 20 Gy which still results in about 20% of patients developing symptomatic pneumonitis and an even greater percentage will experience asymptomatic reduction in pulmonary function. Pneumonitis generally occurs within 3-6 months after exposure, with shortness of breath, cough and occasionally fever. Histologically, it is characterized by interstitial and airspace edema, inflammatory infiltrate (mostly lymphocytes and macrophages), and loss of epithelial cells. Injury occurring at later times usually manifests as progressive shortness of breath with diffuse interstitial fibrosis, foca scarring and loss of alveoli. Currently, there is no drug available that would minimize radiation toxicity to normal lung tissue without interfering with its anti-tumor effect reactions. The aim of this proposal is to perform proof of concept studies to determine if our drug EWA001 will reduce radiation induced lung injury and pneumonitis in animal models. The estimate of the patient population that may benefit from the availability of such a protective agent may be greater than 113 thousand annually in the US alone.