The ability of malignant gliomas to infiltrate remote regions of the brain, far from their primary tumor mass, has continually challenged the development of an effective therapy, and prognosis for patients with these tumors remains poor, with median survival measured in weeks rather than years. Although radiotherapy plays a critical role in extending life for these patients, radiation side effects in CNS can still be devastating and greatly affect quality of life, which prevents the use of higher, cancer-sterilizing doses of radiation to treat the invasive aspects of this disease. This application seeks to demonstrate a new radiobiologic element of particle therapy delivered at ultra-high dose rates, which may reduce normal tissue toxicity in CNS and allow the safe use of higher radiation doses to greater volumes of potentially involved brain, compared to conventional radiotherapies. Recent studies by our group demonstrate the new method is experimentally feasible. We propose to test our new ideas using rodent models of glioma. Furthermore, we will investigate the resulting morphologic, cognitive, and pathologic changes after irradiation to quantify the toxicity of the new method, which we expect to be lower than toxicities of conventional therapies. Collectively, these aims will provide the preclinical data and new biologic knowledge needed to advance therapy towards human clinical trials to improve treatment of malignant glioma and other brain tumors.
The proposed research is relevant for the nearly 200,000 people in the US each year diagnosed with brain cancer or brain metastases because it will demonstrate a new method of particle therapy that may provide a means to safely increase radiation doses and improve disease control for brain tumors with lower risk of neurologic side effects than that of existing radiotherapy methods. The assembled scientific team provides cross-disciplinary expertise in physics, behavioral neuroscience, imaging, radiation oncology, surgery, and neurobiology. The project is relevant to NIH's mission because we seek to extend healthy life and reduce the burden of treatment for patients with malignant glioma and to reduce the cognitive side effects for survivors of pediatric brain cancer.