Mitigation of Radiation Therapy Induced Neuroinflammation and Cognitive Dysfunction

PROJECT SUMMARY Cognitive decline and deterioration of long term cognitive performance are major side effects of CNS cancer treatmentBrain metastases are the most common CNS malignancies and a common cause of morbidity and mortality in aboutof all cancer patients with systemic diseaseaffecting overpatients in the US annuallyAs most systemic chemotherapy agents do not cross the blood brain barrierthe main treatment modalities for brain metastases include surgerywhole brain radiation therapyWBRTand or stereotactic radiosurgeryThe multidisciplinary management of brain metastases aims to achieve durable tumor control within the brain without compromising neurocognitive functioningHowevercurrent results are disappointingDespite the advantages of WBRT for disease controlcognitive impairment can be seen as early astomonths after WBRTand affects approximatelyof patientswith memory and executive function being the major cognitive domains affectedAbnormal levels of proinflammatory cytokinesPICinduced in response to ionizing radiation have been proposed as a potential mechanism underlying WBRT induced cognitive impairmentShortly after radiation treatment of a tissuea cascade of cytokines and chemokines is initiated and these mediators perpetuate and augment the inflammatory response for long periods of timeleading to chronic inflammation and tissue injuryMWis an orally activesmall molecule drug candidate that restores injuryor disease induced dysregulation of PIC production towards homeostasis without immunosuppressionMWselectively attenuates the PIC cascade that occurs in a diverse array of animal modelsincluding mitigation of CNS and skin radiation injury even when given days after radiation exposureOur goal in the proposed clinical feasibility study is to test the hypothesis that plasma PIC levels are stabilized in patients receiving MWin the course of WBRT for the treatment of brain metastases and that MWtreatment can attenuate therapy induced cognitive dysfunction in these patientsOur specific aims areAimPreparation for clinical studyAimRecruitment and conduct of the clinical studyAimEvaluation of clinical study outcomesThis pilot study will provide data regarding the feasibility of the clinical use of MWas an adjunct to WBRTthe current standard of careto reduce the cognitive decline after radiation therapy for patients with brain metastases NARRATIVE Whole brain radiation therapy is a common treatment for cancer patients with brain metastasesbut causes abnormal inflammation and long term cognitive deficits in a large percentage of the patientsThis pilot clinical study will test the ability of a promising small molecule drug candidateMWto reduce the radiationinduced inflammation and cognitive decline in patients undergoing radiation therapyIf successfulthis study has the potential to provide a safe and effective new adjunct treatment strategy to prevent the long term neurologic deficits associated with radiation therapy