Cognitive decline and deterioration of long-term cognitive performance are major side effects of CNS cancer treatment. Brain metastases are the most common CNS malignancies and a common cause of morbidity and mortality in about 40% of all cancer patients with systemic disease, affecting over 170,000 patients in the US annually. As most systemic chemotherapy agents do not cross the blood brain barrier, the main treatment modalities for brain metastases include surgery, whole brain radiation therapy (WBRT)) and/or stereotactic radiosurgery. The multidisciplinary management of brain metastases aims to achieve durable tumor control within the brain without compromising neurocognitive functioning. However, current results are disappointing. Despite the advantages of WBRT for disease control, cognitive impairment can be seen as early as 3 to 4 months after WBRT, and affects approximately 80-90% of patients, with memory and executive function being the major cognitive domains affected. Abnormal levels of proinflammatory cytokines (PIC) induced in response to ionizing radiation have been proposed as a potential mechanism underlying WBRT-induced cognitive impairment. Shortly after radiation treatment of a tissue, a cascade of cytokines and chemokines is initiated and these mediators perpetuate and augment the inflammatory response for long periods of time, leading to chronic inflammation and tissue injury. MW151 is an orally active, small molecule drug candidate that restores injury- or disease-induced dysregulation of PIC production towards homeostasis without immunosuppression. MW151 selectively attenuates the PIC cascade that occurs in a diverse array of animal models, including mitigation of CNS and skin radiation injury even when given days after radiation exposure. Our goal in the proposed clinical feasibility study is to test the hypothesis that plasma PIC levels are stabilized in patients receiving MW151 in the course of WBRT for the treatment of brain metastases and that MW151 treatment can attenuate therapy-induced cognitive dysfunction in these patients. Our specific aims are: Aim 1 Preparation for clinical study. Aim 2 Recruitment and conduct of the clinical study. Aim 3: Evaluation of clinical study outcomes. This pilot study will provide data regarding the feasibility of the clinical use of MW151 as an adjunct to WBRT, the current standard of care, to reduce the cognitive decline after radiation therapy for patients with brain metastases.
Public Health Relevance Statement: NARRATIVE Whole brain radiation therapy is a common treatment for cancer patients with brain metastases, but causes abnormal inflammation and long-term cognitive deficits in a large percentage of the patients. This pilot clinical study will test the ability of a promising small molecule drug candidate, MW151, to reduce the radiation- induced inflammation and cognitive decline in patients undergoing radiation therapy. If successful, this 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.
Project Terms: Affect; Aftercare; Animal Model; arm; Attenuated; attenuation; Automobile Driving; Bioavailable; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cancer Patient; cancer therapy; Canis familiaris; capsule; Cardiovascular system; Chemicals; chemokine; chemotherapy; Chronic; Clinical; Clinical Research; Clinical Trials; Cognitive; Cognitive deficits; cognitive performance; cognitive testing; cohort; common treatment; Contracts; Country; Cranial Irradiation; cytokine; Data; Deterioration; Disease; disorder control; Documentation; Dose; drug candidate; Drug Stability; effective therapy; executive function; Feasibility Studies; Funding; Genetic; Goals; Grant; Homeostasis; Immunosuppression; Impaired cognition; Inflammation; Inflammatory Response; Injury; Intellectual Property; Ionizing radiation; irradiation; Lead; Legal patent; Malignant neoplasm of central nervous system; Malignant Neoplasms; Measurement; Mediator of activation protein; Medical; Memory; Metabolic; Metastatic malignant neoplasm to brain; Microglia; Modality; Modeling; Monitor; Morbidity - disease rate; mortality; multidisciplinary; Neurocognitive; neurogenesis; Neuroglia; neuroinflammation; Neurologic Deficit; Neurons; novel; off-patent; Operative Surgical Procedures; Oral; Outcome Study; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Pilot Projects; Placebos; Plasma; preclinical development; Preparation; prevent; Process; Production; Radiation; radiation effect; Radiation exposure; Radiation Injuries; radiation mitigation; Radiation therapy; Radiosurgery; Rattus; recruit; research clinical testing; respiratory; response; Safety; safety study; Schedule; Sentinel; side effect; Skin; Small Business Technology Transfer Research; small molecule; standard of care; stressor; success; Systemic disease; Testing; Time; Tissues; Toxic effect; Toxicology; treatment strategy; tumor; United States; United States National Institutes of Health
