ABSTRACT This K08 proposal describes a 5-year career development plan with the goal of supporting Dr. Ramon Francisco Barajas’ advancement to the role of independent early stage physician-scientist. Dr. Barajas has completed clinical training in Diagnostic Radiology and Neurological Radiology at the University of California, San Francisco and is currently Assistant Professor in the Departments of Radiology and Advanced Imaging Research Center at Oregon Health & Science University (OHSU). Edward Neuwelt MD, an expert in drug delivery and molecular imaging with a strong record of training physician-scientists, will serve as principle mentor. Lisa Coussens PhD, renowned tumor immunologist; Kenneth Krohn PhD, positron emission tomography (PET) imaging expert; William Rooney PhD, neurobiology magnetic resonance imaging (MRI) expert; and Rochelle Fu PhD, expert clinical trial biostatistician, will serve as co-mentors. This project proposes Dr. Barajas’ undertake further training in preclinical glioblastoma models, human glioblastoma PET/MRI clinical trial implementation and management, tumor immunology, research ethics, grant writing and biostatistics by means of prospective research and formal course work. OHSU has a rich and collaborative environment, with a strong commitment to promoting career development for early stage faculty. Dr. Barajas will be provided with at least 80% protected research time making OHSU an ideal setting to carry out this program for transitioning to an independently funded research career. The long-term scientific objective is to define innovative biomarkers of glioblastoma therapeutic resistance. Neuroinflammation (pseudoprogression) is a hallmark of effective therapy and prognostic of overall survival. However, pseudoprogression and recurrent disease appear identical by standard of care gadolinium enhanced MRI (Gd-MRI). Changes within the hypoxic immune microenvironment may serve as biomarkers of effective therapy and unique feature of pseudoprogression development. A critically unmet clinical need for immunotherapeutic response assessment is the ability to monitor the hypoxic immune microenvironment. We address this significant gap in knowledge by pursuing two specific aims: 1) Define glioblastoma immunotherapy- mediated innate immune activation and tumoricidal efficacy by 11.75T Ferumoxytol (Fe)-MRI, and 2) Determine if Ferumoxytol-enhancement and hypoxic volume are imaging profiles of glioblastoma immunotherapy-mediated pseudoprogression or true progression in a clinical trial. Preclinical glioblastoma models (aim 1) and human clinical trials (aim 2) will be undertaken. The overall hypothesis is that Gd- and Fe-enhanced FMISO PET/MRI can assess the biological features responsible for immunotherapy efficacy. This translational research and career development proposal will support a mentored early stage investigator in this area of multidisciplinary research to directly address the major challenges of developing life prolonging therapeutic approaches for primary brain tumors; the validation of imaging biomarkers capable of specifically monitoring therapeutic efficacy.

PROJECT NARRATIVE Glioblastoma, one of the deadliest primary brain neoplasms, continues to portend a very poor prognosis with a median survival of 14.6 months despite aggressive surgical and medical therapies. Immunotherapeutic approaches have shown promise in improving clinical outcomes, however, known biological features of therapeutic resistance (immune suppression and tumoral hypoxia) are not defined by standard of care gadolinium enhanced magnetic resonance imaging. This translational research and career development proposal will support an early stage investigator in this area of multidisciplinary research to directly address the major challenges of developing life prolonging therapeutic approaches for primary brain tumors; the validation of imaging biomarkers capable of specifically monitoring therapeutic efficacy.