NEUROPATHOLOGY/TISSUE BANK CORE

ABSTRACT – NEUROPATHOLOGY CORE Surgical resection and/or radiotherapy effectively reduce the growth of brain metastases (BMs) in many patients. However, after initial responses, BMs frequently acquire resistance to radiation and exhibit local and distant progression which significantly contributes to the morbidity and mortality of cancer patients. Early clinical results for targeting BMs by immunotherapies, including immune checkpoint inhibition (ICI), are encouraging and indicate that combination of radiation and immunotherapies will be very beneficial to BMs patients. Currently, it is not feasible to identify patients at risk to develop BMs prior to radiologic or clinical manifestation and to determine responses to radiation and immunotherapies. BMs are clonally distinct from the primary cancer intrinsically heterogeneous, which provides a challenge for effectively treating BMs. It is therefore critical to identify predictive and prognostic BM biomarkers for cancer patients. We propose two aims to address these unmet need in patients with solid cancers. In Aim 1. we will generate a repository for matched primary cancer- brain metastases specimens for clinicopathologic and molecular correlations to support Projects 1, 2 and 3. We will integrate patient-material collection into the Projects by providing regulatory oversight, quality control, processing, storage, and tracking of archived material. Matched primary cancer-BMs specimens from different solid cancers types will be analyzed for clinicopathologic and molecular correlations using tissue microarrays (TMAs) and the nanoString nCounter platform. Collectively, Aim 1-related research is expected to yield predictive biomarkers and prognostic biomarkers for rational integration of multidisciplinary treatments. In Aim 2. we propose to centrally generate and validate clinically relevant, experimental syngeneic and xenogeneic BM models to catalyze Projects 1, 2 and 3-related research. We will leverage the available fresh tissue collected from cancer and BM surgeries to generate tools for all Projects, including single-cell resources and in vitro (2D/3D-neurosphere) and in vivo BM models. Dr. Petritsch, who is heading a patient-derived modeling team, will lead the Neuropathology Core. Dr. Vogel, who is the Director of Neuropathology, will be a Co-Investigator. The Core will therefore leverage significant institutional resources already in place to support the U54, and the clinical trials that we expect to result from this proposed work. The Core will centrally annotate the attached clinical, treatment and outcomes data for all collected BMs specimens, which include FFPE tissue, TMAs, fresh tissue and validated 2D/3D and in vivo model-derived resources. The Neuropathology Core will closely interact with the Administrative and Data Management and Toolkit Cores. By integrating clinicopathologic studies with in vitro and in vivo modeling of the brain metastatic process, the Neuropathology Core will catalyze BM research for the entire length of the grant. 1