CoBRE TME-Determining MRI guided focused ultrasound parameters to safely open the blood-brain barrier in Alzheimer's disease

Lockman, Paul

Abstract

The efforts described in this CoBRE application will support development of a Center of Excellence within the West Virginia University Health Sciences Center (WVU HSC) that will focus on studies of the tumor microenvironment (TME), designated the TME CoBRE. The overarching critical need for continued emphasis in this area is driven, in part, by that fact that cancer mortality is a significant health disparity in the Appalachian region, specifically in West Virginia. Novel approaches that can impact disease must consider the interplay between a tumor and its host environment which influences growth, malignancy, metastatic potential, and therapeutic response. This proposal seeks to develop the careers of promising junior scientists and recruit additional investigators to study the biology of, and novel therapeutic approaches that will benefit from, a mechanistic understanding of the diverse TME. The five highly translational projects within this application focus on the microenvironment of different tumor types, including cancers initiating in the bone marrow, head and neck, breast, and brain. The administrative core will manage the overall budget and provide assistance in annual reporting and submission of extramural applications for all CoBRE Project Leaders. In addition, this core will provide oversight of mentoring, which includes two primary advisors for each investigator as well as an external advisor, and a network including previous CoBRE graduates and the Director of Core Resources. In addition, the support team include commercialization experts who will provide training in entrepreneurship and innovation. The investigators will be supported by the expansion of three cores built out of existing cores at WVU, fully leveraging past IDeA support. We will expand our transgenic mouse facility with the development of a patient-derived xenograft core to evaluate tumor biology and drug efficacy in tumors taken directly from Appalachian patients, aligned with the robust translational nature of the TME group. In addition, a new single cell analysis core will be established in the existing flow cytometry core to investigate the genomics of single cells isolated from the TME. We will also emplace new imaging technologies to support microbeam irradiation, microCT, pre-clinical MRI, and real time microenvironment imaging of pO2 and pH in our current animal imaging facility. Lastly, we will develop a pilot project program during years two through five to recruit new junior faculty to the TME CoBRE. The investigators are well integrated into established programmatic areas in the West Virginia University Cancer Institute that meet every other month for focused discussion on therapies for, and the biology of, the TME. The mentoring atmosphere, core facilities, and significant institutional support that are central to this effort will provide a rich environment to nurture investigator independence and success around the critical scientific area of TME.

Public Health Relevance

It is recognized that there is bi-directional cell signaling between tumor cells and their host environment that results in enhanced tumor cell survival, growth and promotion of invasion into other tissues. Most cancer victims succumb to their disease because of the size of the tumor and/or metastases to different organs. This CoBRE will 1) increase our mechanistic understanding of the constant interaction between the tumor and its environment, 2) position junior faculty for success by improving competitiveness for extramural support through diverse training opportunities and specific mentoring strategies and 3) develop critical infrastructure for the projects of focus in the current application but also to recruit additional tumor microenvironment focused scientists to West Virginia.