Simultaneous Multinuclear (Na+/H+) Metabolic MRI For Sodium-, pH-, and Oxygen-Sensitive Images in Human Brain Tumors
Abstract
The overall goal of this project is to develop and test a new MRI technique that can provide images of tumor acidity, oxygen consumption, and salinity (sodium concentration) in clinically feasible time frames for use in studying the microenvironment and metabolism of human brain tumors and corresponding response to immunotherapy. As such, this project will address the Fiscal Year 2020 (FY20) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas of Brain Cancer and Immunotherapy. Routine clinical MRI is performed solely using hydrogen H+ nuclei, as it is the most abundant element in the body in the form of water (H2O). However, other nuclei, including sodium (23Na or Na+) are visible on MRI and also play critical roles in biochemistry of living tissues. Despite being the second-most abundant nucleus in the body that is visible on MRI, its signal is 10,000 times lower than hydrogen. Therefore, a single sodium MR image takes 10 to 30 minutes to complete, which is comparable to the duration of an entire routine clinical H+-MRI exam. This limitation makes sodium MRI impractical for routine clinical use. To overcome this challenge, we are working closely with Siemens engineers to develop a new technique that interleaves sodium and H+ image acquisition, allowing us to acquire fast images of tumor acidity and oxygen consumption simultaneously with sodium images in around 15 minutes total. We hypothesize this technique will be extremely valuable for studying brain tumor metabolism and the tumor microenvironment. Abnormal metabolism is a hallmark of cancer. In brain tumors, this abnormal metabolism often leads to increased tumor acidity from both secretion of lactic acid (i.e., think of how your legs burn after you run fast – this is also due to lactic acid from the same mechanism) as well as increased protons from activity of an enzyme called the “sodium-proton-exchanger” (NHE), which exchanges a sodium for a proton ion. Expression of NHE1, a specific type of NHE, is overexpressed in primary brain tumors and is more active in higher grade, or more aggressive tumors. Increased expression of NHE1, presumably due to increased acidity of the tumor, has been shown to result in treatment resistance for both temozolomide (standard of care for newly diagnosed glioblastoma) and immunotherapies. Thus, we hypothesize our proposed technique for measuring acidity, oxygen consumption, and salinity would be valuable for studying NHE1 and the interplay between microenvironmental factors within the tumor. In the current application we will (Aim 1) finish our development and testing of this new MRI technique. After that (Aim 2) we will use this imaging technology to identify and biopsy areas of abnormal metabolism, then correlate with tumor tissue markers of abnormal metabolism. Lastly, (Aim 3) we will explore whether these imaging measurements can be used to predict and/or quantify response to immunotherapies, since data suggest acidic tumors and tumors overexpressing NHE1 will not respond well to these types of treatment. We believe this new imaging technique will help cancer patients in a number of ways. First, the ability to perform sodium and proton MRI at the same time in a short exam will make multinuclear imaging possible in the clinic. We think this technique will be particularly advantageous for identifying metabolic profiles of different tumor subtypes, including identifying more aggressive tumors (i.e., higher grade), secondary vs primary malignant gliomas (i.e., IDH mutants vs wild types), and oligodendrogliomas vs astrocytomas (i.e., 1p19q codeleted from noncodeleted tumors), as all these subtypes have unique metabolic signatures that correspond to their genetic programming. We believe this technology will also be useful for patient management, early detection of treatment failure, and for use in testing new therapies, including immunotherapies. Above this, we hypothesize this new technique will help a number of patient
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110620
Entities
People
- Benjamin M Ellingson
Organizations
- United States Army
- University of California, Los Angeles