Cancer remains one of the leading causes of death in the industrialized world. In recent years, there has been a resurgence of interest in tumor lactate metabolism since lactate has been associated with metastases and poor prognosis in cancer patients. Recent discoveries have identified that the cell surface lactate receptor HCA1 is associated with tumorigenesis and metastasis and thus an attractive imaging target and possible therapeutic target. However, because lactate exhibits low affinity and a fast turnover rate, current in vivo molecular imaging techniques are not well suited to image these types of targets. We have developed a novel MRI based approach for detecting the low affinity binding of natural (no chemical modification) substrates to molecular targets and a unique molecular pump scheme that enhances the sensitivity two to three orders of magnitude thus making this technology applicable for in vivo studies. Importantly, this method can be implemented on standard MRI hardware and thus rapidly translated to the clinic. We propose developing, optimizing, and validating this approach for imaging the binding of lactate to HCA1 receptors in breast cancer.
In AIM 1, we will validate the specificity of detecting lactate-HCA1 binding in vitro using (i) perfused breast cancer cells that express different levels of the HCA1 receptor, and (ii) MRI pulse sequence optimization.
In AIM 2, we will validate the specific binding of lactate to breast cancer cells in vivo. We will further probe lactate binding using the infusion of L-lactate or D-glucose (metabolized to lactate), both FDA approved for iv use in humans.
These aims are expected to result in a MRI method for imaging the binding of low-affinity ligands to a cell target. Due to the nature of the labelling approaches, these MRI methods will be highly tunable to a broad range of other substrates-target pairs.

Public Health Relevance

The development of imaging methods for early diagnosis and monitoring of targeted therapies is vital in ensuring positive outcomes for cancer patients. We propose to develop a new method to image the dynamic binding of ligands to cell surface targets in vivo using standard MRI hardware. This approach will result in a new tool for non-invasively monitoring the delivery of natural (no chemical modification) substrates to novel targets in cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21EB025295-01A1
Application #
9597502
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Liu, Guoying
Project Start
2018-08-01
Project End
2021-04-30
Budget Start
2018-08-01
Budget End
2019-04-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Hugo W. Moser Research Institute Kennedy Krieger
Department
Type
DUNS #
155342439
City
Baltimore
State
MD
Country
United States
Zip Code
21205