PROJECT SUMMARY
Cancer cells undergo metabolic reprogramming in order to meet elevated energy requirements to fuel
proliferation, thus resulting in their differential utilization of many essential metabolites compared to normal cells.
Recent advancements in the field of cancer metabolic reprogramming demonstrated significant increase in
efficiency of standard cancer treatments when combined with cancer metabolic inhibitors. However, tumor
metabolic reprogramming remains poorly understood for the majority of cancers. Moreover, many recent reports
revealed evidence that the metabolism of cancer cells in vitro can differ significantly from that of in vivo because
in vitro models lack complexity of the tumor microenvironment. However, the progress of studying tumor
metabolism in vivo is significantly hampered by the lack of efficient tools that allow real-time noninvasive imaging
and quantification of metabolite absorption in animal models of cancer which closely reflect human pathologies.
Current strategies have significant limitations and mostly rely on MRI, nuclear imaging techniques such as
PET/SPECT, and endpoint ex vivo quantification of metabolite absorption (ex. MS). Here, we propose to develop
a novel optical imaging platform that has several important advantages over the existing methods, and allows
noninvasive evaluation of the uptake of several essential metabolites using highly sensitive and quantifiable
bioluminescent imaging. The method is independent of radioactive and/or short-lived isotopes, less costly, and
allows longitudinal monitoring of metabolite absorption during disease progression (e.g., cancer development or
clinical intervention such as chemotherapy). While the first application of this approach has been already
successfully validated by us using glucose as an example (Maric et.al., Nat Methods, 2019), we propose to
expand this technology to develop novel probes to study uptake of several amino acids, fatty acids, and
nucleosides that all play central role in cancer metabolic reprogramming. We will perform thorough validation of
this platform in cells, healthy transgenic mice and murine animal cancer models to assure that the reagents fulfill
the requirements for physiological behavior, stability, safety, and robust signal generation both in vitro and in
vivo. In addition, we will optimize in vivo delivery routes, vehicles, and concentrations to achieve high
signal/background ratios. In summary, the overall goal of this study is to generate a novel optical imaging platform
that would become a universal analytical tool for monitoring nutrient uptake in live cells and animal models of
disease. While we plan to apply this platform to unravel tumor metabolic reprogramming, the same method could
be adapted for studies of several other important human pathologies, in which changes in metabolism are known
to play a significant role, such as diabetes, neurodegenerative diseases, nonalcoholic steatohepatitis (NASH),
and many others. Therefore, this novel technology is expected to have a strong, enabling, and long-lasting impact
on many physiological and pathological investigations in the field of metabolism and will become a valuable tool
for drug discovery, applicable to oncology and other metabolic disorders.
