In Vivo Imaging of Mitochondrial Membrane Potential in Non–Small Cell Lung Cancer

Take-Away Points

• ■ Major Focus: To investigate tumor metabolism in mouse models of non–small cell lung cancer (NSCLC) using the PET tracer 4-[¹⁸F]fluorobenzyl-triphenylphosphonium (¹⁸F-BnTP).

• ■ Key Result: Tumor uptake of ¹⁸F-BnTP was high in adenocarcinoma and low in squamous cell carcinoma and predicted tumor response to mitochondrial metabolic inhibition.

• ■ Impact: Imaging agents such as ¹⁸F-BnTP may help noninvasively assess tumor metabolic characteristics other than glucose uptake and lead to targeted therapy.

Malignancy is characterized by changes in energy production at the cellular level, and metabolic alterations are used to detect and treat cancer. For example, the effectiveness of PET imaging with [fluorine 18]fluoro-d-deoxyglucose (¹⁸F-FDG) depends on altered glucose uptake and glycolysis within cancer cells. Another metabolic process that can be abnormal in malignancy is oxidative phosphorylation. Oxidative phosphorylation occurs within mitochondria and is dependent on an electrochemical gradient generated by the electron transport chain called the mitochondrial membrane potential. ¹⁸F-BnTP is a cationic lipophilic PET radiotracer that localizes to mitochondria based on membrane potential. Momcilovic et al use ¹⁸F-BnTP to study cellular metabolism in vivo in mouse models of NSCLC.

The authors found two distinct populations of NSCLC tumors based on ¹⁸F-BnTP uptake. Adenocarcinomas showed high uptake of ¹⁸F-BnTP, while squamous cell carcinomas showed low ¹⁸F-BnTP uptake. Differences in ¹⁸F-BnTP uptake between the two types of tumors occurred independent of tumor mitochondrial content, indicating that differential uptake resulted from mitochondrial activity and not the number of mitochondria. The investigators used ¹⁸F-FDG to further assess metabolic variability among NSCLC. While all squamous cell carcinomas showed ¹⁸F-FDG avidity, only a portion of the ¹⁸F-BnTP-avid adenocarcinomas demonstrated ¹⁸F-FDG uptake. Tumors with mixed histology demonstrated these same patterns of tracer uptake in squamous cell and adenocarcinoma regions. The authors additionally demonstrated that only tumors with high ¹⁸F-BnTP responded to treatment with IACS-010759, an inhibitor of oxidative phosphorylation currently in clinical trials for treatment of advanced solid tumors. These data show that histologic subtypes of NSCLC exhibit different metabolic characteristics detectable with imaging. Currently, classification of NSCLC requires invasive tissue sampling. The results from Momcilovic et al show the potential of multitracer PET imaging to noninvasively distinguish subtypes of NSCLC and guide targeted therapy.

Highlighted Article

• Momcilovic M, Jones A, Bailey ST, et al. In vivo imaging of mitochondrial membrane potential in non-small-cell lung cancer. Nature 2019;575:380–384. doi: https://doi.org/10.1038/s41586-019-1715-0