[18F]Fluorocholine and [18F]Fluoroacetate PET as Imaging Biomarkers to Assess Phosphatidylcholine and Mitochondrial Metabolism in Preclinical Models of TSC and LAM.

Abstract

PURPOSE:

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations of the TSC1 or TSC2 gene, characterized by neurocognitive impairment and benign tumors of the brain, skin, heart, and kidneys. Lymphangioleiomyomatosis (LAM) is a diffuse proliferation of α-smooth muscle actin-positive cells associated with cystic destruction of the lung. LAM occurs almost exclusively in women, as a TSC manifestation or a sporadic disorder (TSC1/TSC2 somatic mutations). Biomarkers of whole-body tumor burden/activity and response to rapalogs or other therapies remain needed in TSC/LAM.

EXPERIMENTAL DESIGN:

These preclinical studies aimed to assess feasibility of [18F]fluorocholine (FCH) and [18F]fluoroacetate (FACE) as TSC/LAM metabolic imaging biomarkers.

RESULTS:

We previously reported that TSC2-deficient cells enhance phosphatidylcholine synthesis via the Kennedy pathway. Here, we show that TSC2-deficient cells exhibit rapid uptake of [18F]FCH in vivo and can be visualized by PET imaging in preclinical models of TSC/LAM, including subcutaneous tumors and pulmonary nodules. Treatment with rapamycin (72 hours) suppressed [18F]FCH standardized uptake value (SUV) by >50% in tumors. Interestingly, [18F]FCH-PET imaging of TSC2-deficient xenografts in ovariectomized mice also showed a significant decrease in tumor SUV. Finally, we found rapamycin-insensitive uptake of FACE by TSC2-deficient cells in vitro and in vivo, reflecting its mitochondrial accumulation via inhibition of aconitase, a TCA cycle enzyme.

CONCLUSIONS:

Preclinical models of TSC2 deficiency represent informative platforms to identify tracers of potential clinical interest. Our findings provide mechanistic evidence for testing the potential of [18F]FCH and [18F]FACE as metabolic imaging biomarkers for TSC and LAM proliferative lesions, and novel insights into the metabolic reprogramming of TSC tumors.

• Authors: Eline E Verwer, Taylor R Kavanagh, William J Mischler, You Feng, Kazue Takahashi, Shuyan Wang, Timothy M Shoup, Ramesh Neelamegam, Jing Yang, Nicolas J Guehl, Chongzhao Ran, Walter Massefski, Ye Cui, Souheil El-Chemaly, Peter M Sadow, William M Oldham, Marie F Kijewski, Georges El Fakhri, Marc D Normandin, Carmen Priolo
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 23 Pg. 5925-5938 (12 01 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 30054282 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Biomarkers
• Fluoroacetates
• Phosphatidylcholines
• fluorocholine
• Choline

Topics

• Aged
• Animals
• Biomarkers
• Choline (analogs & derivatives)
• Disease Models, Animal
• Female
• Fluoroacetates
• Heterografts
• Humans
• Image Processing, Computer-Assisted
• Immunohistochemistry
• Lipid Metabolism
• Lymphangioleiomyomatosis (diagnosis, etiology, metabolism)
• Male
• Mice
• Mice, Transgenic
• Mitochondria (genetics, metabolism)
• Oxygen Consumption
• Phosphatidylcholines (metabolism)
• Positron-Emission Tomography (methods)
• Rats
• Tuberous Sclerosis (diagnosis, etiology, metabolism)