바로가기  >

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.

Author information

Verwer EE1, Kavanagh TR#2, Mischler WJ#2, Feng Y2, Takahashi K1, Wang S3, Shoup TM1, Neelamegam R1, Yang J4, Guehl NJ1, Ran C4, Massefski W5, Cui Y2, El-Chemaly S2, Sadow PM6, Oldham WM2, Kijewski MF3, El Fakhri G1, Normandin MD1, Priolo C7.
1
Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
2
Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
3
Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
4
Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
5
Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
6
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
7
Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. cpriolo@partners.org.
#
Contributed equally