Abstract
<div>AbstractPurpose:<p>Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations of the <i>TSC1</i> or <i>TSC2</i> 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 (<i>TSC1/TSC2</i> somatic mutations). Biomarkers of whole-body tumor burden/activity and response to rapalogs or other therapies remain needed in TSC/LAM.</p>Experimental Design:<p>These preclinical studies aimed to assess feasibility of [<sup>18</sup>F]fluorocholine (FCH) and [<sup>18</sup>F]fluoroacetate (FACE) as TSC/LAM metabolic imaging biomarkers.</p>Results:<p>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 [<sup>18</sup>F]FCH <i>in vivo</i> 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 [<sup>18</sup>F]FCH standardized uptake value (SUV) by >50% in tumors. Interestingly, [<sup>18</sup>F]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 <i>in vitro</i> and <i>in vivo</i>, reflecting its mitochondrial accumulation via inhibition of aconitase, a TCA cycle enzyme.</p>Conclusions:<p>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 [<sup>18</sup>F]FCH and [<sup>18</sup>F]FACE as metabolic imaging biomarkers for TSC and LAM proliferative lesions, and novel insights into the metabolic reprogramming of TSC tumors.</p></div>
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