Choline is a nutrient obtained through the diet. In our bodies' cells, choline undergoes several chemical modifications to generate lipid species that represent main structural components of all cell membranes. This is a requisite for cells to grow and double. It has been shown that tumor cells rely on choline utilization (metabolism) more than normal cells, and this evidence has led to studies centered on the use of intermediates of choline metabolism as biomarkers (substances used as indicators of disease) for imaging tumors in humans. In particular, the choline-Positron Emission Tomography (PET) technology uses radiolabeled derivatives of choline to noninvasively detect (image) body cells that have an increased uptake and consumption of choline. This bioimaging technology is safe for humans and has been used worldwide in the diagnostics of prostate and other tumors.
We discovered that cells with loss of function of the TSC2 tumor suppressor gene (preclinical models of Tuberous Sclerosis Complex, TSC) consume higher levels of choline from their culture media and exhibit higher intracellular levels of choline derivatives than control cells with functional TSC2. These choline derivatives are also secreted specifically by TSC2-deficient cells. Importantly, we found that some of these choline derivatives are measurable in the blood of patients with Lymphangioleiomyomatosis (LAM), which is a clinical manifestation of TSC. Together, our results suggest that specific choline derivatives can serve either as blood biomarkers or imaging biomarkers in TSC. Currently, a critical unmet need in TSC patients who develop LAM is a sensitive and specific indicator (blood or imaging biomarker) of disease progression and response to therapy.
The objectives of this proposal are to test the feasibility of choline-based imaging in mouse models of TSC and to determine how choline utilization is regulated in TSC2-deficient cells.
If successful, this study will have large applicability in the diagnostics of TSC patients, especially those who develop LAM. The availability of a sensitive imaging procedure to detect disease progression and response to therapy would be critical in clinical trials, and would help clinical decision-making during follow-up of those patients who start Rapamycin treatment, which currently is the only approved drug therapy for TSC. Importantly, the PET diagnostic procedure is a noninvasive procedure and is commonly used in the oncology clinics. Following this preclinical study, the next immediate step will be to design an imaging clinical trial with TSC patients.
We expect that our findings will contribute to advance both the field of TSC research and the care of patients with TSC by providing new sensitive means to detect disease progression and response to Rapamycin and other potential therapies.