Novel Metabolic Biomarkers in Tuberous Sclerosis Complex

Principal Investigator: PRIOLO, CARMEN
Institution Receiving Award: BRIGHAM AND WOMEN'S HOSPITAL, INC.
Program: TSCRP
Proposal Number: TS150071
Award Number: W81XWH-16-1-0165
Funding Mechanism: Exploration - Hypothesis Development Award
Partnering Awards:
Award Amount: $250,633.00


Acetate is a nutrient utilized by the body's cells to generate energy and also make lipids that are main structural components of all cell membranes. These are requisites for cells to grow and double. It has been shown that tumor cells rely on acetate utilization (metabolism) more than normal cells, and this evidence has led to studies centered on the use of acetate and chemically modified acetate (derivatives) as biomarkers (substances used as indicators of disease) for imaging tumors in humans. In particular, the acetate-positron emission tomography (PET) technology uses radiolabeled acetate or derivatives of acetate to noninvasively detect (image) body cells that have an increased uptake and utilization of acetate. This bioimaging technology is safe for humans and has been used world-wide 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) growing in mice accumulate higher levels of a derivative of acetate (fluoroacetate) than control mouse tissues with functional TSC2. In addition, short-term treatment with rapamycin was able to suppress fluoroacetate uptake in TSC2-deficient cells in mice. Our results suggest that fluoroacetate could serve both as an imaging biomarker to monitor disease progression and an early biomarker of rapamycin activity in TSC.

Currently, a critical unmet need in TSC patients who develop lymphangioleiomyomatosis (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 validate the use of acetate-based imaging in mouse models of TSC and to determine how acetate 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.