Targeting Mitochondrial Metabolism in Tuberous Sclerosis Complex
Abstract
The proposed studies will address the following TSCRP Focus Area: Strategies for eradicating tumors associated with TSC and TSC-associated lymphangioleiomyomatosis (LAM), including gaining a deeper mechanistic understanding of TSC signaling pathways and tumor microenvironment. In the short term, our goal is to identify and target druggable vulnerabilities of TSC tumor cells that reside in their unique bioenergetic profile and differentiate them from normal cells. While normal cells in our body are programmed to make energy using the most abundant nutrient present in the microenvironment and can switch from a nutrient to another to keep energy production constant, we found that TSC tumors can burn multiple nutrients at a time to significantly enhance energy production. Mitochondria are specialized structures that constitute the powerhouse of the cell, as majority of energy from sugar, amino acids or fats is produced in these structures through a chain of biochemical reactions. TSC2-deficient cells have enhanced mitochondrial activity compared to normal cells. Their mitochondria are engorged with nutrients. In published data, we used a chemically modified nutrient that is selectively burned into mitochondria, fluoroacetate, to study TSC tumor metabolism in a preclinical model in vivo. We performed Positron Emission Tomography (PET) imaging technology, which uses a radiolabeled form of fluoroacetate to noninvasively detect (image) body cells that have an increased uptake and utilization of this modified nutrient. We found that mitochondria are highly functional in TSC tumors, and, surprisingly, treatment with rapamycin does not suppress mitochondrial metabolism thus allowing TSC tumor cell to remain alive, in a dormant state, during treatment. We therefore investigated the nutrients used by TSC mitochondria and identified two nutrients that are constantly burned in TSC tumor cells: glucose and fats. In molecular studies, we have further identified the proteins responsible for this aberrant nutrient utilization, in the presence and absence of rapamycin as they are not suppressed by the drug: the protein responsible for transforming glucose in a form that can be degraded in mitochondria (pyruvate dehydrogenase), and the protein that transfer fats into mitochondria for degradation (carnitine palmitoyltransferase). Next, we suspected that increasing dietary fat content would affect TSC tumor growth. Indeed, when mice were fed with a high-fat diet (60% fat), tumors generated with patient-derived renal angiomyolipoma cells progressed more rapidly. This is particularly relevant, as a high-fat (Ketogenic) diet has been proposed for children with TSC as a treatment for epilepsy, but the impact on the growth of TSC-associated tumors remains to be definitely determined. Importantly, we conducted a preliminary preclinical trial in mice to test the impact of genetic inhibition of pyruvate dehydrogenase in TSC tumorigenesis. The growth of TSC tumors with downregulation of pyruvate dehydrogenase was dramatically suppressed compared to control cells with functional levels of pyruvate dehydrogenase. This suggests a role for inhibitors of pyruvate dehydrogenase in the treatment of TSC and LAM. Drugs that can inhibit pyruvate dehydrogenase are currently under development. We have tested the first clinically developed pyruvate dehydrogenase/mitochondrial inhibitor in an animal model of TSC. After two week-treatment at a low dose every other day, this inhibitor decreased TSC tumor volume by ~90%. Clinical safety for this compound has been reported in phase 1 clinical trials. We expect that the proposed studies will provide fundamental information on intrinsic and extrinsic mechanisms that promote TSC tumor growth, including aberrant function of mitochondria and abundance of dietary fats. Moreover, we expect to identify drugs that, as single agents or in combination with rapamycin, can halt TSC tum
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310935
Entities
People
- Carmen Priolo
Organizations
- United States Army