TSC is an autosomal dominant genetic disease with an incidence of 1 in 6,000 at birth, and nearly 1,000,000 people worldwide are known to have TSC. TSC is due to genetic inheritance or spontaneous inactivating mutations in either TSC1 or TSC2 genes, and is characterized by the formation of non-invasive benign tumors in many organs.
Rapamycin and its analogues, because of their inhibitory effect on the mTORC1 pathway, have been examined as potential therapeutic agents in the treatment of TSC; however, early studies have demonstrated that while these drugs can reduce tumor size, the tumors return after treatment stops . Therefore, identifying new therapeutic options that can specifically eliminate TSC tumors remains an important goal. Targeting cellular metabolism has received particular attention during the past few years as an alternative strategy for cancer therapy, and could prove an important approach for treating TSC based on the rationale that TSC1/2-/- cells require glucose for survival .
The research of Jiang et al.  sought to examine the effects of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) and a diet free of carbohydrates on the growth of LEF2 cells from a Tsc2-null rat tumor implanted in mice. The exposure of these cells to 2-DG resulted in decreased cell viability at low glucose concentration. 2-DG is an analog of glucose in which the 2-hydroxyl group has been replaced by hydrogen, thus preventing it from undergoing glycolysis. This leads to reduced cellular ATP levels and subsequently cell growth. Jiang et al. show that 2-DG treatment suppresses tumor growth by reducing cell proliferation in this model, although they did not show whether this is accompanied by apoptosis as occurs in vitro . These observations suggest that 2-DG is a promising antitumor therapy and, in fact, this compound is being used to treat osteosarcomas and lung cancers in phase II clinical trials. However, pre-trial studies show that 2-DG, as is the case with other glycolysis inhibitors, does not have a significant effect on tumor growth when used on its own as a monotherapy, although it can sensitize tumors to chemotherapeutic agents such as paclitaxel . The differences between previous studies and the results shown by Jiang et al. raise the question of whether 2-DG effects are dependent on the type of tumor, and if this could be specifically related to the hypersensitivity of TSC2-/- tumors to glucose deprivation.
Jiang et al. also tested the effects of a diet free of carbohydrates in their model, anticipating that this would also deprive the TSC2-/- tumors of glucose, and add to the effects of 2-DG. However their diet (which was carbohydrate-free but not calorie-restricted) produced some unexpected results. In humans a carbohydrate-free diet leads to reduced blood glucose and an increased production of ketone bodies as nutrients other than glucose are used to produce energy , but in the mice fed with a carb-free diet in the study of Jiang et al. levels of β-hydroxybutyrate (HOB), a ketoacid, were not affected and blood glucose remained high . Strikingly, and in contrast to the results of 2-DG treatment, this diet resulted in larger tumors with increased necrosis and zones of liquefaction. These large tumors did not appear to be fueled by glucose, however, as the diet was effective in decreasing the uptake of [18F]-fluorodeoxyglucose (FDG), suggesting that nutrient sources other than glucose are fuelling anabolism and survival under these conditions .
The carb-free diet provides abundant fatty acids that are broken down by beta-oxidation into acetyl-CoA, a major substrate for energy and biomass production through the TCA cycle. Interestingly, a recent report demonstrates that high-grade primary tumors contain elevated levels of fatty acids that contribute to the proliferation of aggressive cancer cells by increasing the levels of signaling lipids such as phosphatidic acid, lysophosphatidic acid and prostaglandin E2 . Consistent with this, Jiang et al.  show that treatment of LEF2 cells with oleic acid results in increased proliferation and survival. In contrast, treatment with the saturated palmitic acid induces apoptosis in LEF2 cells, an observation that might be relevant to the increased areas of necrosis observed in the tumors of carb-free fed mice .
While the carb-free diet failed to inhibit TSC tumor progression, the 2-DG effects on tumor growth are promising and encouraging for future clinical trials in TSC patients. However, toxicity due to off-target effects has been attributed to this compound in clinical trials, and three of ten mice in this study were sacrificed early on account of weight loss during 2-DG treatment , suggesting that there are inherent difficulties in an approach that attempts to starve a tumor but not the organism that hosts it. One way of overcoming toxicity problems while improving efficacy is to use combination therapies, and for TSC-related tumors there are good reasons to consider these in future studies. TSC tumors display low FDG uptake on PET imaging despite increased glycolytic flux , suggesting that a glucose-independent nutrient source is fueling the cells. Moreover, recent work has demonstrated that glutamine is required to maintain the cellular bioenergetics of TSC-/- cells . Therefore combination therapies targeting both glutamine and glucose addiction might be effective.
Cancer therapy is increasingly shifting toward individualized therapeutic approaches based on the genetic abnormalities exhibited by transformed cells. Jiang et al.  demonstrate that targeting glucose addiction is an effective approach for decreasing the growth of tumors driven by TSC mutations. Thus glucose addiction may prove to be the 'Achilles' heel' for the treatment of TSC. Whether these findings will translate to other tumor types, in which the constitutive activation of mTORC1 is a result of different genetic abnormalities, and whether the toxic side effects of 2-DG can be overcome, however, remains to be seen.