Finding a cure for tuberous sclerosis complex: From genetics through to targeted drug therapies

McEneaney, Lauren J.; Tee, Andrew R.

doi:10.1016/bs.adgen.2018.11.003

Cited by 29 publications

(25 citation statements)

References 58 publications

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“…It is involved in the regulation of cytoskeletal dynamics. Additionally, it is not sensitive to the effects of acute rapamycin treatment because the core component, RICTOR, does not bind FKBP12 [43]. Further studies could help to characterize its functions and explore the possibility of interactions with the mTORC1 pathway.…”

Section: Pathophysiologymentioning

confidence: 99%

Tuberous sclerosis: a review of the past, present, and future

Uysal¹,

Şahin²

2020

Turk J Med Sci

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Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder that is characterized by cellular and tissue dysplasia in several organs. With the advent of genetic and molecular techniques, mutations in the TSC1 or TSC2 genes were discovered to be responsible for mTOR overactivation, which is the underlying mechanism of pathogenesis. TSC is a highly heterogenous clinical entity with variable presentations and severity of disease. The brain, heart, skin, eyes, kidneys, and lungs are commonly involved in this syndrome, with neurologic symptoms comprising a significant source of morbidity and mortality. In 2012, the diagnostic criteria for TSC were revised by the International Tuberous Sclerosis Complex Consensus panel, and genetic testing was incorporated into the guidelines. Early detection of cardiac rhabdomyomas or TSC-associated skin lesions can suggest the diagnosis and underlie the importance of clinical vigilance. Animal studies have demonstrated the benefit of using mTOR inhibitors for various symptoms of TSC, and they have been successfully translated into clinical trials with significant improvement in symptom burden. Subependymal giant cell astrocytomas, renal angiomyolipomas, and epilepsy are the three FDA-approved indications in relation to TSC for the use of everolimus, which is a first generation mTOR inhibitor. Rapamycin has been FDA approved for lymphangioleiomyomatosis. Other TSC symptoms that could potentially benefit from this class of medication are currently under investigation. TSC constitutes a unique combination of protean physical symptoms and neurobehavioral abnormalities. TSC associated neuropsychiatric disorders (TAND), including intellectual disability, mood disorders, and autism spectrum disorder, represent significant challenges but remain underdiagnosed and undertreated. The TAND checklist is a useful tool for routine use in the clinical evaluation of TSC patients. A multidisciplinary treatment plan, based on the specific problems and needs of individuals, is the key to management of this genetic condition. Ongoing research studies have been providing promising leads for developing novel mechanistic strategies to address the pathophysiology of TSC.

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Section: Pathophysiologymentioning

confidence: 99%

Tuberous sclerosis: a review of the past, present, and future

Uysal¹,

Şahin²

2020

Turk J Med Sci

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“…The clinical manifestation of TSC is characterized by the benign tumors or hamartomas formation in systemic multiple organs involving kidney, brain, skin, lung, eyes, etc . Until 1990s, the etiology of the TSC was identified as the loss‐of‐function mutation of the TSC1 or TSC2 gene . In cells, TSC1 and TSC2 form a protein complex which inhibited a small GTPase, Ras homologue enriched in brain (Rheb), via the activity of GTPase‐activating protein (GAP) domain of the TSC2 protein.…”

Section: Introductionmentioning

confidence: 99%

“…The allosteric inhibitor of mTOR, rapamycin acutely inhibits mTORC1 while exerts little effect on mTORC2. Currently, rapamycin and its analogs are approved for the clinical therapy of TSC and other hyperactivated mTORC1‐related cancers . However, the clinical use of rapamycin has been limited due to several drawbacks, including the incomplete inhibition of mTORC1 and some side effects such as immunosuppression, hyperglycemia, hyperlipidemia, and infections .…”

Section: Introductionmentioning

confidence: 99%

“…2 Until 1990s, the etiology of the TSC was identified as the loss-of-function mutation of the TSC1 or TSC2 gene. 1,[3][4][5] In cells, TSC1 and TSC2 form a protein complex which inhibited a small GTPase, Ras homologue enriched in brain (Rheb), via the activity of GTPaseactivating protein (GAP) domain of the TSC2 protein. While TSC1 protects TSC2 from degradation and the combination of these two proteins is essential for the TSC complex to fully exert their functional role.…”

Section: Introductionmentioning

confidence: 99%

“…Currently, rapamycin and its analogs are approved for the clinical therapy of TSC and other hyperactivated mTORC1-related cancers. 1 However, the clinical use of rapamycin has been limited due to several drawbacks, including the incomplete inhibition of mTORC1 and some side effects such as immunosuppression, hyperglycemia, hyperlipidemia, and infections. 9 Currently, it is still urgent to explore the novel and efficient approaches to improve the efficacy of rapamycin in the treatment of TSC and other mTORC1-related cancers.…”

Section: Introductionmentioning

confidence: 99%

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Upregulation of 6‐phosphofructo‐2‐kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex

Wang

Tang

et al. 2020

IUBMB Life

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Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the benign tumor formation in multiple organs. The main etiology of TSC is the loss‐of‐function mutation of TSC1 or TSC2 gene, which leads to aberrant activation of mammalian target of rapamycin complex 1 (mTORC1). In this research, we found a significant increase of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3) expression in Tsc1−/− and Tsc2−/− mouse embryonic fibroblasts (MEFs) compared with the control cells. Inhibition of mTORC1 led to a dramatic decrease of PFKFB3 expression, indicating PFKFB3 regulation by mTORC1. Moreover, suppression of mTORC1 inhibited the expression of PFKFB3 in rat uterine leiomyoma‐derived Tsc2‐null ELT3 cells and human tumor cells. Furthermore, we identified hypoxia‐inducible factor 1α (HIF‐1α) as a mediator transmitting the signal from mTORC1 to PFKFB3. Depletion of PFKFB3 inhibited proliferation and tumorigenicity of Tsc1‐ or Tsc2‐deficient cells. In addition, combination of rapamycin with PFK15, a PFKFB3 inhibitor, exerts a stronger inhibitory effect on cell proliferation of Tsc1‐ or Tsc2‐null MEFs than treatment with single drug. We conclude that loss of TSC1 or TSC2 led to upregulated expression of PFKFB3 through activation of mTORC1/HIF‐1α signaling pathway and co‐administration of rapamycin and PFK15 may be a promising strategy for the treatment of TSC tumors as well as other hyperactivated mTORC1‐related tumors.

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Genetics of tuberous sclerosis complex: an update

Marom

2020

Childs Nerv Syst

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Finding a cure for tuberous sclerosis complex: From genetics through to targeted drug therapies

Cited by 29 publications

References 58 publications

Tuberous sclerosis: a review of the past, present, and future

Tuberous sclerosis: a review of the past, present, and future

Upregulation of 6‐phosphofructo‐2‐kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex

Genetics of tuberous sclerosis complex: an update

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