Abstract
The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway has been implicated as a cancer target. Big pharma players and small companies have been developing small molecule inhibitors of PI3K and/or mTOR since the 1990s. Although four inhibitors have been approved, many open questions regarding tolerability, patient selection, sensitivity markers, development of resistances, and toxicological challenges still need to be addressed. Besides clear oncological indications, PI3K and mTOR inhibitors have been suggested for treating a plethora of different diseases. In particular, genetically induced PI3K/mTOR pathway activation causes rare disorders, known as overgrowth syndromes, like PTEN (phosphatase and tensin homolog) hamartomas, tuberous sclerosis complex (TSC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum (PROS), and activated PI3-Kinase delta syndrome (PI3KCD, APDS). Some of those disorders likeTSC or hemimegalencephaly, which are one of the PROS disorders, also belong to a group of diseases called mTORopathies. This group of syndromes presents with additional neurological manifestations associated with epilepsy and other neuropsychiatric symptoms induced by neuronal mTOR pathway hyperactivation. While PI3K and mTOR inhibitors have been and still are intensively tested in oncology indications, their use in genetically defined syndromes and mTORopathies appear to be promising avenues for a pharmacological intervention.
Highlights
Hyperactivation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin signaling pathway has been observed in a high percentage of human cancers inducing growth, survival, and proliferation [1]
Rapalogs are approved for indications in the oncology space and as immune suppressants as well as for use in rare genetic tumors and epilepsy associated with Tuberous Sclerosis Complex (TSC)
While genetic disorders comprising overgrowth and neurological symptoms give a clear rationale for the application of PI3K/mTOR inhibitors in oncology, the prediction of sensitivity or resistance is still subject to discussion and evaluation
Summary
Hyperactivation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway has been observed in a high percentage of human cancers inducing growth, survival, and proliferation [1]. Inhibitors of downstream targets like protein kinase B (AKT/PKB) are in clinical development for oncology indications. Disease PROS: Megalencephaly-capillary malformation syndrome, CLOVES syndrome, hemimegalencephaly, fobroadipose hyperplasia, congenital lipomatous overgrowth, KlippelTrenaunay syndrome Activated phosphoinositide 3-kinase δ syndrome (APDS) APDS PTEN hamartoma tumor syndrome: Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome Smith-Kingsmore syndrome, focal cortical dysplasia, hemimegalencephaly Proteus syndrome, megalencephaly-polymicrogyria-polydactyly-hydrocephalus, Int. J. Disease PROS: Megalencephaly-capillary malformation syndrome, CLOVES syndrome, hemimegalencephaly, fobroadipose hyperplasia, congenital lipomatous overgrowth, Klippel-Trenaunay syndrome Activated phosphoinositide 3-kinase δ syndrome (APDS) APDS PTEN hamartoma tumor syndrome: Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome Smith-Kingsmore syndrome, focal cortical dysplasia, hemimegalencephaly Proteus syndrome, megalencephaly-polymicrogyria-polydactyly-hydrocephalus, megalencephaly Tuberous Sclerosis Complex, focal cortical dysplasia Focal cortical malformation Familial focal epilepsy with variable foci, familial mesial temporal lobe epilepsy Megalencephaly-polymicrogyria-polydactyly-hydrocephalus Polyhydramnios, megalencephaly, symptomatic epilepsy, Pretzel syndrome Peutz-Jeghers syndrome
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