PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases
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 approv...
Main Authors: | , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2019-11-01
|
Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | https://www.mdpi.com/1422-0067/20/22/5792 |
id |
doaj-b6def8ed15a1422292145255b5be80d3 |
---|---|
record_format |
Article |
spelling |
doaj-b6def8ed15a1422292145255b5be80d32020-11-25T01:48:40ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-11-012022579210.3390/ijms20225792ijms20225792PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic DiseasesPetra Hillmann0Doriano Fabbro1PIQUR Therapeutics, Hochbergerstrasse 60C, 4057 Basel, SwitzerlandPIQUR Therapeutics, Hochbergerstrasse 60C, 4057 Basel, SwitzerlandThe 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.https://www.mdpi.com/1422-0067/20/22/5792pi3kmtor inhibitorcancerovergrowth syndromemtoropathytscprosapdspten hamartomabrain penetration |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Petra Hillmann Doriano Fabbro |
spellingShingle |
Petra Hillmann Doriano Fabbro PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases International Journal of Molecular Sciences pi3k mtor inhibitor cancer overgrowth syndrome mtoropathy tsc pros apds pten hamartoma brain penetration |
author_facet |
Petra Hillmann Doriano Fabbro |
author_sort |
Petra Hillmann |
title |
PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases |
title_short |
PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases |
title_full |
PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases |
title_fullStr |
PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases |
title_full_unstemmed |
PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases |
title_sort |
pi3k/mtor pathway inhibition: opportunities in oncology and rare genetic diseases |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2019-11-01 |
description |
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. |
topic |
pi3k mtor inhibitor cancer overgrowth syndrome mtoropathy tsc pros apds pten hamartoma brain penetration |
url |
https://www.mdpi.com/1422-0067/20/22/5792 |
work_keys_str_mv |
AT petrahillmann pi3kmtorpathwayinhibitionopportunitiesinoncologyandraregeneticdiseases AT dorianofabbro pi3kmtorpathwayinhibitionopportunitiesinoncologyandraregeneticdiseases |
_version_ |
1725010822524043264 |