This document summarizes a study investigating the metabolic mechanisms underlying segmental overgrowth disorders and potential treatments. The study found that mutations in the PI3K-AKT pathway, such as in PIK3CA and AKT1, lead to increased cell proliferation and metabolism. Functional studies showed that cell lines with PIK3CA mutations had increased AKT phosphorylation and responded strongly to growth factors, while AKT1 mutant cell lines responded less. Treatment with PI3K or mTOR inhibitors normalized the metabolic profile in both AKT1 and PIK3CA mutant cell lines, suggesting these may be effective treatments. The study provides new insights into the molecular mechanisms and potential targeted therapies for segmental overgrowth disorders.
Recombinant DNA technology( Transgenic plant and animal)
Metabolic investigation of segmental overgrowth: insights into pathogenic mechanisms and treatments
1. Metabolic investigation of
segmental overgrowth:
new insights in pathogenic
mechanisms and
treatments.
Luigi Boccuto, MD
Greenwood Genetic Center
October 26th, 2017
2. Insulin/IGF, FGF, EGF, PDGF,
VEGF, HGF/cMet
Cell survival and
proliferation,
increased
metabolism and
protein synthesis
mTOR
Caspase
p53
GSK3β
NF-κB
PI3K-AKT pathway
17. -
Insulin/IGF, FGF, EGF, PDGF,
VEGF, HGF/cMet
Cell survival and
proliferation,
increased
metabolism and
protein synthesis
mTOR
Caspase
p53
GSK3β
NF-κB
18. Functional studies – Conclusions
Combining AKT phosphorylation test and Biolog PM
arrays can be helpful in:
• distinguishing AKT1 vs. PIK3CA mutations;
• understanding the response of a mutation to
growth factors (insulin, FGF-1, IGF-1, PDGF >> hGH);
• suggesting treatment approaches;
• following up the response of patients to
pharmaceutical protocols.
19. Treatment
• BYL719: selective inhibitor of the p110α subunit of Pi3K (encoded
by PIK3CA), at 40 and 80 nM.
• Wortmannin: inhibitor of the Pi3K complex, at 0.1 and 1 μM.
• Rapamycin: inhibitor of the mTOR pathway, at 0.1 and 1 μM.
mTOR
20. BYL719
CMS15740 BYL719
80 nM vs. untreated
control
CMS15740 BYL719 40
nM vs. untreated
control
CMS15740 (PIK3CA
H1047R, 46%) vs.
control
27. Treatment – Conclusions
• Wortmannin normalized the metabolic
response in Proteus cell lines.
• BYL719 reduced the metabolic response in all
cell lines but is probably toxic (especially at 80
nM).
• Rapamycin normalized metabolic response in
both AKT1+ and PIK3CA+.