SFEBES2013 Poster Presentations Growth and development (9 abstracts)
Pre-clinical investigation of therapy for segmental overgrowth caused by constitutive activation of phosphoinositide-3 kinas: lessons for cancer therapy
Victoria Parker 1 , Matthijis Groeneveld 1 , Qifeng Zhang 3 , Simon Rudge 3 , Marjorie Lindhurst 5 , Susan Huson 4 , Steven O’Rahilly 1 , Leslie Biesecker 5 , Ines Barroso 2 , Michael Wakelam 3 & Robert Semple 1
1Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge Univeristy Hospitals NHS Trust, Cambridge, UK; 2Wellcome Trust Sanger Institute, Hinxton, UK; 3The Babraham Institute, Cambridge, UK; 4Genetics Unit, Manchester Academic Health Science Centre, Manchester, UK; 5The National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Introduction: We recently reported cases of segmental overgrowth due to mosaic heterozygous activating mutations in the p110α catalytic subunit of PI3K. The index case presented with life-long, massive overgrowth of both legs with a lean upper body. Mobility was threatened by continued growth. mTORC1 inhibition has been effective at slowing excess growth due to loss of PTEN function, a negative regulator of PI3K. We hypothesised that mTORC1 inhibition would also be effective in this setting.
Methods/Results: Fibroblasts grown from a leg biopsy were confirmed to have a 50% burden of the p.PIK3CA.His1047Leu mutation, with higher basal and stimulated PIP3 levels and consequent hyperactivation of downstream PI3K-AKT signalling. Treatment of cells with everolimus 5 nmol/l for 120 h reduced basal and insulin-stimulated phosphorylation of AKTser473 and p70S6K, however baseline PIP3 levels were twofold higher with everolimus treatment, this increase being amplified by insulin or EGF.
Discussion: This study highlights that chronic mTORC1 blockade leads to increased PIP3 levels with potential to enhance cytokinesis despite reduced AKT activation. We conclude that sirolimus, an mTORC1 inhibitor, may be effective in this patient, but careful monitoring for malignancy will be required. Our findings further underline concerns that cancers, especially those possessing activating PI3K mutations, could behave adversely with mTORC1-inhibitor monotherapy.
Declaration of funding: This work was supported by the Wellcome Trust grant number 097721/Z/11/Z, 2012 and the Sackler Fund 2012.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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