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New biology of oncogenic PI 3-kinase

Project description

PI3K signalling in oxygen- and nutrient-starved tumours

PI 3-kinase (PI3K) signalling regulates multiple cell functions. The activation of this pathway has been associated with oncogenesis due to the activation of mutations in the PIK3CA gene or the inactivation of the tumour suppressor PTEN, which opposes PI3K signalling. Solid tumours are most often hypoxic and nutrient-starved; research carried out on PI3K signalling thus far has not reflected these cancer-relevant tissue conditions. The EU-funded Oncogenic PI3-kinase project aims to elucidate the PI3K biology in cancer with the aim of uncovering signalling mechanisms of oncogenic PIK3CA under cancer-relevant conditions of long-term starvation and/or hypoxia. Moreover, it aims to elucidate the mechanism of cell death induced by innovative PI3K modulators that kill PIK3CA-mutant cancer cells under conditions of hypoxia.

Objective

PI 3-kinase (PI3K) signalling regulates multiple cell functions and is one of the most frequently genetically-activated pathways in cancer. This is mainly due to activating mutations in PIK3CA (the gene encoding the PI3Kα catalytic subunit) or inactivation of the tumour-suppressor PTEN (which opposes PI3K signalling).

Solid tumours are most often hypoxic and nutrient-starved. The central premise of my proposal is that PI3K signalling has thus far been predominantly investigated under experimental settings not representative of these cancer-relevant tissue contexts. In our view, this has resulted in an incomplete understanding of PI3K biology in cancer. Based on this assertion, I have formulated two key objectives:
(1) To uncover previously-unappreciated signalling mechanisms of oncogenic PIK3CA under cancer-relevant conditions of long-term starvation and/or hypoxia.
(2) To understand the mechanism of cell death induced by an innovative, new type of PI3K modulators, generated by the Host Lab, that kill PIK3CA-mutant cancer cells under hypoxic conditions.

These objectives will be achieved by, respectively:
(1) Biased and unbiased genetic and pharmacological approaches in cells and mice, including probing signalling under conditions of (A) nutrient and/or oxygen starvation (B) sustained low-level signalling due to genetic PIK3CA activation in the heterozygous state and from the endogenous promotor, as is the case in cancer.
(2) Using unique small-molecule PI3K pathway modulators developed in the Host Lab, in cell-biological and signalling studies.

These objectives will merge my expertise in signalling under nutrient-starved conditions with world-class know-how in PI3K cancer studies and drug development in the Host Lab. This proposal aims to make scientific breakthroughs in understanding cancer-related PI3K signalling, promoting the progression of my career and allowing the Host Lab to achieve its key long-term aim to make PI3K-based cancer therapies work.

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Coordinator

UNIVERSITY COLLEGE LONDON
Net EU contribution
€ 212 933,76
Address
Gower street
WC1E 6BT London
United Kingdom

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Region
London Inner London — West Camden and City of London
Activity type
Higher or Secondary Education Establishments
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Other funding
€ 0,00