Oncogenic PI3-kinase · New biology of oncogenic PI 3-kinase
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-05-01 → 2021-04-30
- EU contribution
- €212,934
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
New biology of oncogenic PI 3-kinase
This project studied PI 3-kinases (PI3Ks in short) that regulate fundamental processes in cells. Inhibitors against PI3K family members are now approved for the treatment of leukaemia and breast cancer. We focused on a PI3K family member which has been implicated in disease, including in cancer. Despite extensive research, key elements of PI3K biology are poorly understood, in part because we believe PI3K function has not been investigated in the appropriate conditions and models. The primary cilium is a much-overlooked structure in a cell. This is a small antenna-like structure that projects out of each cell to sense the environment and is important for development and normal adult cell function. Here we have studied a new function for PI3K in controlling the primary cilium biology and identified novel signalling downstream of PI3K signalling. We believe our findings have the potential to uncover insights into long-standing questions the in cilia biology field and help to understand how increased activity of PI3K contributes to disease. Understanding the mechanistic basis of disease informs and is essential for the process of drug development.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- UNIVERSITY COLLEGE LONDON · LondonCoordinatorUnited Kingdom
Links
- View on CORDIS
- DOI: 10.3030/838559
- https://www.ucl.ac.uk/cancer/research/department-oncology/cell-signalling-research-group
Data: CORDIS, © European Union