The role of PI 3-kinase/AKT/mTOR and interacting pathways in haematological cancers
Lead Research Organisation:
Queen Mary University of London
Department Name: Barts Cancer Institute
Abstract
In this proposal, the leading pharmaceutical company AstraZeneca teams up with two groups at the Institute of Cancer at St Bartholomew?s Hospital in London, namely the Centre for Experimental Cancer Medicine and the Centre for Cell Signalling. The aim of this proposal is to facilitate the transition of new anti-cancer drugs into the clinic, with a focus on cancer of the white blood cells. The Centre for Experimental Cancer Medicine has a long-standing expertise in both research and clinical trial work in this type of cancer. The Centre for Cell Signalling has world-class expertise in a group of molecules termed PI 3-kinases, which are new targets that AstraZeneca is aiming to block in cancer cells. Together they will provide new methods to assess how blockade of PI 3-kinase will affect the internal wiring of signals that allow cancer cells to survive and multiply. Jointly, the teams are looking for new ways to monitor the impact of drugs againts PI 3-kinases in patient samples, to better assess and predict potential responsiveness, with a view to selecting patients that may respond to these new therapies and to facilitate entry of these potentially new drugs into the clinic.
Technical Summary
The PI 3-kinase (PI3K)/AKT/mTOR pathway is very frequently deregulated in cancer. Whilst preliminary data implicate this pathway in the pathophysiology of haematological cancers, these data are most often based on cell lines and a small number of clinical samples studied ex vivo. There is therefore a critical need to define the mechanisms by which this pathway is deregulated in primary haematological cancers and in which disease subgroup(s).
Furthermore there are limited studies that define the role of distinct isoforms of PI3K in haematological cancers, with no data that define the relationship between PI3K protein expression and activity status. This is an important issue in oncology and for the rational application of targeted therapies because protein expression often does not correlate with kinase inhibitor responses. It is therefore important to establish assays and methods that better define pathway activation to identify which patient will benefit from a specific inhibitor.
Focusing on B-cell lymphoma and myeloma, we endeavour to answer these important questions by addressing the following aims:
(1) Define PI3K isoform expression at the protein level, including immunohistochemistry.
(2) Relate this protein expression profile to the activation status of the Akt and mTOR kinases and other pathway components, by quantitative mass spectrometry, and physiological effects on primary cancer cells
(3) Assess the impact of pathway-specific inhibitors on
(a) in vitro cell survival/proliferation of cancer cells, with or without stromal cells
(b) the activation status of downstream signalling pathways, using quantitative mass spectrometry and other methods
(c) related signalling pathways (inc MEK, JAK/STAT)
(d) gene expression profiles.
These preclinical studies will provide:
(a) novel mechanistic insights into how the PI3K/Akt and mTOR pathway operates and
(b) define activation of key signalling nodes in patient samples and define responses to specific kinase inhibitors, either as monotherapy or in combination
(c) define predictive biomarkers or molecular endpoints in the subsequent clinical evaluation of these agents in haematological cancer.
These data will be critical for the design and execution of future phase I/II studies in haematological malignancies. Furthermore the focus on primary haematological cancers, with readily available tissue for ex vivo studies, will define exploratory biomarkers and hypotheses that can be further investigated and extrapolated to solid tumours.
Furthermore there are limited studies that define the role of distinct isoforms of PI3K in haematological cancers, with no data that define the relationship between PI3K protein expression and activity status. This is an important issue in oncology and for the rational application of targeted therapies because protein expression often does not correlate with kinase inhibitor responses. It is therefore important to establish assays and methods that better define pathway activation to identify which patient will benefit from a specific inhibitor.
Focusing on B-cell lymphoma and myeloma, we endeavour to answer these important questions by addressing the following aims:
(1) Define PI3K isoform expression at the protein level, including immunohistochemistry.
(2) Relate this protein expression profile to the activation status of the Akt and mTOR kinases and other pathway components, by quantitative mass spectrometry, and physiological effects on primary cancer cells
(3) Assess the impact of pathway-specific inhibitors on
(a) in vitro cell survival/proliferation of cancer cells, with or without stromal cells
(b) the activation status of downstream signalling pathways, using quantitative mass spectrometry and other methods
(c) related signalling pathways (inc MEK, JAK/STAT)
(d) gene expression profiles.
These preclinical studies will provide:
(a) novel mechanistic insights into how the PI3K/Akt and mTOR pathway operates and
(b) define activation of key signalling nodes in patient samples and define responses to specific kinase inhibitors, either as monotherapy or in combination
(c) define predictive biomarkers or molecular endpoints in the subsequent clinical evaluation of these agents in haematological cancer.
These data will be critical for the design and execution of future phase I/II studies in haematological malignancies. Furthermore the focus on primary haematological cancers, with readily available tissue for ex vivo studies, will define exploratory biomarkers and hypotheses that can be further investigated and extrapolated to solid tumours.
