Nuclear IGF-1R as a potential target for precision cancer medicine
Lead Research Organisation:
University of Oxford
Department Name: Oncology
Abstract
The main aim of our research is to understand the contribution of insulin-like growth factor (IGF) signalling to cancer biology, and to exploit this information in the management of patients with cancer. Production of IGF-1 from the liver is regulated by growth hormone, and people with congenital deficiencies of growth hormone or IGF-1 are strongly protected from developing cancer. Conversely, people with high blood levels of IGF-1 are at increased risk of developing cancer. IGFs binds to type 1 IGF receptors that are expressed on the cell surface, promoting cancer cell growth and spread, and resistance to killing by cancer drugs and radiotherapy. Therefore, blocking the action of IGFs offers the potential to suppress cancer development, and increase sensitivity to anti-cancer treatments.
We have shown that IGF receptors are up-regulated in prostate and renal cancers, and detectable in advanced primary tumours and metastatic disease. We also demonstrated that IGF receptors undergo IGF-dependent import into the nucleus of human tumour cells, and nuclear IGF receptor is associated with adverse prognosis in renal cancer. These findings suggest a link with aggressive tumour behaviour, and we are currently investigating the role of IGF receptor in the nucleus
Our other major interest is to develop approaches to exploit IGF receptor and related signalling molecules as targets for cancer treatment. Our research aims to identify factors that influence sensitivity to drugs that block IGF receptor, and test IGF inhibition as a route to sensitise cancers to other forms of treatment. We recently showed that IGF receptor inhibition delays the repair of DNA double-strand breaks, apparently independent of its well-known ability to regulate apoptosis induction. Understanding the basis of this effect may enable effective exploitation of this approach in the clinic.
We have shown that IGF receptors are up-regulated in prostate and renal cancers, and detectable in advanced primary tumours and metastatic disease. We also demonstrated that IGF receptors undergo IGF-dependent import into the nucleus of human tumour cells, and nuclear IGF receptor is associated with adverse prognosis in renal cancer. These findings suggest a link with aggressive tumour behaviour, and we are currently investigating the role of IGF receptor in the nucleus
Our other major interest is to develop approaches to exploit IGF receptor and related signalling molecules as targets for cancer treatment. Our research aims to identify factors that influence sensitivity to drugs that block IGF receptor, and test IGF inhibition as a route to sensitise cancers to other forms of treatment. We recently showed that IGF receptor inhibition delays the repair of DNA double-strand breaks, apparently independent of its well-known ability to regulate apoptosis induction. Understanding the basis of this effect may enable effective exploitation of this approach in the clinic.
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
MR/N013468/1 | 01/10/2016 | 30/09/2025 | |||
1963108 | Studentship | MR/N013468/1 | 01/10/2017 | 30/09/2021 | Jack Mills |
MR/R502224/1 | 01/10/2017 | 31/05/2022 | |||
1963108 | Studentship | MR/R502224/1 | 01/10/2017 | 30/09/2021 | Jack Mills |
Description | Cancer Research UK Oxford Centre Development Fund Award |
Amount | £7,497 (GBP) |
Funding ID | CRUKDF - 0221 - VMIMJM |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2021 |
End | 03/2022 |
Description | MRC DTP Supplementary Funding |
Amount | £22,585 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2021 |
End | 04/2022 |
Description | Oxford Genomics Centre - ChIP-seq Analysis |
Organisation | University of Oxford |
Department | Oxford Genomics Centre |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Generation of IGF-1R ChIP DNA samples from fresh frozen prostate cancer tissue. Analysis and validation of subsequent sequencing data generated by Oxford Genomics Centre. |
Collaborator Contribution | Sequencing of IGF-1R ChIP DNA samples |
Impact | Generation of IGF-1R ChIP-seq dataset from human tissue, which to the best of our knowledge has not previously been generated. |
Start Year | 2021 |
Description | Target Discovery Institute - Mass Spectrometry Analysis |
Organisation | University of Oxford |
Department | Target Discovery Institute (TDI) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provided samples for mass spectrometry analysis |
Collaborator Contribution | Operation of mass spectrometer and subsequent analysis |
Impact | Generation of a nuclear IGF-1R interactome dataset. Successful validation of interaction of IGF-1R with a DNA repair protein, namely DNA-PK catalytic subunit. |
Start Year | 2020 |
Description | Prostate Cancer UK Legacy Day |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Around 30 ex-prostate cancer patients and their partners/close relatives visited our lab. They attended a short talk on the specific prostate cancer related work our lab does from our PI Dr Valentine Macaulay, followed by a lab tour, and interactive activities including using a microscope to look at cells. There was a great amount of discussion and questions from those attending, and an increased interest afterwards to donate to Prostate Cancer UK |
Year(s) Of Engagement Activity | 2019 |