Research output per year
Research output per year
Project Details
Layman's description
Colorectal cancer is the third most common type of cancer in the UK and in the
USA and the second most common cause of cancer-related death. The global economic impact of colorectal cancer is estimated at $99 billion, excluding the costs of patient therapy. Professor Milner's research group has invented a novel method for selective killing of human colorectal cancer cells without adverse effects on normal, non-cancer cells. Funding will be used to confirm one final element of the method. Following successful completion, Yorkshire Cancer Research will release the money it has provisionally awarded to help translate the technique into clinical practice.
USA and the second most common cause of cancer-related death. The global economic impact of colorectal cancer is estimated at $99 billion, excluding the costs of patient therapy. Professor Milner's research group has invented a novel method for selective killing of human colorectal cancer cells without adverse effects on normal, non-cancer cells. Funding will be used to confirm one final element of the method. Following successful completion, Yorkshire Cancer Research will release the money it has provisionally awarded to help translate the technique into clinical practice.
Key findings
FINDINGS/RESULTS
It is widely reported that cancer cells typically exhibit an altered metabolic state compared to their normal counterparts, specifically, generating and releasing lactate, even in the presence of sufficient oxygen to use oxidative phosphorylation. This is known as aerobic glycolysis, or the Warburg effect.
A candidate therapeutic agent developed at the University of York, in the form of a modified short inhibitory RNA (siRNA) duplex, can be used to deplete mRNA transcribed from the SIRT1 gene, producing death among cultured cancer cell lines, but not among cultured non-cancer cells. Death manifests within 48 hours of siRNA treatment. It is postulated that the mechanism by which this occurs is dependent upon the reliance of cancer cells on aerobic glycolysis.
To evaluate the potential of SIRT1 mRNA inhibition in killing cancer cells in a setting more closely resembling clinical presentation, a collaborator was identified who was able to provide i) live tumour and non-tumour tissue derived from colorectal cancer patients and ii) a method of culturing histologically intact fragments, ex vivo.
C2D2 provided funding to undertake preliminary experiments to ascertain whether ex vivo colorectal cancer tissue initially exhibits aerobic glycolysis and whether this metabolic state is maintained with time in culture. Thus, the purpose of the work undertaken was to evaluate the suitability of cultured ex vivo colorectal crypts as a model for screening prototypic therapeutic formulations designed to target and kill cancer cells by depletion of the SIRT1 gene product, without harming non-cancer cells, in cancerous human colorectal tissue.
Using human cell lines of normal and cancerous origins, cultured under aerobic conditions, we confirmed that significant differences in secreted lactate levels were apparent, based upon data generated by the assay system that was selected; colorectal cancer cell medium contained 2 to 3-fold more lactate than medium from normal cells.
Results obtained with human colorectal tissues, maintained ex vivo, were consistent with cell line results. Mean lactate production by cancerous tissues, during a period spanning 48 hours to 96 hours of aerobic incubation, was at least 1.6-fold higher than non-cancer colorectal crypts. Thus we demonstrate that cancer-related Warburg metabolism is maintained, in ex vivo tumour tissue culture, beyond 48 hours.
COLLABORATIONS
The C2D2 project established a collaboration between the University of York’s Professor Jo Milner and the University of East Anglia’s Dr Mark Williams.
STAFF
Dr. Simon Allison served as a consultant to the project from July 2012 to January 2013. He now holds a YCR award and is based at the University of Bradford.
COMMERCIALISATION/TRANSLATION
Approaches have been made to a number of prospective commercial partners, with a view to developing the technology for eventual use in man. While initial discussions were mostly encouraging, substantive progress has not been made due to a reluctance, among prospective partners, to commit to additional R&D activity in this area.
APPLICATIONS SUBMITTED
The application for C2D2 funding was made and was awarded based upon a pending “Commercial Development Award” (CDA) application with the charity, Yorkshire Cancer Research (YCR). YCR had stipulated that the work outlined in the C2D2 application needed to be done in order for its Commercial Development team to recommend funding the pending CDA. Unfortunately, as the C2D2 project neared its (successful) conclusion, YCR undertook a review of its grants procedures and decreed that the pending CDA application would require re-submission to the earliest stage of its newly-defined process. A re-submission has not been made.
Simon J. Allison, £225,000, Yorkshire Cancer Research, 'Utilising human organoid technology and more selective anti-cancer therapeutic agents to improve cancer outcomes', commences January 2015, 36 months
It is widely reported that cancer cells typically exhibit an altered metabolic state compared to their normal counterparts, specifically, generating and releasing lactate, even in the presence of sufficient oxygen to use oxidative phosphorylation. This is known as aerobic glycolysis, or the Warburg effect.
A candidate therapeutic agent developed at the University of York, in the form of a modified short inhibitory RNA (siRNA) duplex, can be used to deplete mRNA transcribed from the SIRT1 gene, producing death among cultured cancer cell lines, but not among cultured non-cancer cells. Death manifests within 48 hours of siRNA treatment. It is postulated that the mechanism by which this occurs is dependent upon the reliance of cancer cells on aerobic glycolysis.
To evaluate the potential of SIRT1 mRNA inhibition in killing cancer cells in a setting more closely resembling clinical presentation, a collaborator was identified who was able to provide i) live tumour and non-tumour tissue derived from colorectal cancer patients and ii) a method of culturing histologically intact fragments, ex vivo.
C2D2 provided funding to undertake preliminary experiments to ascertain whether ex vivo colorectal cancer tissue initially exhibits aerobic glycolysis and whether this metabolic state is maintained with time in culture. Thus, the purpose of the work undertaken was to evaluate the suitability of cultured ex vivo colorectal crypts as a model for screening prototypic therapeutic formulations designed to target and kill cancer cells by depletion of the SIRT1 gene product, without harming non-cancer cells, in cancerous human colorectal tissue.
Using human cell lines of normal and cancerous origins, cultured under aerobic conditions, we confirmed that significant differences in secreted lactate levels were apparent, based upon data generated by the assay system that was selected; colorectal cancer cell medium contained 2 to 3-fold more lactate than medium from normal cells.
Results obtained with human colorectal tissues, maintained ex vivo, were consistent with cell line results. Mean lactate production by cancerous tissues, during a period spanning 48 hours to 96 hours of aerobic incubation, was at least 1.6-fold higher than non-cancer colorectal crypts. Thus we demonstrate that cancer-related Warburg metabolism is maintained, in ex vivo tumour tissue culture, beyond 48 hours.
COLLABORATIONS
The C2D2 project established a collaboration between the University of York’s Professor Jo Milner and the University of East Anglia’s Dr Mark Williams.
STAFF
Dr. Simon Allison served as a consultant to the project from July 2012 to January 2013. He now holds a YCR award and is based at the University of Bradford.
COMMERCIALISATION/TRANSLATION
Approaches have been made to a number of prospective commercial partners, with a view to developing the technology for eventual use in man. While initial discussions were mostly encouraging, substantive progress has not been made due to a reluctance, among prospective partners, to commit to additional R&D activity in this area.
APPLICATIONS SUBMITTED
The application for C2D2 funding was made and was awarded based upon a pending “Commercial Development Award” (CDA) application with the charity, Yorkshire Cancer Research (YCR). YCR had stipulated that the work outlined in the C2D2 application needed to be done in order for its Commercial Development team to recommend funding the pending CDA. Unfortunately, as the C2D2 project neared its (successful) conclusion, YCR undertook a review of its grants procedures and decreed that the pending CDA application would require re-submission to the earliest stage of its newly-defined process. A re-submission has not been made.
Simon J. Allison, £225,000, Yorkshire Cancer Research, 'Utilising human organoid technology and more selective anti-cancer therapeutic agents to improve cancer outcomes', commences January 2015, 36 months
| Status | Finished |
|---|---|
| Effective start/end date | 1/07/12 → 31/03/13 |
Research output
- 1 Article
-
RNA interference by single- and double-stranded siRNA with a DNA extension containing a 3′ nuclease-resistant mini-hairpin structure
Allison, S. J. & Milner, J., Jan 2014, In: Molecular Therapy - Nucleic Acids. 2, 12 p., e141.Research output: Contribution to journal › Article › peer-review