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Dr K Kurian, Prof R Martin, Dr C Galan, Dr S Hauert
No more applications being accepted
Self-Funded PhD Students Only
About the Project
Development of a cheap sensitive blood test for early detection of brain metastasis using fluorescent carbon dots and nanophotonics
Brain cancer is responsible for the most years of life lost of any cancer and less than 20% of brain cancer patients are alive five years after diagnosis. As well as cancers starting within the brain, there are cancers that start in other places such as breast cancer, lung cancer, gut cancer, kidney cancer and skin cancer that travel to the brain which are known as brain metastasis or secondaries which cause death.
We know that around 24,000 patients a year in the UK suffer from brain metastasis and at the moment the only way they are diagnosed using a brain scan. The symptoms of brain metastasis are very non-specific such as headache so it is very difficult for a GP to pick these up before the cancer becomes large and inoperable in the brain. At the moment brain metastases are treated with surgery or chemo/radiotherapy. Brain metastases are so common in small cell lung cancer that patients are given whole brain radiotherapy upfront to try to stop brain metastasis developing. We know that whole brain radiotherapy has side effects which can affect the patient’s mental abilities. The earlier a brain metastasis is picked up, the better the chances are for the patient to have a longer survival.
We would like to develop a cheap test for early diagnosis of brain metastasis that the GP could use in the clinic to help them to decide who to refer on for a scan. We will like to modify a technique using nanoparticles, which has already developed for early diagnosis of urine infections, which could potentially detect cancer cells or proteins in the blood. We are also working on test to identify brain cancers that start within the brain using this technique.
We have recently been awarded a CRUK Early Detection Project Grant to develop a test for brain cancer starting within the brain. We would like to progress this research to develop a test for brain metastasis.
PURPOSE Hypothesis: Fluorescent carbon dots, functionalised with antibodies to known proteins, or novel biomarkers, in combination with FluoretiQ sensing technology, could act as a cheap sensitive blood test to aid early diagnosis in patients with suspected brain metastasis
Aims and Objectives
- Systematic review to identify the novel biomarkers of brain metastasis in addition to known biomarkers
- Mendelian Randomisation: Reverse MR to identify novel biomarkers of brain metastasis
- Work with Nanoparticle test development team, to support development of nanophotonic test
Methodology
Objective 1: Systematic Review : We know that EpCam/ CAM5.2 are biomarkers for epithelial brain metastasis. The PhD student would perform a systematic review to identify the novel and more specific biomarkers for brain metastasis. The PhD student would initially study brain metastasis from lung and breast cancer which are the most frequent brain metastasis. We have already published high impact Cochrane systematic reviews on brain cancer biomarkers (1,2).
Objective 2: The PhD student would undertake Mendelian Randomization using population health datasets to discover novel potential blood biomarkers for patients at risk of brain metastasis and novel markers of metastatic progression. We already have access to GWAS data from the Gliogene Consortium and the Glioma International CaseControl study (GICC) which include tumours starting within the brain. The PhD student will use two sample Mendelian randomization (MR) to explore the causal effects of 1,608 blood proteins on brain metastasis risk and progression.
Preliminary results: Using this technique we have already identified three novel potential protein biomarkers for intrinsic brain tumours. Biomarker discovery: Mendelian randomization (MR) to explore the causal effects of blood proteins on brain metastasis. Outputs: The PhD student will generate a library of novel potential biomarkers for use in early detection of metastasis.
Objective 3: Development of Nanoparticle Test
The PhD student would work with our multidisciplinary team including chemistry, engineering and industry who are currently working on a nanoparticle test for intrinsic brain cancer. Blood samples will be collected from patients referred to Southmead hospital for a suspected brain tumour for CT/MRI scans. We performed in Southmead hospital 33 CT scans and 9 MRI scans between 1 - 30 April 2018 (41 scans a month) for suspected brain metastasis A technician would provide whole blood and spin the blood to extract serum and send to laboratory and prepare currently available samples for nanoparticle test development. We will have blood samples with detailed neuropathologic brain tumour analysis, genetic analysis and overall survivals to validate the test.
Keywords
brain metastasis, lung cancer, breast cancer, early detection, biomarker
How to apply for this project
This project will be based in Bristol Medical School - Population Health Sciences in the Faculty of Health Sciences at the University of Bristol.
Please visit the Faculty of Health Sciences website for details of how to apply
Funding Notes
This project is open for University of Bristol PGR scholarship applications (closing date 25th February 2022)
The University of Bristol PGR scholarship pays tuition fees and a maintenance stipend (at the minimum UKRI rate) for the duration of a PhD (typically three years but can be up to four years).
The University of Bristol PGR scholarship pays tuition fees and a maintenance stipend (at the minimum UKRI rate) for the duration of a PhD (typically three years but can be up to four years).
References
1) Diagnostic accuracy of 1p/19q codeletion tests in oligodendroglioma: a comprehensive meta-analysis based on a Cochrane Systematic Review.
Brandner S, McAleenan A, Jones HE, Kernohan A, Robinson T, Schmidt L, Dawson S, Kelly C, Leal ES, Faulkner CL, Palmer A, Wragg C, Jefferies S, Vale L, P T Higgins J, Kurian KM.
Neuropathol Appl Neurobiol. 2021 Dec 26. doi: 10.1111/nan.12790. Online ahead of print.
PMID: 34958131 Review.
2) Prevalence of BRAFV600 in glioma and use of BRAF Inhibitors in patients with BRAFV600 mutation-positive glioma: systematic review. Andrews LJ, Thornton ZA, Saincher SS, Yao IY, Dawson S, McGuinness LA, Jones HE, Jefferies S, Short SC, Cheng HY, McAleenan A, Higgins JPT, Kurian KM. Neuro Oncol. 2021 Oct 28:noab247. doi: 10.1093/neuonc/noab247. Online ahead of print. PMID: 34718782
3) Ozawa M, Brennan PM, Zienius K, Kurian KM, Hollingworth W, Weller D, Hamilton W, GrantR, Ben-Shlomo Y. Fam Pract. Symptoms in primary care with time to diagnosis of brain tumours. 2018 18;35(5):551-558.
4) Neuro-oncology Top 10 priorities http://www.jla.nihr.ac.uk/priority-setting-partnerships/neurooncology/ top-10-priorities/
5) Späth F, Andersson U, Dahlin AM, Langseth H, Hovig E, Johannesen TB, Grankvist K, Björkblom B, Wibom C, Melin B. Pre-diagnostic serum levels of EGFR and ErbB2 and genetic glioma risk variants: a nested case-control study. Tumour Biol. 2016 Aug;37(8):11065-72. Kurian K and Hauert S 10
6) Howell AE, Zheng J, Haycock PC, McAleenan A, Relton C, Martin RM, Kurian KM. Use of Mendelian randomization for identifying risk factors for brain tumors. Front Genet. 2018 Nov 12;9:525.
7) Haynes HR, Scott HL, Killick-Cole CL, Shaw G, Brend T, Hares KM, Redondo J, Kemp KC, Ballesteros LS, Herman A, Cordero-Llana O, Singleton WG, Mills F, Batstone T, Bulstrode H, Kauppinen RA, Wurdak H, Uney JB, Short SC, Wilkins A, Kurian KM. shRNA-mediated PPARα knockdown in human glioma stem cells reduces in vitro proliferation and inhibits orthotopic xenograft tumour growth. J Pathol. 2018
8) Stupnikov A, O'Reilly PG, McInerney CE, Roddy AC, Dunne PD, Gilmore A, Ellis HP, Flannery T, Healy E, McIntosh SA, Savage K, Kurian KM, Emmert-Streib F, Prise KM, Salto- Tellez M, McArt DG. Impact of Variable RNA-Sequencing Depth on Gene Expression Signatures and Target Compound Robustness: Case Study Examining Brain Tumor (Glioma) Disease Progression. JCO Precis Oncol. 2018 13:2
9) Carruthers RD, Ahmed SU, Ramachandran S, Strathdee K, Kurian KM, Hedley A, Gomez- Roman N, Kalna G, Neilson M, Gilmour L, Stevenson KH, Hammond EM, Chalmers AJ. Replication stress drives constitutive activation of the DNA damage response and radioresistance in glioblastoma stem-like cells. Cancer Res. 2018 78(17):5060-5071
Brandner S, McAleenan A, Jones HE, Kernohan A, Robinson T, Schmidt L, Dawson S, Kelly C, Leal ES, Faulkner CL, Palmer A, Wragg C, Jefferies S, Vale L, P T Higgins J, Kurian KM.
Neuropathol Appl Neurobiol. 2021 Dec 26. doi: 10.1111/nan.12790. Online ahead of print.
PMID: 34958131 Review.
2) Prevalence of BRAFV600 in glioma and use of BRAF Inhibitors in patients with BRAFV600 mutation-positive glioma: systematic review. Andrews LJ, Thornton ZA, Saincher SS, Yao IY, Dawson S, McGuinness LA, Jones HE, Jefferies S, Short SC, Cheng HY, McAleenan A, Higgins JPT, Kurian KM. Neuro Oncol. 2021 Oct 28:noab247. doi: 10.1093/neuonc/noab247. Online ahead of print. PMID: 34718782
3) Ozawa M, Brennan PM, Zienius K, Kurian KM, Hollingworth W, Weller D, Hamilton W, GrantR, Ben-Shlomo Y. Fam Pract. Symptoms in primary care with time to diagnosis of brain tumours. 2018 18;35(5):551-558.
4) Neuro-oncology Top 10 priorities http://www.jla.nihr.ac.uk/priority-setting-partnerships/neurooncology/ top-10-priorities/
5) Späth F, Andersson U, Dahlin AM, Langseth H, Hovig E, Johannesen TB, Grankvist K, Björkblom B, Wibom C, Melin B. Pre-diagnostic serum levels of EGFR and ErbB2 and genetic glioma risk variants: a nested case-control study. Tumour Biol. 2016 Aug;37(8):11065-72. Kurian K and Hauert S 10
6) Howell AE, Zheng J, Haycock PC, McAleenan A, Relton C, Martin RM, Kurian KM. Use of Mendelian randomization for identifying risk factors for brain tumors. Front Genet. 2018 Nov 12;9:525.
7) Haynes HR, Scott HL, Killick-Cole CL, Shaw G, Brend T, Hares KM, Redondo J, Kemp KC, Ballesteros LS, Herman A, Cordero-Llana O, Singleton WG, Mills F, Batstone T, Bulstrode H, Kauppinen RA, Wurdak H, Uney JB, Short SC, Wilkins A, Kurian KM. shRNA-mediated PPARα knockdown in human glioma stem cells reduces in vitro proliferation and inhibits orthotopic xenograft tumour growth. J Pathol. 2018
8) Stupnikov A, O'Reilly PG, McInerney CE, Roddy AC, Dunne PD, Gilmore A, Ellis HP, Flannery T, Healy E, McIntosh SA, Savage K, Kurian KM, Emmert-Streib F, Prise KM, Salto- Tellez M, McArt DG. Impact of Variable RNA-Sequencing Depth on Gene Expression Signatures and Target Compound Robustness: Case Study Examining Brain Tumor (Glioma) Disease Progression. JCO Precis Oncol. 2018 13:2
9) Carruthers RD, Ahmed SU, Ramachandran S, Strathdee K, Kurian KM, Hedley A, Gomez- Roman N, Kalna G, Neilson M, Gilmour L, Stevenson KH, Hammond EM, Chalmers AJ. Replication stress drives constitutive activation of the DNA damage response and radioresistance in glioblastoma stem-like cells. Cancer Res. 2018 78(17):5060-5071
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