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Imaging redox regulation in metastatic cancers


   School of Biomedical Engineering & Imaging Sciences

   Friday, August 12, 2022  Funded PhD Project (UK Students Only)

About the Project

Cancer can spread throughout the body (metastasis) by which time it is no longer curable through surgery alone. Metastasis is the leading cause of death in cancer patients, and are frequently therapy-resistant. Emerging evidence indicates that metastatic tumour cells undergo metabolic reprogramming to survive the oxidative stress they experience during tissue invasion and circulation in the blood.

Here, we will develop new molecular imaging agents and reporter systems to dynamically trace redox changes that occur upon metastasis using advanced animal models of lung and breast cancer. Using these new tools, we will seek to answer the following unresolved questions:

(1)  Can we monitor the cellular redox state in cancer cells and tumour models of metastasis?

(2)  Can we image and identify cells in the primary tumour that undergo redox changes prior to them leaving the primary tumour?

(3)  Is the metabolic reprogramming of metastatic disease a vulnerability that we can exploit using targeted radionuclide therapy?

  

Project description

Tumour cells experience substantial oxidative stress when they detach from the extracellular matrix and enter the circulation. Cell death frequently follows intravasation and restricts the metastatic capabilities of tumour cells (1). The oxidative environment of the bloodstream further limits metastatic efficiency. In surviving cells, multiple antioxidant mechanisms are upregulated to prevent oxidative stress and permit cell survival (2). Suppressing oxidative stress by increasing endogenous and exogenous antioxidant availability in vivo further promotes metastasis in multiple models of cancer (3).

The project will be organised in four stages to address the questions listed above. These stages are described in the following: 

Stage 1 - Characterisation of the novel PET radiotracer, [18F]FSBG.

This radiotracer is specifically transported inside metastatic tumour cells by the amino acid transporter system xc-. System xc- provides the rate-limiting precursor for glutathione, the body’s most abundant antioxidant. Using a first-generation system xc- radiotracer, [18F]FSPG, we have shown that tumour retention was redox-sensitive, predicted responders from non-responders, and could detect early response to chemotherapy (4-6). Preliminary studies have shown that the new radiotracer [18F]FSBG provides improved uptake and contrast compared to the first-generation radiotracer.

The PhD student will characterise this radiotracer across a panel of human and mouse metastatic cancer cell models following different redox manipulations. PET imaging will be performed to dynamically assess radiotracer pharmacokinetics, accompanied by ex vivo validation in tissues/organs (biodistribution, radiotracer metabolism) (7). The specificity of tumour radiotracer retention will additionally be evaluated in isogenic tumours lacking system xc- (generated by CRISPR/Cas9 knock-out).

Stage 2 - Is the redox microenvironment altered in metastatic disease?

Using advanced mouse models of lung and breast cancer, we will evaluate whether [18F]FSBG can image the tumour redox microenvironment in primary tumours and in animals with disseminated disease. Metastasis will be identified using the NIS reporter gene expressed in the cancer cells, which we previously established (9). [18F]FSBG and NIS signals will be imaged both by radionuclide imaging using different radioisotopes (e.g. 18F and 99mTc).

The PhD student will perform these imaging experiments alongside ex vivo characterization of primary and metastatic tumour tissues (genetic and metabolomic analyses). This will validate [18F]FSBG in vivo and reveal if redox status differences detectable by this radiotracer occur between primary and metastatic lesions. 

Stage 3 - Does tumour hypoxia contribute to persistently altered redox status and contribute to metastasis?

We will exploit an in vivo fate-mapping approach (8) to identify cancer cells that had experienced hypoxia at any point in their life-courses using radionuclide imaging. Our approach is based on established fluorescence-radionuclide reporters (9) exclusively controlled by the cellular hypoxia regulation system HIF and has already undergone extensive evaluation.

The PhD student will generate new cancer cell lines expressing this hypoxia reporter system and thereby enable the in vivo visualization, spatiotemporal monitoring, and subsequent ex vivo identification and analysis of cancer cells that were pre-exposed to hypoxia. [18F]FSBG imaging will be exploited before and after metastasis in this model and imaging data correlated with reporter-expressing ‘post-hypoxic’ lesions. This will also reveal if [18F]FSBG can also image hypoxia-induced redox changes in vivo.

Stage 4 - Can we selectively target metastatic lesions for treatment?

Finally, we will exploit the metabolic vulnerability of metastases through the selective therapeutic targeting of xCT. Following diagnostic xCT imaging, we will administer an xCT-targeting agent tagged with a therapeutic radionuclide, known as radioligand therapy.

The PhD student will use an xCT-specific radioligand that is currently in development in the Witney Group. It is envisaged that this development stage will be finished before the PhD student embarks on its use. We will evaluate whether and to what extent this form of xCT-targeted molecular radioligand therapy can improve survival in animal models of metastasis.

Eligibility Criteria

Home students only will be eligible for a full UKRI award, including fees and stipend.

Prospective candidates should have a 1st or 2:1 Masters-level qualification in biological sciences/biochemistry/molecular biology/cancer biology, together with some relevant practical experience working in a laboratory environment. Candidates must possess excellent knowledge in biochemistry, cancer cell biology, and molecular biology, and demonstrate the ability to work collaboratively as part of a multidisciplinary team. Previous experience with mammalian cell culture is essential, while experience in flow cytometry, biochemical enzyme assays, immunoblotting, and DNA work is desirable. Experience in small animal experimentation is beneficial but not a prerequisite.

We welcome eligible applicants from any personal background, who are pleased to join diverse and friendly research groups. 

Application Procedure

Please submit an application for the Biomedical Engineering and Imaging Science Research MPhil/PhD (Full-time) programme using the King’s Apply system. Please include the following with your application:

  • A PDF copy of your CV should be uploaded to the Employment History section.
  • A 500-word personal statement outlining your motivation for undertaking postgraduate research should be uploaded to the Supporting statement section.

Funding information: Please choose Option 5 “I am applying for a funding award or scholarship administered by King’s College London” and under “Award Scheme Code or Name” enter BMEIS_DTP. Failing to include this code might result in you not being considered for this funding.


Funding Notes

Candidates who meet the eligibility requirements for Home Fee status will be eligible to apply for this project. Home students will be eligible for a full UKRI award, including fees and stipend, if they satisfy the UKRI criteria below, including residency requirements. To be classed as a Home student, candidates must meet the following criteria:
· be a UK National (meeting residency requirements), or
· have settled status, or
· have pre-settled status (meeting residency requirements), or
· have indefinite leave to remain or enter.

References

1. Paoli P, Giannoni E, Chiarugi P. Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta. 2013;1833:3481-98.
2. Schafer ZT, Grassian AR, Song L, Jiang Z, Gerhart-Hines Z, Irie HY, et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature. 2009;461:109-13.
3. Faubert B, Solmonson A, DeBerardinis RJ. Metabolic reprogramming and cancer progression. Science. 2020;368.
4. Greenwood HE, Nyitrai Z, Mocsai G, Hobor S, Witney TH. High-Throughput PET/CT Imaging Using a Multiple-Mouse Imaging System. J Nucl Med. 2020;61:292-7.
5. Greenwood HE, Witney TH. Latest Advances in Imaging Oxidative Stress in Cancer. J Nucl Med. 2021;62:1506-10.
6. McCormick PN, Greenwood HE, Glaser M, Maddocks ODK, Gendron T, Sander K, et al. Assessment of Tumor Redox Status through (S)-4-(3-[(18)F]fluoropropyl)-L-Glutamic Acid PET Imaging of System xc (-) Activity. Cancer Res. 2019;79:853-63.
7. Pereira R, Gendron T, Sanghera C, Greenwood HE, Newcombe J, McCormick PN, et al. Mapping Aldehyde Dehydrogenase 1A1 Activity using an [(18) F]Substrate-Based Approach. Chemistry. 2019;25:2345-51.
8. Godet I, Shin YJ, Ju JA, Ye IC, Wang G, Gilkes DM. Fate-mapping post-hypoxic tumor cells reveals a ROS-resistant phenotype that promotes metastasis. Nat Commun. 2019;10:4862.
9. Fruhwirth GO, Diocou S, Blower PJ, Ng T, Mullen GE. A whole-body dual-modality radionuclide optical strategy for preclinical imaging of metastasis and heterogeneous treatment response in different microenvironments. J Nucl Med. 2014;55:686-94.

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