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Investigating the upstream regulation of LMTK3 oncogenic kinase and elucidating its involvement in breast cancer progression


Project Description

LMTK3 is an oncogenic kinase whose expression levels has been implicated in cancer cell invasion, endocrine/chemotherapy resistance, poor prognosis and overall tumour progression in different types of malignancies. We initially described LMTK3 as a regulator of Estrogen Receptor alpha (ERα) able to protect it from ubiquitin-mediated proteasomal degradation. In a cohort of BC patients (n>600), LMTK3 protein levels and intronic polymorphisms were significantly associated with disease-free and overall survival and predicted response to endocrine therapy, data we validated in an Asian cohort where we also showed that LMTK3 is associated with more aggressive tumours and chemo-resistance in BC. Moreover, we have demonstrated the contribution of LMTK3 in BC invasion and migration via cross-talk between RTKs and integrins. Recently, we showed a new scaffolding function of LMTK3 that results in cancer progression through chromatin remodelling. Other groups have also published mechanistic/translational data in other tumour types/settings, validating these findings.
Since LMTK3 has been proposed as a potential new therapeutic target in breast cancer and considering its involvement in additional tumours, there is urgent need to:
A) Further decipher the signalling pathways that LMTK3 is implicated in and
B) Develop selective chemical tools/LMTK3 inhibitors and examine their effects in BC (in vitro/cell-based studies).
Ultimately, the elucidation of downstream LMTK3-signalling and the development/optimisation of LMTK3 inhibitors may have potential for broad clinical utility.
Amongst the primary objectives of this project will be to identify novel upstream pathways that are responsible for the activity of LMTK3. The identification of such genes/proteins will help us map LMTK3 in the tumour signal transduction pathways and will further lead to the development and optimisation of drugs targeting LMTK3.
A variety of biochemical, biophysical and structural biology techniques including crystallography and electron microscopy (Mancini lab) will be used for this work, in order to generate various LMTK3 truncated domains, that will be used as substrates for identifying upstream interacting proteins (eg. kinases that are able to phosphorylate certain key residues on LMTK3 that are important for its function) and elucidate their 3D structure/properties. In parallel, combination of different cellular/molecular biology techniques as well as specific in vitro and in vivo tools/models (Giamas lab) will allow to test the significance of our findings (e.g. 2D and 3D cell-based assays as well as cancer mouse models).
In addition, considering that the Giamas lab has already developed a novel small molecule LMTK3 inhibitor (as well as other derivatives), a major issue that needs to be addressed is related to the mechanism of action of these drugs and their further optimisation. The Mancini lab will provide extensive help for this objective via their expertise in structural biology (eg. setting up different co-crystallisation studies).

Funding Notes

A Ph.D. studentship (42 months) is available from 01/05/2020. This School funded position covers tuition fees and a stipend at standard RCUK rates and is open to Home / EU applicants.

Ideal candidates will have a strong background in cell signalling with additional experience of biochemistry. Eligible applicants will have recently received an MSc and/or a First or high 2:1 BSc in a relevant subject. Candidates for whom English is not their first language will require an IELTS score of 6.5 overall, with not less than 6.0 in any section.

For enquiries about the project, contact Prof Georgios Giamas ()

References

How to apply:

Please submit a formal application using our online application system at http://www.sussex.ac.uk/study/phd/apply, including a CV, degree transcripts and certificates, statement of interest and names of two academic referees. On the application system, use Programme of Study – PhD Biochemistry

Please make sure you include the project title and Supervisor’s name with your statement of interest on the application form.

Related Subjects

How good is research at University of Sussex in Biological Sciences?

FTE Category A staff submitted: 47.61

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