Treating Glioblastoma: Tricyclic antidepressants repositioned and administered as a cancer therapy by a novel nanoparticle delivery system in vitro.

Cancer is a disease that is rapidly increasing. The initiation and progression of cancer is a central topic of countless research with discoveries of multiple pathways implicated in formation and advancement of this debilitating disease. One of the most aggressive and deadly forms of cancer worldwide is undoubtedly Glioblastoma which affects the brain. Glioblastoma tends to be diagnosed at a very late stage with a 10-year survival rate of 0.71% (Tykocki T, Eltayeb M, 2018). Trying to identify a treatment for this devastating cancer is of the utmost importance. However, the issue with drug discovery is that it can take up to a decade to come to fruition after undergoing many legal and ethical obstacles. Drug repurposing is becoming increasingly popular in the context of disease treatment, as the risk of using current established therapies for other diseases and repositioning them for cancer treatment means lower development costs and less risk to the patient due to the compounds having already undergone safety and efficacy studies during numerous clinical trials (Jourdan et al 2020). The most obvious category of drugs to repurpose for Glioblastoma are those therapeutics known to have high Blood Brain Barrier (BBB) penetrance such as antidepressants (Lyne and Yamini 2021). Tricyclic antidepressants are promising, and several studies has shown an increase in cancer survival in mice when administering some members of the tricyclic family of compounds. tricyclic antidepressants such as imipramine or amitriptyline are thought to inhibit cancer cell proliferation by various means, including targeting receptor signalling and inducing apoptosis (Timilsina et al 2022, Chen et al 2023), however what is not known is how these drugs affect complex cancer signalling pathways and the efficacy of the delivery of these compounds. 

It is fully established that signalling pathways contribute and regulate the formation and progression of cancer, and many of these are involved in the progression and severity of glioblastomas. Two pathways which account for 90% of glioblastoma progression are the classical Receptor Tyrosine Kinase (RTK), PI3K, mTOR, Wnt and Hippo signalling pathways. The Hippo Signaling Pathway is an evolutionary conserved pathway with a key role as a regulatory pathway in organ growth control and maintenance (Piccolo et al 2013). The two main effectors, YAP and TAZ if dysregulated, can result in over proliferation and uncontrolled cell division and ultimately develop into advanced malignancy and in some cases cause drug resistance in glioblastoma. (Casati et al 2021). The second interlinked pathway comprising RTK, PI3K, mTOR, Wnt has been shown when targeted to inhibit growth and induce apoptosis in glioblastoma using pathway specific inhibitors (Omeljaniuk et al 2021, Barzegar Behrooz et al 2022). 

The aims of this project are threefold. The first aim is to try to identify the mechanism behind the use of novel compounds in glioblastoma by initially carrying out a small-scale screen on repurposed tricyclic antidepressants by assessing basic cancer traits such as proliferation, viability and invasion. The second aim of this project is to analyse improvements in drug delivery in vitro using nanoparticle delivery of compounds which potentially may enhance the efficacy and allow optimisation of the dosage of these compounds, the final aim is to investigate the effect of identified drugs candidates on key cancer signalling pathways to see if they can result in regression of the cancer. Inhibition of key cancer causing/progression pathways such as Hippo, RTK, PI3K, mTOR and Wnt by using repurposed drugs and if this may allow the development of key therapeutics to target cancers via key receptor signalling from commercially available alternative medication.  

This project will provide extensive training in a wide range of cell and molecular biology, biochemistry, and analytical techniques, including but not limited to Immunoblotting, Immunofluorescence, confocal microscopy, PCR, scratch-based assays, Mass Spectroscopy and potential RNA sequencing analysis. 

Applicants should have a first or upper second-class honours degree in a relevant area to the project. A Master’s degree or equivalent qualification or other evidence of research skills and experience is preferred. 

To apply for this project, please submit an application for October 2025 entry at this link (How to apply for a research degree (PhD, Professional Doctorate, MPhil, MA/MSc by Research) - Kingston University London) and ensure that you upload a document as part of your application that states you are applying for a studentship and the name of the project that you are applying for.