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Repurposing drugs to enhance the activity of oncolytic viruses in platinum-resistant ovarian cancer


Project Description

We are seeking applications for a fully-funded PhD fellowship for clinically qualified candidates to commence in October 2020. The Fellowship will be supervised by Dr. Michelle Lockley (https://www.bartscancer.london/staff/dr-michelle-lockley/), a Clinician Scientist and Consultant Medical Oncologist, who leads a translational research group at Barts Cancer Institute. Dr Lockley and her team aim to improve treatments for women with advanced and chemotherapy-resistant ovarian cancer. This project will build on established research within her group to develop novel immune-based combination therapies.
Oncolytic adenoviruses are an exciting new class of immunotherapeutic agent with promising activity. Unfortunately, clinical adoption has been compromised in ovarian cancer by the need for systemic administration of high viral doses, which can cause severe toxicities in patients. To address this we have used a drug repurposing approach to discover existing, clinically-tested compounds that can enhance the activity of oncolytic adenoviruses. This project will extend our successful strategy for validating and mechanistically interrogating these hit drug/virus combinations, focusing on oncolytic adenoviruses that are already being evaluated in international Phase III clinical trials, including one for with Dr Lockley is UK Chief Investigator. To ensure clinical application of our findings, hit drug/virus combinations will be tested in accurate preclinical ovarian cancer models that we have already developed and characterised. Finally, we will functionally interrogate the mechanisms that underpin our top virus/drug combinations as this might potentially reveal new therapeutic targets for future immunotherapy combinations. This integrated approach, using clinically available drugs and oncolytic viruses, together with our range of accurate ovarian cancer models and primary tissue, will facilitate rapid clinical translation. The Barts ECMC will be invaluable in supporting the development of clinical trials of our new drug/virus combinations.

The Fellow will be embedded in a dynamic team within the Barts Cancer Institute and we will support them to develop expertise in a range of laboratory techniques. They will also have the opportunity to work with primary human tissue. Previous clinical fellows and PhD students in Dr Lockley’s group have all attended and presented their work at International conferences and contributed to high impact publications. Dr Lockley’s current Clinical Fellow has begun to progress her research findings to a clinical trial in collaboration with the National Cancer Research Institute Gynae work stream. Our expectation is that, upon project completion, this Fellowship will also lead to the development of a clinical trial testing our top virus/drug combinations.

Funding is for three years at current, MRC rates and will include PhD fees (at home/EU levels) and up to £6000 pa for consumables. Further consumables / funding for travel may be available on application.

Funding Notes

The Trustees of The Medical College of Saint Bartholomew’s Hospital Trust (MCSBHT) have offered funding for three research studentships (two in medicine and one in dentistry), for clinically qualified candidates within the Barts and The London School of Medicine and Dentistry to commence in October 2020, leading to a PhD degree.

Funded studentships will be open to potential students with a clinical qualification and GMC / GDC registration at any career stage below consultant. They will be funded for three years at current, MRC rates. Studentships will include PhD fees (at home/EU levels) and up to £6000 pa for consumables. Further consumables / funding for travel may be available on application.

References

1. Browne A, Tookman LA, Ingemarsdotter CK, et al. Pharmacological Inhibition of beta3 Integrin Reduces the Inflammatory Toxicities Caused by Oncolytic Adenovirus without Compromising Anticancer Activity. Cancer Res 2015; 75(14): 2811-21.
2. Lockley M, Fernandez M, Wang Y, et al. Activity of the adenoviral E1A deletion mutant dl922-947 in ovarian cancer: comparison with E1A wild-type viruses, bioluminescence monitoring, and intraperitoneal delivery in icodextrin. Cancer Res 2006; 66(2): 989-98.
3. Ingemarsdotter CK, Tookman LA, Browne A, et al. Paclitaxel resistance increases oncolytic adenovirus efficacy via upregulated CAR expression and dysfunctional cell cycle control. Mol Oncol 2015; 9(4): 791-805.
4. Hoare J, Hockings H, Saxena J, et al. Platinum resistance induces diverse evolutionary trajectories in HGSOC. In preparation 2019.
5. Walton J, Blagih J, Ennis D, et al. CRISPR/Cas9-Mediated Trp53 and Brca2 Knockout to Generate Improved Murine Models of Ovarian High-Grade Serous Carcinoma. Cancer Res 2016; 76(20): 6118-29.

How good is research at Queen Mary University of London in Clinical Medicine?

FTE Category A staff submitted: 144.11

Research output data provided by the Research Excellence Framework (REF)

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