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Discovering drugs that can enhance the activity of oncolytic viruses in the treatment of platinum-resistant ovarian cancer


Barts Cancer Institute

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Dr M Lockley , Dr S Martin No more applications being accepted Competition Funded PhD Project (European/UK Students Only)

About the Project

The most common ovarian cancer histology is high grade serous cancer (HGSC), accounting for 70% of cases. HGSC is initially sensitive to platinum chemotherapies such as cisplatin and carboplatin but more than 80% of women subsequently relapse. Platinum-containing chemotherapy is used repeatedly during the disease course but women eventually die from untreatable, platinum-resistant cancer1,2. Immune-targeted therapies could potentially address this intractable clinical problem but as yet immune checkpoint inhibitors have not shown benefit in HGSC.

Oncolytic viruses are a novel form of immunotherapy. We have repeatedly demonstrated their efficacy in ovarian cancer3-5, including in chemo-resistant disease6. Unfortunately, clinical application has been hampered by the need for systemic administration of high viral titres, creating challenges in virus preparation within hospital pharmacies and putting patients at risk of severe treatment-related side effects. To address this, we employed a drug screening approach to identify compounds that synergise with replicating, oncolytic viruses in platinum-resistant HGSC and have already identified 25 potential hit drugs. Our compound library includes 1170 small molecules, 90% of which are marketed drugs and so any identified compound already has a toxicity profile and can quickly be taken to clinical trial.

The Clinical Fellow will explore the hit compounds that we have already identified in combination with oncolytic viruses that are undergoing clinical testing. We will exploit our extensive range of clinically relevant models7-9 and human samples to determine the mechanistic basis of our most effective combination and to potentially reveal new targets for future immune therapy combinations.

The Research Environment:
Dr Lockley (Primary supervisor) is a Clinician Scientist and Reader in Medical Oncology, specialising in ovarian cancer. The Fellow will join her successful laboratory research team in the Centre for Cancer Cell and Molecular Biology at the Barts Cancer Institute (BCI), where Dr Lockley and Dr Martin (2nd supervisor and Reader in Cancer Cell Biology) are deputy co-leads. Dr Lockley and Dr Martin have a longstanding, productive collaboration with a track record in supervising PhD students working on similar drug repurposing projects. All students from both their groups have submitted their PhD thesis within four years and generated at least one first author publication. In addition, Dr Lockley has supported her most recent Clinical Fellow to develop their PhD research into a clinical trial. Dr Lockley is a Postgraduate Clinical Tutor at BCI, responsible for monitoring and mentoring Clinical Fellows during their higher degrees, while Dr Martin leads the BCI postgraduate research degree programme as the Director of Graduate Studies (DGS). This supervisory partnership will ensure rigorous supervision and mentorship of the Clinical Fellow as well as supporting the delivery of robust research findings and timely award of a PhD degree.

The Fellow:
This project will suit a committed candidate with enthusiasm for carrying out a period of in depth and clinically-focused laboratory research towards a PhD. We will provide training in a range of cell biology techniques (cell culture, viral preparation, cell viability assays, western blot, qRT-PCR, siRNA, CRISPR-Cas9 gene editing, fluorescence activated cell sorting, xenograft models) as well as direct experience working with primary human tissue. Our aspiration is that the novel drug/virus combinations that the Fellow discovers will be incorporated in future clinical trials for women with high grade serous ovarian cancer and there is additional potential to uncover novel therapeutic targets. Some prior research experience, either lab-based or clinical, is desirable. A demonstrated ability to communicate well, work effectively within a team and maintain accurate records are all essential criteria.

How to apply
To apply, please click the 'institution website' button.

The successful candidate must be a registered clinician in the UK.

Funding Notes

These studentships will fund a student 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. Hoppenot C, Eckert MA, Tienda SM, Lengyel E. Who are the long-term survivors of high grade serous ovarian cancer? Gynecol Oncol 2018; 148(1): 204-12.
2. Bowtell DD, Bohm S, Ahmed AA, et al. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer 2015; 15(11): 668-79.
3. 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.
4. 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.
5. Leyton J, Lockley M, Aerts JL, et al. Quantifying the activity of adenoviral E1A CR2 deletion mutants using renilla luciferase bioluminescence and 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography imaging. Cancer Res 2006; 66(18): 9178-85.
6. 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.
7. Hoare JI, Hockings H, Saxena J, et al. Platinum resistance induces diverse evolutionary trajectories in high grade serous ovarian cancer.
Preprint (2020): https://www.biorxiv.org/content/10.1101/2020.07.23.200378v1
8. 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.
9. Walton JB, Farquharson M, Mason S, et al. CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity. Sci 017; 7(1): 16827.


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