PhD project: Hallden2020-10-03T15:17:18+00:00

A novel strategy to eliminate solid cancers by combining oncolytic adenoviruses and epigenetic drugs to activate the host anti-tumour immune-responses.

Primary Supervisor: Dr Gunnel Halldén, Centre for Biotherapeutics and Biomarkers, Barts Cancer Institute, QMUL

Secondary Supervisor: Dr Michelle Holland Department of Medical and Molecular Genetics, King’s College London

Background: Late-stage pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC) are aggressive cancers of unmet medical needs. Major reasons for the poor treatment outcomes are the development of resistance to all current treatments including immune-checkpoint inhibitors. A promising therapeutic approach is oncolytic adenoviruses (OAds) that kill cells through unique mechanisms. Our cancer selective replicating OAd mutants specifically kill cancer cells by lysis in turn recruiting and re-activating host anti-tumour immune responses. In our preclinical models, intratumoural delivery efficiently inhibited tumour growth while systemic delivery was less efficacious due to neutralization by blood factors. To eliminate distant metastatic lesions, administration directly into the blood-stream is necessary and further engineering of the OAds to resist blood factor interference are underway. We found that retargeting of the viruses to specific tumour antigens in combination with enhancers of viral replication resulted in high uptake at distant tumour sites. We previously demonstrated that OAds re-sensitised treatment-resistant PDAC cells to apoptosis inducing chemotherapeutics resulting in elimination of resistant tumours. Currently, we have found that less toxic drugs such as those altering the epigenome significantly increased viral activity and cancer cell killing in response to the OAds.

The PhD project will focus on identifying epigenetic compounds that enhance viral efficacy and delineating the mechanisms. The overall goal is to develop improved therapies for patients afflicted by PDAC and TNBC. During infection with adenovirus, viral proteins reprogram the host cell epigenetics to change the distribution of specific host histone marks (e.g. histone acetylation) across the genome. This redistribution alters the genes expressed in the infected cell to shut off host genes that respond to limit infection and activate genes that cause the cell to enter the cell cycle. These events are absolute requirements for adenovirus propagation and occur during specific stages of the viral life cycle by regulated expression of viral genes. One example is the viral E1A protein that directly binds to host p300/CBP, facilitating the redistribution of histone marks to silence some groups of genes and switch others on.

In this project, genome-wide profiles of these marks and how they are altered soon after infection with the OAds will be generated using a cutting edge high-throughput sequencing based approach called ‘cut and run.’ This will provide insight into how viral proteins manipulate the host genome and identify key genes and pathways involved in the setting of therapeutic OAds. This data will be combined with a screen to determine which epigenome-targeting drugs are most effective at promoting viral replication, specifically in cancer cells. Collectively, this will provide the basis to select target pathways for functional validation (e.g. siRNA/viral mutants/small molecules). Understanding these pathways will pave the way towards developing even more specific drugs to enhance the anti-tumour activity of the oncolytic viruses. The findings will be validated in preclinical tumour models in healthy mice or those with a compromised immune response.

We are looking for an enthusiastic hard-working student with a BSc or MSc in biology, virology, molecular biology or similar. A strong interest to learn and apply bioinformatics to genomics, oncology and virology is desirable.

Potential research placements

1. Training in molecular biological techniques, including extraction of DNA/RNA, QC and preparation of high-throughput sequencing libraries. This will be in parallel to training in both R/python and analysis of publicly available ChIP-seq data following adenoviral infection for comparison for self-generated data in the later stages of the project. Dr Holland, KCL.

2. Training in basic laboratory techniques such as mammalian cell culture, flow cytometry, immunohistochemistry and PCR. Thorough training in all virus-related techniques including mutant construction, production and characterisation. Design of in vivo studies and evaluation using small animal imaging will be an essential part of the training. Dr Halldén and Dr Tizong Miao, BCI, QMUL.

3. Basic computerised programming for complex analysis of data derived from own experiments and from databases. The student will be exposed to working as part of big multidisciplinary team focused on bioinformatics, developing databases for PDAC and mining of data networks for validation in wet labs. Prof Claude Chelala, BCI, QMUL.

The funding for this studentship covers students with home tuition fee status only. For more information on home tuition fee status please visit the UKCISA website. Please note that we will only be able to offer studentships to candidates that have home tuition fee status or provide evidence that they can fund the international portion of the tuition fee from external sources (i.e. not self-funded).

References

1. Man, Y.K.S., et al., Systemic delivery and SPECT/CT in vivo imaging of 125I-labelled oncolytic adenoviral mutants in models of pancreatic cancer. Sci Rep Sep 6;9(1):12840. doi:10.1038/s41598-019-49150-9. (2019)

2. Baker, A.T., et al., Designer Oncolytic Adenovirus: Coming of Age. MDPI Cancers, 10(6)201; https://doi.org/10.3390/cancers10060201 (2018)

3. Man, Y.K.S., et al., The novel oncolytic adenoviral mutant Ad5-3Δ-A20T retargeted to αvβ6-integrins efficiently eliminates pancreatic cancer cells. Molecular Cancer Therapeutics. 17:575-587. doi: 10.1158/1535-7163.MCT-17-0671. (2018)

4. Aguirre-Hernández C, et al., Sensitisation to mitoxantrone-induced apoptosis by the oncolytic adenovirus AdΔΔ through Bcl-2-dependent attenuation of autophagy, Oncogenesis, Jan 24;7(1):6. doi: 10.1038/s41389-017-0020-8 (2018)

5. Pantelidou C, et al., The E1B19K-deleted oncolytic adenovirus mutant AdDelta19K sensitizes pancreatic cancer cells to drug-induced DNA-damage by down-regulating Claspin and Mre11, Oncotarget, Mar 29;7(13):15703-24. doi: 10.18632/oncotarget.7310 (2016)

For any informal enquiries regarding the project please contact Dr Gunnel Hallden: g.hallden@qmul.ac.uk
For any general enquiries relating to the CRUK CoL Centre training programme please contact Annabelle Scott: annabelle.scott@ucl.ac.uk
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