Francis Crick Institute
Crick Cancer Clinical Research Fellow Programme
Three-Year Clinical Research Training Fellowships 2016
Names of project supervisors:
Crick supervisor: Professor Michael Way
CRUK Centre/University supervisor: Professor Hani Gabra (Imperial College)
Title of research project:
Oncolytic Vaccinia virus treatment of ovarian cancer: finding
novel targets for combination therapies.
Description of the research project:
The poor outcome of advanced ovarian cancer to current interventions justifies
exploration of new therapeutic approaches to improve patient outcome. Oncolytic
viral therapies offer the potential to improve on existing treatments to combat
cancer. The poxvirus Vaccinia is being developed as an oncolytic agent given its
proven safety profile having been used as the vaccine to eradicate smallpox.
Moreover, it does not transform cells, accumulates in tumours and rapidly spreads
to metastases in vivo.
In particular, Vaccinia has a strong tropism for ovaries
and an intrinsic ability to kill ovarian epithelial cancer cells in mouse models
(Chalikonda et al., 2008; Whilding et al., 2013).
Current viral backbones that are used in clinical oncolytic trials have deletions in
the viral Thymidine Kinase (JX-594) or TK and Vaccinia Growth Factor, VGF (JX929/963) (Kim et al., 2009). These deletions increase the therapeutic index of
the virus but do not enhance its intrinsic cytolytic activity. More recent strains are
also “armed” to express non-viral proteins that increase anti-tumour activity
and/or attract immune cells. Another less explored approach is to design
recombinant viruses that increase their intrinsic oncolytic potential, especially
when combined with chemotherapeutic agents.
The Way Laboratory is investigating how Vaccinia inhibits cell death during
infection. We have found that two virus-encoded proteins, VGF and F1L, synergise
to prevent apoptosis during infection (Postigo et al., 2006; 2009). An RNAi screen
with a recombinant virus lacking these proteins has identified just over 100 hits
that accelerate virus-induced cell death. Many of these hits are targets for cancer
therapy in their own right, against which inhibitors are being developed or exist.
Using the information from our screen we aim to perform siRNA screens and
chemical inhibitor studies to identify molecular targets for combination therapy with
Vaccinia. The impact of infection with wild-type or recombinant virus on ovarian cancer
cell survival will be assessed after treatment with siRNA and/or in the presence of chemical
inhibitors. As proof of principle we have already demonstrated that one lead from our RNAi
screen is synthetic lethal with the recombinant virus, making it a potential candidate for
combination therapy with existing chemical inhibitors. Additional assays, with our other
candidate hits will be conducted on HeLa cells, an epithelial cell line routinely used for work
with Vaccinia, as well as a panel of well-­‐defined ovarian cancer cell lines including
PEO1, PEA1, PEO14.
In summary, the project constitutes an exciting innovative approach
to improve Vaccinia-based oncolytic strategies, and seeks to translate these basic findings
towards the clinic.
References:
1. Chalikonda S, Kivlen MH, O'Malley ME, Eric Dong XD, McCart JA, Gorry MC, Yin XY,
Brown CK, Zeh HJ 3rd, Guo ZS, Bartlett DL. (2008). Oncolytic virotherapy for ovarian
carcinomatosis using a replication-selective vaccinia virus armed with a yeast
cytosine deaminase gene. Cancer Gene Ther. 15:115-25.
2. Kirn DH, Thorne SH. (2009) Targeted and armed oncolytic poxviruses: a novel multimechanistic therapeutic class for cancer. Nat Rev Cancer. 9:64-71.
3. Postigo A, Cross JR, Downward J, Way M. (2006) Interaction of F1L with the BH3
domain of Bak is responsible for inhibiting Vaccinia-­‐induced apoptosis. Cell Death Differ.
13:1651-662.
4. Postigo A, Martin M, Dodding M, Way M. (2009) Vaccinia-induced EGFRMEK signaling and the anti-apoptotic protein F1L synergize to suppress cell
death during infection. Cellular Microbiology. 11:1208–1218.
5. Whilding LM, Archibald KM, Kulbe H, Balkwill FR, Öberg D, McNeish IA. (2013)
Vaccinia virus induces programmed necrosis in ovarian cancer cells. Mol Ther.
21:2074-2086.
Summarise the medical/clinical component of the research, as well as the relevance to
the Crick Cancer CRF programme:
Development of Vaccinia-based oncolytic viruses has focussed on increasing
their therapeutic index and enhancing immune activation by “arming” the genome
with host proteins. Our approach to identify specific (and preferentially druggable) hits
that synergize with a recombinant virus similar to those currently in clinical trials provides
fresh avenues to target ovarian cancer. The targets we have identified through synthetic
lethal approaches may also contribute to better systems oncology understanding of
ovarian cancer therapies.
The project provides an excellent opportunity for a clinical fellow to work on a basic
science-driven project that has immediate translational applications to improving patient
outcomes. Daily supervision will be provided by Dr. Antonio Postigo, a senior member of
the Way lab, who has extensive experience and knowledge of Vaccinia, regulation of cell
death and siRNA screens. Our collaborator Professor Hani Gabra, Deputy Head of the
Division of Cancer and Director of the Ovarian Cancer Acton Research Centre at
Imperial College will provide defined epithelial ovarian cancer cell lines and patient
samples. The first year will focus on target definition and validation in tumour cell lines.
In subsequent years, in collaboration with Professor Hani Gabra, we extend our findings
to appropriate xenograph and genetically engineered mouse models of ovarian cancer
and evaluate the effect of oncolytic viruses in patient--‐derived epithelial ovarian cancers
in vitro.
This collaborative project builds on the strengths of the partners and will provide the
candidate with an excellent training in basic biology, high throughput screening, systems oncology
and mouse models of ovarian cancer.
Project supervisors’ contact details:
Crick supervisor:
Name: Professor Michael Way
Telephone: 0207 2693733
Email: Michael.way@crick.ac.uk
CRUK Centre / University supervisor:
Name: Professor Hani Gabra
Telephone: +44 20 7594 2792
Email: h.gabra@imperial.ac.uk