Oncolytic HSV1716 in combination with targeted anti cancer agents : identification of synergistic interactions and their mechanisms of synergy

Braidwood, Lynne (2016) Oncolytic HSV1716 in combination with targeted anti cancer agents : identification of synergistic interactions and their mechanisms of synergy. PhD thesis, University of Glasgow.

Abstract

Oncolytic viruses are multifunctional cancer agents with huge clinical potential, and recently the first Herpes Simplex Virus (HSV) oncolytic virus has been approved as a licensed cancer treatment. Increasingly, it is becoming apparent that no one cancer treatment is likely to be a ‘golden bullet’ – a treatment that, on its own is enough to cure all cancers. The answer seems to lie in combination therapies; by combining more than one type of treatment the chances of success, in terms of patient survival, increase.
The aim of the project was to investigate the potential of HSV1716 in combination with other anti-cancer agents. As there is a vast array of current and potential cancer therapies, a high throughput screen using a range of cancer cell lines spanning a number of indications currently of clinical interest to Virttu Biologics was set up. This exploratory screen revealed a number of interesting results – synergies between HSV1716 and other drugs were seen across a number of different classes of drugs. This thesis first describes this ‘fishing’ exercise, then investigates the mechanism of action by which a subset of those drugs, highlighted as acting either synergistically or enhancing the amount of cell death in combination with HSV1716, are acting.
mTOR inhibitors (targeted agent), doxorubicin (a chemotherapeutic) and two receptor tyrosine kinases, Sorafenib and Sunitinib, were identified in the screen. Subsequent analysis of these combination revealed that, despite the differences between the classes of drugs, all worked to greatly reduce viral replication, indicating that mechanisms other than viral oncolysis are killing cancer cells.
The mechanism by which these cells were dying was investigated, HSV1716 in combination with mTOR inhibitors increased levels of intrinsic, mitochondrial driven apoptosis.
Much of the observed enhanced cell killing was seen at low level of HSV1716 infection – where only 1 in 10 cells was infected with virus. It was postulated that there is also some form of secreted signal that sensitises non infected cells to apoptosis. If this is the case these cells may be sensitised to the effect of drugs – and hence the levels of cell killing would be increased relative to the non viral sensitised cells. The experiments detailed in this thesis indicate that this is indeed the case: HSV1716 infected cells secrete a ‘death signal’ that can be exported to non-infected cells. This signal itself increases cell death in non-infected cells but may also sensitise cells to the effect of drugs.
Within the clinic, oncolytic viruses are effective agents at reducing tumour bulk by viral oncolysis and promote an anti-tumour immune response. The work presented in this thesis suggests that the virus may also induce infected cells to secret a factor that sensitises the surrounding cancer cells, generally resistant to apoptosis, to become more sensitive to apoptosis. These sensitised cells are then more susceptible to the effects of other anti-cancer agents.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: oncolytic virus, herpes simplex virus, HSV1716, Seprehvir, anti cancer agents synergy.
• Subjects: Q Science > QR Microbiology
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: Graham, Professor Sheila
• Date of Award: 2016
• Depositing User: Dr Lynne Braidwood
• Unique ID: glathesis:2016-7999
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 Mar 2017 13:17
• Last Modified: 08 Nov 2017 11:42
• URI: https://theses.gla.ac.uk/id/eprint/7999

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