Tumour assassination – using smart targeted treatments to enhance anti-cancer radiation responses

After qualifying as a doctor, Professor Kevin Harrington started his first job in oncology, and knew straight away that this was where he was supposed to be. Head and neck cancers, which include tumours of the mouth, throat and voice box, grabbed his interest while he was a PhD student. “These cancers represent a diverse group of diseases with varied challenges for treatment and generally poor survival rates” Professor Harrington explains. “Head and neck cancers are perceived as one of the trickier cancers to treat, as delivering radiation to the affected area can be technically very challenging. But unlike many other cancers, head and neck cancers can be cured by radiotherapy; it’s just a question of delivering the radiotherapy effectively to the area.” 

Professor Kevin Harrington joined the ICR in 2001, and is now professor in biological cancer therapies at the ICR, and an honorary consultant clinical oncologist at The Royal Marsden NHS Foundation Trust. He has two areas of research interest: oncolytic virotherapy (the use of genetically modified viruses as selective cancer therapeutics) and the discovery and development of new drugs that enhance the radiation response in cancer cells.

It was during his PhD years that his interest in oncolytic virotherapy began. Here he used liposomes to target radiosensitisers - drugs that make tumour cells more sensitive to radiation therapy – directly to the tumour site. “The problem with using liposomes was that once the drug got there, we couldn’t do much else with it. It was by chance that the laboratory next door to me was working on gene therapy, and my colleague who was leading the group offered me a postdoctoral position in his new group at the Mayo Clinic where we looked into using viruses as a delivery system for therapeutic genes, some of which were able to enhance the effects of radiotherapy.”

Now, Professor Harrington is genetically altering a number of viruses so that they selectively destroy cancer cells. “Some viruses have naturally evolved to grow preferentially in cancer cells because of the cells’ specific genetic defects, but we can genetically modify others to grow selectively in cancer cells,” he reveals. “Not only do these modified viruses kill cancer cells directly, but they also trigger an immune response, just like a vaccine would, that helps eliminate residual cancer cells. Even more interestingly, our early stage research shows that some of these modified viruses also enhance the cytotoxicity of standard anticancer treatments by making cancer cells more sensitive to drugs or radiation, while the standard treatments may also favourably alter the effect of some viruses on cancer cells.”

Early trials using oncolytic virotherapy (given with chemoradiotherapy) have shown it to be effective compared with chemoradiotherapy alone. A modified form of the herpes simplex virus - the cold sore virus - is now being tested in Phase III trials both as a single agent therapy in patients with advanced malignant melanomas (the most deadly form of skin cancer), and also as a combination therapeutic with chemoradiotherapy in patients with head and neck cancers. Initial results from the malignant melanoma trial are expected in 2013. Reovirus - commonly found in humans’ respiratory and gastrointestinal tracts without causing any symptoms – has been shown to magnify the effects of radiotherapy and combination chemotherapy in laboratory tests, and is now in a Phase III trial in patients with relapsed head and neck cancers. “We are getting better at this area of research, and are seeing fewer side-effects and advanced rates of cure compared to current therapies. I hope these new targeted treatments using these viruses will improve patients’ outcome,” Professor Harrington states.

Testing novel targeted radiosensitisers both in the laboratory and clinical setting also interests Professor Kevin Harrington. Current work includes blocking the action of the heat shock protein HSP90. Silencing HSP90 using the compounds 17-AAG, DMAG and NVP-AUY922 stops tumours growing by preventing the activity of many cancer-causing proteins. Importantly, many of these proteins are also involved in helping cancer cells survive after a dose of radiation. So, by blocking HSP90, the cancer becomes extremely vulnerable to the combination of the drug and radiation. Checkpoint Kinase (Chk1) is another attractive target, as it plays a key role in a biochemical pathway responsible for reducing the effectiveness of traditional cancer therapeutics, such as chemotherapy and radiotherapy. Recently, Professor Harrington’s team has confirmed that a Chk1 inhibitor discovered at the ICR makes cancer cells very sensitive to the effects of radiation therapy. Therefore, giving a patient a Chk1 inhibitor and radiation at the same time could boost the radiation effect and improve outcomes.

Radiosensitisers have been given in clinical studies in patients with high-risk head and neck cancer. Trials include those in which drugs are given to patients before they go on to receive standard therapies (so-called window-of-opportunity trials), Phase I and II trials of lapatinib plus chemoradiotherapy, and a Phase III trial of lapatinib with post-operative chemoradiotherapy - data from this last study will be presented in the next year. Future areas of research will include a first-in-man Phase I study of a new ATR inhibitor in patients receiving palliative radiotherapy.

“My favourite part of the research process is when I am in the office doing tedious paper work, and a colleague will knock on the door with their latest research results. That first look at the data – that show you either that your hypothesis has been validated, or that you have to modify your thinking in ways that can give you new insights – is a huge thrill and gives me the motivation and drive to carry on my research.”