Cancer Research at Bath (CRAB)

Newest developments in cancer research in and around Bath

Posts By: Ellie Childs

The link between smoking and cancer

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Tobacco smoking is the single largest extrinsic risk factor for cancer in developed countries, causing almost one in five cases of cancer and 28% of cancer-related deaths in the UK in 2005. Worldwide, smoking causes more cancer deaths than all other known risk factors, and causes even more deaths from vascular and respiratory diseases than from cancer.

The most common cancers worldwide are those of the lung, breast and colorectum, while the most common causes of cancer-related death are lung, stomach and liver cancers. Lung cancer is thus of particular concern as not only is it one of the most common cancers, it is also one of the most common causes of cancer death. It was reliably established in the 1950s that the major cause of lung cancer is smoking tobacco, particularly cigarettes, with more than 4 in 5 lung cancer cases in the UK being caused by smoking. Smoking also increases the risk of at least 13 other cancers, including: larynx (voice box), oesophagus, mouth and pharynx (upper throat), bladder, pancreas, kidney, liver, stomach, bowel, cervix, ovary, nose and sinus, as well as some types of leukaemia. In the past few decades, it has also been increasingly clear that there is also cancer risk from second-hand smoking.

Cumulative risk of death from lung cancer in men at ages 45-75 years

Cumulative risk (%) of death from lung cancer (in the absence of other causes of death) in men at ages 45-75 years: in continuing cigarette smokers, ex-cigarette smokers who stopped at age 50 or age 30 and lifelong nonsmokers, based on lung cancer death rates for men in the United Kingdom in 1990. Taken from: Peto, R., Darby, S., Deo, H., Silcocks, P., Whitley, E. & Doll, R., 2000. Smoking, smoking cessation and lung cancer in the US since 1950: Combination of national statistics with two case-control studies. Br. Med. J., 321, pp.323-329.

Tobacco consumption was originally popularised in America, then in Europe in the 16th and 17th centuries, and subsequently globally. Cigarettes, which became the most common method of smoking tobacco in the 20th century, have been shown to be significantly more dangerous than the pipe or cigar smoking common in the 19th century. The spread of cigarette smoking in some countries during the 20th century was driven by tobacco companies themselves.

More recently, major efforts have been made in some countries to discourage smoking to some success - for example, cigarette consumption has been halved in a few countries (including the USA, the UK, Canada and France) over the past few decades. However, consumption has increased rapidly in many developing countries, and over one billion people currently smoke worldwide, with 30 million young adults taking up the habit each year. The emergence of increasingly large multinational tobacco companies with global reach could lead to even greater consumption in the future.

Based on current smoking patterns, smoking is expected to cause about 150 million deaths in the first quarter of the 21st century, and 300 million in the second quarter. Thus, helping large numbers of smokers to quit and many young adults not to start smoking in the first place in the next couple of decades could avoid hundreds of millions of smoking-related deaths.

Projected numbers of death from smoking in 21st century.

Projected numbers of deaths from tobacco smoking during the twenty-first century. Taken from: Prabhat, J., 2009. Avoidable global cancer deaths and total deaths from smoking. Nature Reviews Cancer, 9, pp.655-664.

At the 13th CR@B Symposium on 27th April, Dr Jenny Hatchard, Research Associate in the Department for Health at University of Bath, spoke about how tobacco companies are the vector of smoking-related cancers.

Other topics that will be covered by speakers from several different universities and RUH Bath include: integration of approaches in behavioural science and cancer research, synthesis of multimodal PET and SPECT imaging agents towards hypoxia-selective inhibitors, symptom appraisal of pain and cancer survival, and the influence of tumour microenvironment on drug response and targeting tumour stroma.

 

Inside cancer: how genes influence cancer development

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'Inside cancer: how genes influence cancer development' is a free, introductory online course developed by researchers at University of Bath, on the FutureLearn platform.

Inside Cancer aims to be a beginner's guide to cancer genetics, targeted at anyone interested in the topic - from sufferers to academics. The course is now running in its second year, being available in the spring and autumn of each year, and has already had over 30,000 participants, from more than 90 countries.

Inside cancer main

Inside Cancer's main page on FutureLearn.

It is entirely a collaborative effort, with many leading researchers from the University of Bath and consultant oncologists from Royal United Hospital in Bath involved in its teaching, many of whom are CR@B members. When Inside Cancer was first designed, all of the academics sat down together at the first session to decide its structure, and that is the format that remains today.

The course is six weeks long, structured into four main sections: basic principles of cancer (week 1); the genetics of cancer, DNA mutations and their importance, and epigenetics (week 2); cell signalling and typical hallmarks of cancer (weeks 3-4); and finally diagnostics and cancer therapy (weeks 5-6).

The course team behind Inside Cancer from University of Bath. Many consultants from Royal United Hospital in Bath are also involved in the course.

The team of University of Bath researchers behind Inside Cancer. Many consultants from Royal United Hospital in Bath are also involved, particularly in the later weeks.

Additionally, every year, a clinical oncologist is invited to give a live lecture to end the course, most recently Dr. Tania Tillett, a consultant medical oncologist from Royal United Hospitals Bath, who spoke about malignant melanoma (a type of cancer that develops from pigment-containing cells known as melanocytes, often occurring in the skin). Gordon McVie, former Director General of Cancer Research UK (1996-2002), gave the first lecture in the series when the course first began. He, along with Umberto Veronesi, also established ecancer.org, a website dedicated to both cancer professionals and patients for news, research, e-learning and videos in the field.

The lead educator, Dr. Momna Hejmadi, a Senior Fellow in the Department of Biology & Biochemistry at University of Bath, wanted to run this MOOC (Massive Open Online Course) due to a personal interest in free and global education for all. It began as a 'trial run', being the first FutureLearn course developed at University of Bath, and has been extremely well-received by learners, with 98% of participants saying that they would recommend the course. A major part of the FutureLearn approach is discussion with others on the course, and the 'buzz' around the content and seeing their benefit has been extremely rewarding for the educators.

Registration for the upcoming Inside Cancer course is now open, to start on March 7th.

 

 

Recent developments in cancer research: an overview

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Cancer research has yielded huge gains, leading to longer lives and improved quality of life for the millions of people diagnosed with the disease globally each year. Just 11 days ago, on World Cancer Day, Cancer Research UK announced that cancer death rates have fallen by almost 10% in the last ten years in the UK. In the following, a few examples of key recent advances will be described, including immunotherapeutic approaches, traditional treatment methods and targeted therapies.

Fast development in cancer immunotherapy

In recent years, cancer immunotherapy – treatments that enhance the immune system’s ability to fight cancer – have become a major area of research and seen their potential begin to become realised.

At the 10th CR@B Symposium, Dr. Joseph Dukes, Head of Preclinical Biology at Immunocore Ltd, spoke about his company's work on bi-specific drugs based on T-cell receptors that bind to human leukocyte antigen (HLA) peptide on cancer cells and recruit and re-direct host immune T-cells, which kill the target by apoptosis (programmed cell death). Immunocore's lead candidate, IMCgp100, potently re-directs T-cells to kill gp100-expressing tumour cells, does not cross-react with normal cells that do not express gp100, and shows signs of durability and promising efficacy; thus acting as an interesting approach for anti-cancer targeted immunotherapy.

Durability of IMCgp100 - CT scans of a patient over one year of treatment at maximum tolerated dose (MTD). Taken from: Dukes, J., 2014. 'ImmTACs: Bi-specific TCR-anti-CD3 fusions for potent redirected killing of cancer cells.' Paper presented at 10th CR@B Symposium, Bath, 12 November.

Durability of IMCgp100 - CT scans of a patient over one year of treatment at maximum tolerated dose (MTD). Taken from: Dukes, J., 2014. 'ImmTACs: Bi-specific TCR-anti-CD3 fusions for potent redirected killing of cancer cells.' Paper presented at 10th CR@B Symposium, Bath.

Last April, it was found that patients with advanced melanoma had a better response to a combination of two immunotherapeutic drugs, ipilimubab (Yervoy) and nivolumab, than ipilimubab alone, although there were higher rates of serious side effects in patients receiving the combination therapy.

Kaplan-Meier curves for progression-free survival in patients with wt-BRAF tumours treated with the combination regimen or iplimumab alone. Taken from: Postow, M.A., et al., 2015. Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. The New England Journal of Medicine, 372, pp. 2006-2017.

Another immunotherapy drug, pembrolizumab, displayed improved tumour response and survival rates, again in melanoma patients, and also showed promising early results in treatment of advanced lung cancer - the leading cause of cancer-related death worldwide.

One study on prostate cancer in mice published last August suggested that magnetic fields from an MRI (which are normally used to give an image of the tumour to provide information about its size and localisation, not in treatment itself) could direct cancer-fighting viruses to tumours, through addition of super para-magnetic particles iron oxide nanoparticles to modified immune cells that carry the virus.

Representative RARE images for MDM+OV with or without magnetic resonance targeting (MRT) show a marked difference in tumour size at the beginning and end of therapy. Taken from: Muthana, M., et al., 2015. Directing cell therapy to anatomic target sites in vivo with magnetic resonance targeting. Nature Communications, 6, p. 11.

Representative RARE images for MDM+OV with or without magnetic resonance targeting (MRT) show a marked difference in tumour size at the beginning and end of therapy. Taken from: Muthana, M., et al., 2015. Directing cell therapy to anatomic target sites in vivo with magnetic resonance targeting. Nature Communications, 6, p. 11.

Use of such oncolytic viruses is one of many methods being explored in cancer treatment, but, until now, precise targeting has been a major obstacle in its success, so this method of directing cell therapy using magnetic resonance targeting may overcome the problem. Further studies, however, are required to test if the approach is successful in humans, particularly for tumours located deep within the body.

Advance in treatments

In addition to the successes with immunotherapy, there have also recently been significant advances in well-established treatments, such as surgery and chemotherapy. One example is the use of a novel approach with low-intensity electrical fields to prevent growth of tumour cells trialled on patients with newly-diagnosed glioblastoma multiforme, a highly common brain cancer with a very low survival rate (<3-5% after 5 years). These 'tumour-treating fields' were shown to delay disease progression and increase two-year survival rates compared to patients undergoing standard therapy (brain surgery followed by radiotherapy and chemotherapy).

Targeted therapies, which precisely target and attack cancer cells with little damage to normal cells, were also reported to have many successful developments. In 2012, it was first reported that a mutation resulting in the activation of Bruton's tyrosine kinase (BTK), which promotes rapid division of tumour cells, occurs frequently in patients with Waldenström's macroglobulinemia (WM), a rare type of lymphoma. By April last year, it was shown that use of a specific inhibitor of BTK triggers apoptosis of WM cells with that mutation, with high response rates and a 95% two-year survival rate.

Kaplan-Meier curves for progression free (A) and overall survival (B) in 63 previously-treated patients with Waldenström's macroglobulinemia when treated with iprutinib, a small molecule inhibitor of BTK. Taken from: Treon, S.P., et al., 2015. Ibrutinib in Previously Treated Waldenström's Macroglobulinemia. The New England Journal of Medicine, 372, pp.1430-1440.

Kaplan-Meier curves for (A) progression-free and (B) overall survival in 63 previously-treated patients with Waldenström's macroglobulinemia when treated with iprutinib, a small molecule inhibitor of BTK. Taken from: Treon, S.P., et al., 2015. Ibrutinib in Previously Treated Waldenström's Macroglobulinemia. The New England Journal of Medicine, 372, pp.1430-1440.

As with many diseases, drug resistance is a key problem in cancer treatment. Precision medicine approaches, based upon ever-increasing knowledge of the molecular basis of cancer and mechanisms of drug resistance, have made marked gains in overcoming treatment resistance in a range of difficult-to-treat cancers, including blood, ovarian, lung and breast cancers.

Active role of Cancer Research at Bath

Cancer Research at Bath (CR@B) itself has been involved in the publication of over 40 journal articles within the last year alone. One recent study, funded in part by CR@B and published less than two weeks ago, investigated so-called 'junk' non-coding DNA to find that GNG12-AS1, a stretch of non-coding RNA transcribed from junk DNA, prevents uncontrollable cell division and suppresses metastasis (the spread of cancer from its primary site to other parts of the body). The area where GNG12-AS1 is located in the genome is often damaged in breast cancer patients, so regulation of cellular growth is lost and the cancer cells migrate.  The research was published in Nature Communications on 2nd February 2016.

If you'd like to read more about recent discoveries and developments in cancer research, this year's annual reports produced by the American Society of Clinical Oncology and Cancer Research UK in particular were extremely useful in the compilation of this overview, and contain a wealth of interesting studies that I was unable to include!