Wednesday, January 26, 2011

Building bridges for tomorrow’s medicine

More than 16,000 new cases of cancer are diagnosed in Ireland each year. Despite aggressive treatment, for some of these patients, current cancer therapies will not enough to save their lives. But there is hope on the horizon. Buzzwords like “translational research”, “personalised medicine” and “smart drugs” now form part of a more optimistic lexicon describing new potential for effective, targeted approaches to cancer therapy.
Translational medical science is an exciting and rapidly evolving domain, and no where more so than in cancer research, which is now reaping the benefits of the translational approach to research. The primary goal of “translational” research is to integrate discoveries in the laboratory with clinical trials and observational studies in hospital and outpatient settings - taking pioneering developments more rapidly from the “bench-to-bedside”.

A team approach
A central strength is that translational research has fostered extensive cooperation between basic researchers, clinical investigators and the pharmaceutical industry. In cancer medicine, this broad-based partnership is generating many new and innovative, targeted treatments that work more effectively and with less toxicity.
This emerging field presents a promising future for cancer medicine, not only in terms of discovering potential cures, but also developing new diagnostic and prognostic tools as well as less toxic therapies that could add decades to a cancer patient’s life.
All Irish universities now have state of the art biosciences and translational research centres which integrate with the clinical research centres in Irish hospitals. For example, Molecular Medicine Ireland links five medical schools and their associated academic hospitals in a partnership that translates “eureka’ events in the lab into improved diagnostics and therapies for patients.

A driving force behind many of the Irish translational cancer research endeavours is ICORG - the All-Ireland Co-operation Oncology Research Group. ICORG is a national network of over 400 clinical and laboratory-based cancer researchers which has built up an enviable international research reputation over the last 13 years, securing affiliations with some of world’s leading cancer research centres and companies in the US and Europe engaged in clinical and translational cancer research.
In so doing, ICORG has also secured very early access for Irish cancer patients to the latest and most novel therapeutics available anywhere in the world.
For instance, ICORG is playing a pivotal role in the development and evaluation of a new test which may permit the individualisation of treatment of early stage (Node negative, estrogen receptor positive) breast cancer. This TAILORx trial has recently completed a global enrolment of over 11,000 breast cancer patients with the largest single recruitment site being in Ireland.
The study is evaluating the ability of a revolutionary new 21 gene test, called Oncotype Dx, to predict and distinguish patients who are likely to need more aggressive therapy from those who’s cancer is unlikely to spread and can therefore be saved the toxicity and side effects of this form of treatment.
Due to the huge clinical and patient interest in this molecular-based diagnostic tool and the diagnostic value of the test, a leading Irish insurance company announced late last year that it would cover the €3,180 test cost in all of its health insurance plans.

At the interface of basic and clinical research
Dr Robert O’Connor
“There’s no question that translational medicine is really the only way forward now in identifying better treatments and diagnostic tools for cancer, and our clinicians and scientists in Ireland are very active in this field,” confirms Dr Robert O’Connor, who is Biological Science lecturer and a Senior Programme Leader in Translational Cancer Pharmacology, at the National Institute for Cellular Biotechnology in Dublin City University (DCU).
“Translational research is at the interface of clinical and laboratory science. It focuses on developing new and safer medicines and diagnostic tools. We know clinically and scientifically that cancer is a very complex set of diseases. It’s not a specific disease; each cancer is individual to each patient. While some breast cancers, for example, respond very well to treatment in some women, other breast cancers don’t, even if the cancer is at the same stage and looks identical in other ways.
“This is where translational medicine is helping us to better individualise treatment, it’s helping to identify the molecular characteristics that give us the most information about that form of cancer, what is likely to happen to it and what treatments will be most effective.”
This is a two-way process with scientists and clinicians using advanced laboratory techniques to gather basic information on the important fundamental mechanisms underlying cancer and governing growth; progression and treatment response using cultured cell models, clinical samples from patients, and observing differences between normal and disease states, expression of disease biomarkers and response to therapy.
Such work is only meaningful when conducted in partnership with specialist clinical resources, which treat patients in a carefully controlled manner using international standards of treatment and research to collect clinical, diagnostic information and provide high quality patient samples.
One of the labs at the National Institute for Cellular Biotechnology, DCU
This direct collaboration between clinical staff and lab researchers promotes the discovery of disease biomarkers and drug targets that is resulting in more rational drug design, and more effective and safe treatments that can be quickly and efficiently introduced into medical practice via clinical trials.
“It’s taking laboratory research directly to patients. Where putative markers have been identified, you then want to see if it is a valid marker in ‘real’ cancer because, as scientists, we can develop a nice hypothesis in the lab but cancer, in reality, is a lot more complex in the patient,” says Dr O’Connor.
This approach to coordinated translational research has led Irish researchers identifying important new diagnostic markers such as the proteins urokinase plasminogen activator and plasminogen activator inhibitor 1, whose significance in breast cancer treatment was first identified by Professor Joe Duffy, St Vincent’s University Hospital Dublin.

Focusing on emerging anti-cancer drugs
“Until about ten years ago any investigation of a new drug would have gone through a standard development process. A new drug for breast cancer would have gone into a clinical trial of breast cancer patients; the trial would run its course over months or years and after an evaluation was conducted, the researchers would report on the response rate in the whole patient population.
“Nowadays, translational medicine is allowing us to take a closer look at the individual tumours within those breast cancer patients. We can look at additional information to see if there is more we can learn about the treatment, for example, can we identify markers that will tell us which patient will respond or which patients will not? And can we find markers that will tell us early on that the patient has responded to treatment?
“This is very important because many of our tools in clinical cancer research only give information on treatment response several months after treatment begins. This is extremely valuable time as, in some advanced malignancies, it is all too common for the first type of treatment given to have limited effect and therefore patients may be exposed to side effects and toxicity while the agent itself is not helping shrink their tumour and this may only become evident months later. Translational research is providing tools that indicate upfront which patients should or should not receive particular treatments and more rapidly identifying those responding to treatment - and should therefore continue - from those nor responding and should therefore move to another treatment option.
“So translational medicine tries to identify new targets for treatment, new markers that will indicate whether treatment is working or not, and new ways of conducting trials,” he explains.

Biological markers
Biomarkers are molecular characteristics of precancerous or cancerous cells that can aid in predicting cancer development, behaviour, and prognosis. Biomarkers can be grouped into three major categories: diagnostic, prognostic, and predictive.
Diagnostic markers aid in diagnosing disease, such as measurement of the rate of change of PSA levels in prostate cancer or CA-125 in ovarian cancer. Prognostic markers, such as hormone receptors, angiogenic markers, growth factor receptors and proliferation markers, provide information about the likely clinical course of a disease. Predictive markers can help anticipate the course of a disease and how a patient may respond to particular types of therapy. Together with diagnostic and prognostic markers, predictive markers can help physicians formulate a more individualised treatment plan.
“Our clinical trials are moving now away from being focused purely on the anatomical type of cancer that a patient has, whether its breast or brain cancer, for example, to examining the cancer’s molecular characterisation,” says Dr O’Connor.
“It is an evolving area. In a lot of cases now we are starting to get a handle on some of those indicators. We are making discoveries now that may provide us with the tools in the not-too-distant-future to molecularly characterise a person’s cancer and identify the best possible treatment for that particular patient.”
An illustrative case is the identification in 1987 of the human epidermal growth factor receptor 2 (HER2) gene, which is present in about 20% of cases of invasive breast cancer.
Interestingly, the team which identified this protein is led by Professor Denis Slamon, at the UCLA Department of Medicine, who has since been collaborating closely with a number of Irish cancer research institutions to further research on breast cancer.
HER2 is part of a family of genes that play roles in regulating cell growth. Women whose breast cancer had more copies of the HER2 gene spread the fastest and had a worse prognosis.
“When it was originally discovered HER2 was a negative prognostic marker. If your breast cancer demonstrated the over expression of this marker there was a likely to be a poor outcome due to rapid growth of that tumour. But using translational research methods, treatments were developed specifically to target and inhibit the HER2 protein,” Dr O’Connor says. “In some cases it appears that this has given rise to cure, but in the majority of cases what it means is that patients can be given a much less toxic treatment over a long duration that will basically manage and control their breast cancer much more effectively.”
In another exciting development, progress has been made in a treating a particular subtype of lung cancer. In approximately 3 to 5% of Non Small Cell Lung Cancers NSCLC - the most common form of lung cancer - a gene called ALK-1 is found to have fused with another (EML4) and the product drives the growth of this tumour.
In these patients, a recent study found that 90% responded to treatment with a new ALK-targeting drug called Crizotinib. This response is all the more noteworthy as NSCLC generally responds very poorly to standard forms of treatment.
This initial success with Crizotinib is a good illustration of the ultimate goal for translational research; to marry the identification of specific tests, which characterise individual cancers with the novel agents and therapeutic strategies that will achieve high efficacy with minimal toxicity in that specific molecular form of cancer.

Building bridges to the medicine of tomorrow
Examples of other such successes are emerging with increasing regularity in other forms of cancer. This revolution in biotechnology and interdisciplinary collaboration has become critically important in adding to the armamentarium of anti-cancer therapies. Its potential is reflected in the fact that most of the clinical trials in Ireland run by ICORG have a translational component.
National Institute for Cellular Biotechnology, DCU
“Advances in this field can be a frustratingly slow sometimes for patients, their families and researchers. But conducing this research to the highest possible standards is essential, and this takes time,” Dr O’Connor notes. “In the lab we can get results relatively quickly, but clinical research often takes quite a bit longer, because of the complexities of cancer in patients and the vital safeguards that must be employed. It is very satisfying, however, for any researcher to see a hypothesis that developed in the lab, be taken to patients in Irish hospitals in a clinical trial and for any positive result to be found.
“On the negative side, very few people actually understand what translational medicine is and its unique importance in this field. It is only in the last two years that we have started to see funding agencies begin to specifically support this kind of research. The funding environment and the support structures in the hospitals and industry are also still in their infancy.”
Yet, translational research in recent years has yielded not only significant advances in cancer therapeutics but also improvements in the ability of doctors to predict the clinical course of a patient's disease based on individual tumour characteristics.
This collaboration of scientists and doctors, companies and patients, is vital in translating laboratory findings into clinically applicable therapies.
“Translational medicine is always a team approach; it’s never one individual,” stresses Dr O’Connor. “You can have a charismatic leader or advocate, vital for maintaining the momentum but in reality it’s always a team approach. Having good integration between the research nurses, the medical staff, the scientists, the regulatory authorities and pharmaceutical companies, that’s where we are really making advances in Ireland. We’re coming together as a group, a co-operative, and that allows us to do things in an exciting way that we just couldn’t do on our own.”

USEFUL Web links:

All Ireland Cooperative Research Group

The National Institute for Cellular Biotechnology

Molecular Medicine Ireland

Translational research pioneer Professor Dennis Slamon

Further information on Crizotinib

HRB-SFI Translational Research Awards

Oncotype Dx breast cancer test

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