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Lung cancer: Trinity scientists are hopeful of new treatments

Lung cancer is the most common cause of cancer deaths in Ireland, affecting both men and women. More than 2,700 new cases are diagnosed annually, equivalent to more than seven new patients in Ireland each day. Unfortunately, many patients with lung cancer are diagnosed in the later stages as there is no lung screening programme in place. Whilst we typically associate lung cancer with cigarette smoking, even those who have never smoked can develop this cancer, making up about 15% of all cases. This is an increasing problem - the National Cancer Registry predicts that lung cancer will increase significantly by 2040, especially among women.

To coincide with World Cancer Day we spoke to Dr Martin Barr, an award-winning Clinical Scientist and Clinical Senior Lecturer at the Thoracic Oncology Research Group at the Trinity St James’s Cancer Institute, about his research into drug resistance and the development of new drug candidates for this disease. Patients with early-stage lung cancer usually undergo surgery with the aim of curing them of cancer. For those with more advanced disease, additional treatment is required, and resistance to cancer drugs poses an enormous challenge to doctors. Dr Barr explains:

In patients with advanced disease, treatment options include chemotherapy which is given alone, or in combination with targeted or immune therapies. This largely depends on the presence of mutations or abnormal proteins present on tumour cells. In the clinic, drug resistance has become a significant challenge for oncologists. While anti-cancer therapies work by killing tumour cells within the tumour, a rare subgroup of cells, known as cancer stem cells, continue to grow and divide even in the presence of cancer treatments. This results in tumour recurrence and disease progression which often proves fatal.”

Researchers spend a lot of time and money on developing new drugs, and many of those new therapies are found to be ineffective after years of research. For this reason, the use of drugs that are already used for other diseases (and are therefore known to be generally safe and tolerated) represents an attractive option for researchers. These drugs may be tested as anti-cancer therapies which tend to be a quicker and cheaper alternative. One such drug, Disulfiram, has shown promise for lung cancer.

Our research has shown that the FDA-approved drug, Disulfiram (Antabuse), kills lung cancer cells that have stopped responding to the chemotherapy drug, cisplatin. We identified increased cancer stem cell activity in cisplatin-resistant lung cancer cells that is targeted by Disulfiram. These findings are critically important in the context of drug-resistant lung cancer. There remains a discord however, between the significant anti-cancer effects of Disulfiram reported in the laboratory and its ineffectiveness in previously reported clinical trials. We believe this may be due to the delivery, rapid metabolism and subsequent inactivity of the drug in patients. Furthermore, a lack of reliable biomarkers of resistance, together with an incomplete understanding of drug resistance mechanisms, have limited the success of treatment responses to chemotherapy in patients with lung cancer.”

Dr Barr and the team at the Thoracic Oncology Research Group continue to explore new ways to deliver Disulfiram which may overcome the current shortfalls & failures of the clinical trials on Disulfiram in cancer. The team envisage that their findings will provide important data supporting a potential clinical trial of Disulfiram in lung cancer in the future. The team are also engaged in exciting studies on the use of a blood test for detecting resistance mutations in a particular group of patients with lung cancer. At the moment, doctors require a lung biopsy to diagnose lung cancer, an invasive procedure which may also be limited due to inaccessible or insufficient tumour tissue, tumour heterogeneity and the risks associated with repeat biopsies. In other words, they would like to see a difficult (and possibly insufficient) lung biopsy procedure replaced with a simple blood test. Dr Barr describes the team effort involved in these important studies:

We worked in collaboration with Medical Oncology departments in St James’s Hospital, University Hospital Limerick and Midlands Regional Hospital, with the support of Roche Molecular Systems, to determine if we can detect EGFR mutations and predict the emergence of the T790M resistance mutation in lung cancer patients during treatment. The personalised use of liquid biopsy in lung cancer has the potential to guide treatment and monitor patients for the emergence of drug resistance and disease relapse

The team believe that their work could significantly improve treatment responses, quality of life, and survival outcomes in patients with lung cancer and potentially, other cancer types. In addition, it could reduce disease burden and healthcare costs, while significantly impacting personalised medicine practices and positively impacting cancer patients and their families. Data from further pre-clinical studies could lend vital evidence for a change in the way lung cancer patients are treated and as such, influence current policies and practices in oncology departments in Ireland and beyond.

Dr Barr co-established (and co-manages) the lung cancer biobank at the Trinity St James’s Cancer Institute. This crucial resource provides a key bio-resource of matched normal and tumour lung tissues and blood from consented surgical and oncology patients for use in clinical and translational studies. These samples, together with their associated clinical, pathological and survival data, allow researchers to correlate and translate important findings from the laboratory into the real-world setting. These studies are possible due to multidisciplinary collaborations with various departments and institutions within St James’s Hospital and Trinity College Dublin, including Trinity Translational Medicine Institute, Cardiothoracic Surgery, Histopathology, Cancer Molecular Diagnostics, the Trinity St James’s Biobank Network, and Remedy Biologics.

Dr Barr emphasises the team’s strong links with researchers and patient advocates in Ireland and internationally:

Our laboratory is a member of the Irish Lung Cancer Alliance. This is a network of clinical and translational lung cancer researchers that provides a platform to foster the development of innovative investigator-led clinical trials & collaborative translational research in Ireland. Importantly, our research is also supported by patient-research advocates who play key roles in our translational research studies. Our laboratory has a well-established collaboration with the European Thoracic Oncology Platform (ETOP), involving multiple medical research institutions which promote the exchange of ideas and research in the field of thoracic malignancies. Our participation in ETOP-led studies at St James’s Hospital aims to expedite knowledge of emerging molecular biomarkers which have clinical significance in lung cancer and to facilitate a more rapid translation of biomarker knowledge to the clinic.”

For more information on Lung Cancer, see here: https://www.cancer.ie/cancer-information-and-support/cancer-types/lung-cancer

Dr Barr can be contacted by email at barrma@tcd.ie