Dr George R Simon, Professor of Medicine and Section Chief, Translational Research, Department of Thoracic/ Head and Neck Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas talks about the SPORE programme for controlling lung cancer incidence and explains the role and impact of DNA repair pathways in therapeutic efficacy, in an interview with Viveka Roychowdhury
India has a high burden of lung cancer. What are the causes specific to the country for this growing incidence?
About 1.8-2 million new lung cancer cases are estimated to occur globally, 6.9 per cent of which are from India. Globally, the disease is one of the commonest cancers and cause of cancer related deaths, and in India, lung cancer is the commonest cancer and cause of cancer related mortality in men.
Factors that are known to contribute to the growing incidence of lung cancer in India include smoking, bidi smoking, exposure to biomass fuel and environmental pollution. The incidence and pattern of lung cancer tend to differ with geographic region and ethnicity and largely reflect the prevalence and pattern of smoking in the country.
As the Section Chief, Translational Research, Department of Thoracic/Head and Neck Medical Oncology, what are the most promising areas of research to treat lung cancer?
Today, most research on lung cancer is focussed on areas of prevention, early detection and treatment. Promising lung cancer treatment options that have emerged include video-assisted thoracic surgery (VATS) to treat small lung tumours, image guided radiation therapy (IGRT), newer combinations of chemotherapy drugs, immunotherapy and targeted therapy. Several new and exciting targeted therapies and immunotherapies have been approved in the last two years. These drugs have dramatically improved the lung cancer landscape. Newer treatment strategies evolve as resistance develops to existing treatments. Understanding these resistance treatments leads to the development of newer drugs to mitigate emerging mechanisms of resistance.
Could you give us more details of SPORE, the Specialized Program of Research Excellence programme and what hope does it offer lung cancer patients?
Specialized Programs of Research Excellence (SPORE) is a cornerstone of National Cancer Institute (NCI’s) efforts to promote collaborative, interdisciplinary translational cancer research. SPORE grants involve both basic and clinical/applied scientists working together and support projects that will result in new and diverse approaches to the prevention, early detection, diagnosis and treatment of human cancers. Each SPORE is focussed on a specific organ site, such as breast or lung cancer, on a group of highly related cancers, such as gastrointestinal cancers and sarcomas, or on a common pathway or theme that ties together the cancers under study.
Lung cancer became an early focus of the SPORE Programme due to the huge burden in terms of morbidity and mortality. The lung cancer SPORE was originally given jointly to MD Anderson and The University of Texas Southwestern Medical Center in Dallas in 1996. Both institutions have received $6.5 million in SPORE renewed funding. The collaboration has produced several key findings including the identification of three lung cancer tumour suppressor genes on chromosome 3 that dramatically reduced human lung cancer growth in mice. Apart from this, lung cancer SPORE has also been granted to University of Colorado Cancer Center, University of Pittsburgh & Yale University. Other lung cancer SPORE’s have been granted to other institutions over time.
What have been the drawbacks associated with traditional chemotherapeutics and treatment pathways to treat lung cancer?
Traditional chemotherapeutics cannot distinguish between normal healthy body cells and cancerous cells, which means that they damage while they cure. They work by attacking cells that divide quickly, which is a characteristic of cancer cells. However, other cells in the body, such as those in the bone marrow (where new blood cells are made), the lining of the mouth and intestines, and the hair follicles, also divide quickly. In addition to the cancer cells, these healthy body cells are also affected. Traditional chemotherapeutics are a non-direct, aggressive treatment option, which lead to side effects such as hair loss, mouth sores, nausea, vomiting, diarrhoea, fatigue, and an increased risk of easy bruising or bleeding. Today, we are moving towards targeted, personalised medicine which takes advantage of the inherent differences that exist between normal cells and cancer cells, and only targets to eliminate the latter. Lung cancer is a typical cancer type to be treated by driver mutation status (EGFR, ALK, ROS). EGFR mutation which is more common in Asians (25 – 65 per cent) is a targetable mutation and can be treated with generations of tyrosine kinase inhibitors. More recently there are immunotherapies which seems to work better in patients whose tumour’s express higher levels of a biomarker called PD-L1.
What is the role and impact of DNA repair pathways in therapeutic efficacy?
Tumour cells possess certain DNA repair pathways that enable these cells to survive DNA damage induced by chemotherapeutic treatments, which reduce cancer treatment efficacy. We are now exploring the use of DNA repair inhibitors, particularly small-molecule inhibitors, which prevent these repair mechanisms within tumour cells. These inhibitors hold promise for damaging tumour cells, with their specificity taking us several steps closer to truly personalised medicine.
What is the approach used in DNA repair targeted therapy? What have been the results so far?
We have sufficient evidence that suggests that all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically-induced DNA damage impacts treatment efficacy. This has led to researchers targeting DNA repair pathways and proteins to develop anti-cancer agents that increase sensitivity of the cancer cell to traditional chemotherapeutics.
Platinum-based DNA damaging agents such as cisplatin and carboplatin form the foundation of many lung cancer treatment regimes today. These drugs are selectively lethal to rapidly dividing cells, where they cause irreparable DNA damage, subsequently directing cancer cells towards apoptotic cell death. However, although this approach shows initial efficacy, our main challenge with these agents remains the eventual development of drug resistance, the precise mechanisms of which remain poorly understood.
The deregulation of DNA repair proteins within cells may provide an attractive therapeutic window. Such an approach is exemplified by the PARP inhibitors, which show potential use in the treatment of cancers deficient of functional BRCA1 or BRCA2. In addition, these drugs may show increased efficacy in combination with DNA-damaging agents.