Smoking gun

Environment, genetics, age: there are lots of influencing factors behind lung cancer. Researchers are working hard to understand the molecular principles of the disease, with a view enlisting the support of the body’s immune system.

Vienna – It’s always the same with bad habits: people who smoke think that it will all turn out alright somehow clinging onto the idea that not every cigarette and cigar smoker dies from cancer. “But it’s all in vain, as smoking has been identified as the main risk factor,” cautioned Wolfgang Hilbe, oncologist at Vienna’s Wilhelminenspital, who is concerned about women in Austria. The number of female lung cancer patients has doubled over the past 30 years.

What smokers risk with every drag: toxic vapours disrupt the processes of a powerful cell production machine, the human body. The organism needs oxygen, which it stocks up on via the lungs – what sounds mechanical is in fact a complex interaction between a large number of different cells. It is all fine as long as this process continues without a hitch – for a lifetime. And the human body is actually designed with this in mind. The genes are responsible for making sure that the right proteins are produced for creating the cells. There is even a kind of quality control system: the body’s immune system not only provides protection from external threats, it also makes sure that internal cell production and disposal processes are working properly. If the immune system discovers cells that somehow look ‘different’ it dispatches its killer troops to purge them. Smokers increase the chance of a system malfunction which may end up being overlooked and allow a cell to go rogue.

“The chances of recovery are good if the bronchial carcinoma can be surgically removed,” is what Leopold Öhler, head of oncology at the St.-Josef-Spital in Vienna tells every new lung cancer patient who sits down in front of him. The progress of the disease and whether there is any metastasis is even more important. The first consultation inevitably raises the smoking question. In 85 percent of cases sufferers are active or former smokers. “Nicotine addiction is a disease,” Öhler clarified.

Cumulative danger

Harmful vapours modify the behaviour of the cells, meaning that proteins with modified structures are produced. What’s fatal is if the immune system overlooks this error. “A changed cell is susceptible to further abnormal development,” explains Öhler. If this genetic error becomes a driver mutation, then what started out as a local event in the lung becomes a systemic error. Cancer cells transcend organ boundaries and spread through the blood to other parts of the body, where they form metastasis. “It depends on the time of the diagnosis and which type of cell in the lung the cancer spreads from,” the oncologist noted. Lung cancer experts make a distinction between small cell lung cancer (SCLC) which originates in the neuroendocrine cells of the lungs and non-small cell lung cancer (NSCLC). While SCLCs grow more quickly and metastasise in the brain, NSCLCs often develop more slowly and tend to spread to bones and the adrenal glands.

Researchers working on Level 0 of Vienna General Hospital are trying to pinpoint these processes at a molecular level. “We identify and monitor proteins from tumour tissue samples,” said MedUni Vienna pathologist Lukas Kenner, whose CBmed Biomarker Research in Medicine research centre is conducting detective work at a cellular level. The facility brings different professions: there are surgeons who perform biopsies, lab technicians who dehydrate them, embed them in paraffin, cut them into wafer thin samples and dye them to differentiate between healthy cells and tumour cells. Biochemists such as Gerald Stübinger who use mass spectrometry to identify proteins involved in cancer. “We determine the molecular weight and the exact structure,” he said. All of these results are fed into a database.

“There are millions of mutations but only very few of them are capable of bringing the whole system to its knees,” confirmed Lukas Kenner. Finding these mutations is a major challenge but also an opportunity for new therapies. And this is exactly what is hoped will happen with the help of nuclear medicine and its radioactive molecules.

What is clear is that oncologists and patients alike are dissatisfied with current lung cancer therapies. If the disease is at an advanced stage, chemotherapy and targeted therapies that block different receptors on the tumour cell itself are only effective for very short periods, as tumour cells are highly adaptable. If a medicine blocks their growth, they quickly find alternative mechanisms for spreading. “The biology of the process has been extremely hard to predict up until now,” said Christoph Zielinski, chief oncologist at MedUni Vienna. Over the past few years researchers have observed that tumour cells seem to have the potential to put the body’s immune system into a kind of shock- induced paralysis. T-cells, the immune system’s crack commandos, fail to recognise the tumour cells as being foreign or dangerous and remain inactive allowing the tumour to grow. But the new molecular targeted therapies and immunotherapies are giving oncologist grounds for hope. “It is as if we can reactivate the immune system with these medications,” revealed Zielinski. But he adds an important caveat: molecular targeted therapy is only an option for 15-25 percent of lung cancer patients and only effective if the tumour shows molecular changes such as an ALK or EGFR mutation in the laboratory. In such cases the effects of checkpoint inhibitors in immunotherapy are particularly impressive: “We do win back years of life with both options.”

However, as confirmed by lung cancer specialist Hilbe, much of what is going on in molecular medicine is still very much a work in progress, and testing combinations of medicines in clinical studies is an important and consider- able task if current therapy schemata are to be improved. Researchers are always particularly upbeat whenever statistical analysis shows that a kind of plateau has been reached. And this is happening with immunotherapy right now. Medicines that have already proved their effectiveness against special forms of skin cancer are now being used with precisely defined lung cancer patient groups.

Russian roulette

“Theoretically, immunotherapy can be used in various parts of the body,” noted Leopold Öhler, because the immune system does not stop at the boundaries of the organs and is active all over the body. At present, these experiences are being collated and analysed so that they can be used wherever they increase life expectancy for cancer patients. One way of reducing the risk would be to prevent poisonous air from entering the lungs in the first place. In theory, any cigarette could trigger a cellular catastrophe in the body.