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www.european-hospital.com 5ONCOLOGY anisms Deepening knowledge of the cancer genome Ludger Weß reports The German Cancer Research Centre DKFZ in Heidelberg The term ‘cancer’ describes more than 200 different diseases and every single one needs to be clearly understood and requires, ideally, individual treatment. To do this we need to deepen our understanding the cancer genome. ‘In the ageing population the ‘cancer’ diagnosis increases but, thanks to modern medicine, mor- tality decreases,’ declared Professor Christof von Kalle, Speaker of the Board of the National Centre for Tumour Diseases (NCT) at the German Cancer Research Centre (DKFZ) in the Helmholtz Society during the European Cancer Research Congress in Munich. Anja Behringer reports. Dr von Kalle, who heads the NCT Translational Oncology Department, is particularly pleased with the excellent technological facilities that will advance interdisciplinary per- sonalised cancer medicine above all in genomics, proteomics, imaging, radiotherapy, immunology and pre- vention. Today patients’ tumour cell genes can be analysed to design a custom-made therapy. Beyond primary tumour cells, metastases have become a major object of interest in cancer research. For decades scientists have assumed that the protein coding is the most important – if not the only – func- Report: Chrissanthi Nikolakudi Radiotherapy always encounters particular challenges when a tumour is ‘mobile’. This is when radiotherapy must be carried out over several weeks. Within that period the tumour position, shape and expansion typically will keep changing. Thus radio- therapy needs continuous adap- tation to maintain continuously precise radiation. The treatment of lung cancer and of tumours located in the upper abdo- men is at particular risk of missing the tumour and therefore endanger- ing treatment success, because these tumours change position by sev- eral centimetres due to a patient’s natural breathing. Up to the 1990s there was no method to account for this movement in radiation calcula- tions, so the patient had to be given expanded radiation. Classic radiation therapy based on 3-D spatial resolution only cap- tures the tumour’s position, shape and expansion and then targets it. Speaking at the 20th Annual Congress of the German Society for Radiation Oncology (DEGRO), Professor Matthias Guckenberger, specialist for Precision Radiotherapy and Director of the Clinic for Radiation Oncology at the University Hospital Zurich, explained: ‘If the 4th dimension, i.e. time, comes into play because of tumour movement then conventional treatment is no longer sufficient and we need 4-D radiotherapy.’ 4-D radiotherapy is also known as Stereotactic Body Radiotherapy or Stereotactic Ablative Therapy. This non-invasive procedure depends on imaging procedures such as CT, MRI and PET/CT to locate the tumour precisely. 4-D CT then facilitates individual and precise measure- ments of the tumour movement for each patient. Based on the extent of the move- ment of tumours in the upper abdo- men, for instance, a strategy to compensate for the movement is then selected. ‘If the tumour moves by more than 5-10mm, 4-D radio- therapy is needed,’ Guckenberger said. The physician then has a num- ber of procedures and technologies available to target the highly mobile tumours precisely. ‘One of these,’ he explained, ‘is to use gating, that is, to stop radiation whenever the tumour moves from its focal point. Once it moves back into its original position radiation is then resumed. ‘In the case of tracking, the radia- tion moves dynamically and in syn- chronisation with the tumour, i.e. it always pursues it,’ he added. ‘There are different procedures that are all equally as good. The important thing is to decide on one procedure and then to implement it consist- ently, with experience and quality assurance.’ In practice, the treatment team, of doctors, physicists and radiog- raphers, carries out this treatment in three steps. First, the extent of tumour movement is calculated dur- ing the radiotherapy-planning meet- ing. Next, the radiation is adapted to this movement. Finally, radio- therapy, adapted to the patient’s breathing, commences. 4-D radiotherapy fights tumours affected by respiration movement with high doses. ‘This is a big advantage of the procedure: the treatment is intensive, but short, Guckenberger pointed out. ‘The procedure has a lower risk of side effects and can be carried out on an out-patient basis.’ Results from stereotactic body radiotherapy performed at 13 German and Austrian treatment cen- tres are also consistently excellent. Small lung cancers can be treated so effectively with the aid of 4-D radiotherapy that the clinical results are comparable with those achieved through surgery. This also enables successful treat- ment of patients who cannot under- go surgery due to concomitant dis- eases. Stereotactic body radiotherapy is now increasingly also used to treat liver and kidney cancers as well as spinal metastases – with very prom- ising results. tion of the genome, with the genes providing the necessary ‘coding plan’. Surprisingly, however, only about two percent of the genome is indeed protein-coding sequences while 98% do not carry any cod- ing information at all. Nevertheless, 70-90% of the genome is translated into the language of the messen- ger: ribonucleic acid (RNA). These non-coding RNA molecules, cop- ies of the genome without protein codes, are important products of the genome. Members of the Helmholtz junior researcher group ‘Molecular RNA Biology & Cancer’ at Heidelberg University Hospital focus on this ‘young’ class of molecules. The sci- entists assume that they play an important role in cancer develop- ment and therefore might be impor- tant biomarkers or target structures for therapies. Dr Sven Diederichs, Head of the junior researchers group, reports that they could link one of these non-coding RNA molecules to lung cancer progression. The RNA is associated with the development of metastases – the cause of death in the majority of patients who suffer lung cancer, responsible for more deaths worldwide than any other type of cancer. In a second step, the scientists demonstrated that a mixture of two synthetic long peptides (SLPs), each incorporating one of the mutant amino acid sequence and an adju- vant, were able to eradicate the tumour as effectively as checkpoint immunotherapy. ‘These findings offer important mechanistic insights into the mode of action of checkpoint immune reg- ulators, and point the way towards personalised approaches based on the SLP immunotherapy concept,’ said Professor Cornelis Melief, Chief Scientific Officer of ISA and a co- author of the paper. ‘Checkpoint blocking is capable of activating existing inert T cells against mutant antigens. Now we know that an adjuvanted SLP-based immunother- apy, with similar anti-tumour effects to checkpoint immunotherapy, can be created.’ The preliminary successes of can- cer immunotherapy clearly demon- strate the potential of this approach. Most likely, a combination of vari- ous strategies will in the future lead to even higher response rates and less side effects in treating cancer. Tackling mobile tumours Precision radiotherapy with 4-D imaging Matthias Guckenberger MD, is director of the Clinic for Radiation Oncology at the University Hospital Zurich, Switzerland. Following his habilitation on ‘Image Guided Precision Radiotherapy’, in 2012 he gained the professorship for Radiotherapy at the Medical Faculty of the Julian Maximilian University of Würzburg, Germany. The professor also manages the Working Group for Stereotactic Body Radiotherapy for the German Society for Radiation Oncology (DEGRO). Tissue section of a human bladder tumour after immunotherapy simulation in a tissue culture system. The activated immune microenvironment contains groups of immune cells spread over the entire tissue section Treatment plan for a 4-D radiation therapy Source:ImagecourtesyofVarianMedicalSystems Source:ProvecsMedical

EH 6/2014

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