MOLECULAR PATHOLOGY of LUNG CANCER OBJECTIVE to Provide Comprehensive Histopathological and Genomics-Based Biomarker Diagnostics of Lung Cancer

PROFESSOR REINHARD BÜTTNER Cutting-edge cancer diagnostics

Professor Reinhard Büttner discusses how his research into lung cancer is fuelling the translation of large-scale molecular tumour diagnostics and personalised treatment strategies into clinical practice

When I started to work as Professor of diagnosis, such as lung cancer and melanoma. Pathology at the Universities of Aachen and Following this, we then multiplex these Bonn, Germany, I became the reference genes from very small biopsies using a deep pathologist in the German consortia for parallel-sequencing approach. This type of hereditary colon and breast cancers, and I sequencing allows us to detect a few mutated helped perform genomic testing of tumour cancer alleles within a mixture of normal cells samples on a large scale. Later, I met some and many normal, non-mutated alleles. Thus, highly motivated lung cancer specialists, the pathologists prepare the groundwork for oncologists and molecular biologists at the development of therapeutic strategies by the University of Cologne. Together with identifying the biomarkers that enable them Roman Thomas and Jürgen Wolf, I envisioned to predict which therapies are likely to be the Network Genomic Medicine (NGM) effective in specific patients. to translate large-scale molecular tumour diagnostics and individualised therapies Through NGM, you currently work with into clinical practice. I decided to move many collaborators across Germany. to Cologne, and we founded the Network What approaches have you taken to in 2010. It has grown rapidly since then facilitate these collaborations? and is now being supported by long-term Can you outline your particular area of cancer survivors. The NGM functions both as a service interest in oncology and describe how your network for genomic tumour diagnostics professional career has developed to date? Could you outline your role within the and as a communication structure. As Lung Cancer Group Cologne, Germany, members of the Network, we regularly It has always been my belief that a and explain its goals? meet to come up with ideas for new studies, comprehensive molecular understanding of communicate our goals and address requests genomic changes in cancer cells will pave I work as part of a multidisciplinary team, from our collaborators. Additionally, we the way for better therapies. I therefore went together with bioinformatics, pathologists, are currently extending NGM’s structure to into pathology, after which I sought training medical and radiation oncologists and support clinical studies at the sites of our in a professional research environment as a molecular biologists. We review all the various partners. postdoctoral researcher at the Gene Center histological, genomic and clinical data in the University of Munich, Germany, and of the patients and make comprehensive What have been your most significant later at the University of Texas MD Anderson therapeutic recommendations. My specific findings to date? How do you hope your Cancer Center in Houston, USA. At that time, role involves leading and steering all tasks work will progress in the future? we believed that the ‘differentiation’ of cancer related to histopathological and genomic cells would prevent tumour growth. This inspired diagnostics. I act as a bridge between the For the first time, the NGM has me to study genes in cancer cells that are being genomics scientists in the lab and the demonstrated the feasibility of personalised regulated by differentiation under treatment clinicians by interpreting the data into a cancer medicine in practice. We have been with retinoic acid – an approach that is applied clinically useful diagnostic context. able to comprehensively analyse genomic today in some types of leukaemia. Later, we alterations at a large scale for lung cancer recognised that some mutations and molecular How are you concentrating your patients. We have also shown that novel, pathways are highly characteristic for certain diagnostic efforts to screen for targeted therapies do make a difference tumours. For instance, some show specific informative genomic lesions? to patient outcomes, as they significantly defects in DNA repair mechanisms. increase survival rates and pave the way We avoid whole-genome analysis because for their more widespread implementation Could you provide some background into this is currently not amenable to very in routine clinical practice. Looking to the your current research on the pathology of deep sequencing. Instead, we multiplex future, our goal is essentially very simple: we lung cancer? all informative genes for a specifictumour want to make lung cancer a curable disease.

WWW.RESEARCHMEDIA.EU 67 PROFESSOR REINHARD BÜTTNER

Targeted treatments

As part of the Network Genomic Medicine at the Centre for Integrated Oncology in Cologne, Germany, researchers are studying the molecular alterations that drive tumour progression. They are using this information to develop specific and individualised cancer therapies with the goal of long-term patient survival

ONE OF THE most common and aggressive DRIVING DIAGNOSTICS patients, adding validity to their reassignments cancers, lung cancer is a devastating disease with a of large-cell lung carcinomas. Most significantly, poor prognosis. According to Cancer Research UK, Moving towards treating tumours in a more genome-based diagnosis improved the overall only 32 per cent of lung cancer patients will live for comprehensive and targeted way, Büttner survival rates of patients with epidermal growth one year following diagnosis and just 10 per cent and his colleagues are concentrating on factor receptor (EGFR)-mutant and anaplastic will live for five years. Unfortunately, the disease developing diagnostics that screen for all lymphoma kinase gene (ALK)-rearranged cancers, is notoriously difficult to diagnose, meaning it informative genomic lesions. For example, in hailing a seismic shift in tumour diagnostics. is often not noticed until the later stages of its a study conducted in collaboration with the “Personally, I would compare this shift with the pathogenesis. There is therefore an urgent need Clinical Lung Cancer Genome Project, the introduction of immunohistochemical staining in to develop more robust diagnostic strategies NGM researchers aimed to pinpoint genetically histopathology,” Büttner states. “Comprehensive that can detect lung cancer in its earliest stages. defined and clinically relevant subtypes of genomic analysis will lead to better tumour Equally, more effective and less toxic therapies are lung tumours. They characterised clinically classification and diagnostics, more precise needed for patients in the late stage of the disease. annotated lung tumours from all histological therapies and, crucially, to the ability to monitor subtypes. Their analyses revealed that in over tumours as they undergo therapy.” In response, as part of the Network Genomic half of all cases, at least one oncogenic genome Medicine (NGM), researchers in the Centre alteration would be potentially responsive to EPIGENETIC EXPLORATIONS for Integrated Oncology, Cologne, Germany, targeted therapeutic strategies, including some are conducting innovative research into personalised interventions that are currently Not all tumours are the result of genomic lung cancer. The multidisciplinary team is being clinically evaluated. mutations; indeed, it is thought that some studying the molecular mechanisms that are driven by epigenetic changes that cause underpin genomic changes in cancer cells, pathological oncogene expression. For instance, with an overall focus on histopathological overexpression and high activity of the lysine- and genomic diagnostics. Composed of lung specific histone demethylase (LSD1) is a major cancer specialists, oncologists and molecular feature of lung cancer progression. At the NGM, biologists, the NGM is aiming to advance Büttner’s laboratory was one of the the researchers are therefore using preclinical clinical approaches to lung cancer and make first in Europe to implement next- mouse models and clinical samples from therapies more effective, less toxic and patients to investigate the functions of LSD1 in personalised to individual patients. generation sequencing into routine driving lung cancer growth. Motivated by the exciting possibilities clinical diagnostics Currently, Büttner and his colleagues are that personalised cancer treatment offers, engaged in a project that is examining renowned pathologist and co-founder of the the functions of histone methylases and NGM Professor Reinhard Büttner is leading Moreover, the researchers found key differences demethylases in lung cancer; specifically Germany’s largest and most prominent between and within histological subtypes they are studying LSD1-driven oncogenic screening effort for cancer patients. Through of the tumours, calling into question the signal pathways. The researchers are using the use of next-generation sequencing validity of the original histomorphological advanced experimental techniques, including (NGS) technologies, Büttner and his team diagnosis. Interestingly, the reassigned tumour chromatin immunoprecipitation linked to are generating new insights into genomic subtypes – which were further confirmed by the NGS of LSD1-targeted gene promoters, alterations in cancer biopsies: “Integrating immunohistochemical analyses – disqualified and applying them to both cell systems and genomic information and histopathology will most types of large-cell carcinoma. Tested on transgenic mouse models with lung cancer- substantially change the practice of tumour 5,145 lung cancer patients, the researchers’ novel, specific mutations: “As a bona fide oncogene, diagnostics, leading to more selective and genomics-based diagnostic algorithm proved LSD1-driven cancers in vitro react to LSD1 individualised cancer treatment,” he asserts. successful in diagnosing some 75 per cent of the inhibition,” discloses Büttner. “It is our aim to

68 INTERNATIONAL INNOVATION INTELLIGENCE MOLECULAR PATHOLOGY OF LUNG CANCER OBJECTIVE To provide comprehensive histopathological and genomics-based biomarker diagnostics of lung cancer. Within the Network Genomic Medicine, every cancer biopsy is analysed on a central diagnostic platform, and each patient is counselled to provide established and cutting-edge personalised tumour therapies. KEY COLLABORATORS Professor Dr Jürgen Wolf, University Hospital of Cologne, Germany • Professor Dr Roman Thomas, University of Cologne, Germany • Professor Dr Roland Schüle, University of O Freiburg, Germany GERMAN PARTNERS Center for Integrated Oncology (CIO) Cologne Bonn • German Cancer Aid • German Ministry for Science and Technology (BMBF) • German Research Foundation (DFG) • Ministry of Innovation, Science and Research North Rhine-Westphalia • Patients’ Tumor Bank of Hope (PATH) translate these fi ndings in vivo and introduce successfully identifying huge numbers of epigenetic inhibitors into clinical practice for biomarkers for cancer, driving the development CORPORATE PARTNERS lung cancer therapy.” of targeted and precise therapeutic concepts. Targos Molecular Pathology GmbH, Germany • Qiagen, Germany • Roche Molecular With a fi rmly established lung cancer research INTEGRATING BIG DATA Diagnostics, USA • Pfi zer, USA • Merck- programme, lung cancer remains the most Serono, Germany • Novartis, Switzerland • Büttner’s laboratory was one of the fi rst in frequently performed test at the NGM, GlaxoSmithKline, UK • Bristol-Meyers Squibb, Europe to implement NGS into routine clinical followed by melanoma, gastrointestinal USA • AstraZeneca, UK diagnostics and, at present, his team performs tumours and chronic lymphocytic leukaemia. some 5,000 NGS-based tests every year. Büttner and his team are planning to expand FUNDING With each test ordinarily resulting in 1 GB of their diagnostic programmes and apply their European Union • Ministry for Innovation, data, the analysis of these data represents research to other types of tumours: “We are Science and Research North Rhine-Westphalia a major challenge for the researchers and constantly coming up with studies that aim • BMBF • German Cancer Aid • DFG clinicians who are seeking to understand and to drive the rapid development of new and CONTACT diagnose disease: “This is a problem that must relevant diagnostics and therapies for cancer be addressed since data analysis has to be patients,” Büttner enthuses. Ultimately, Professor Reinhard Büttner performed as part of a point-of-care analysis the researchers intend for their innovative Director and provide informative results within a very diagnostic methods and personalised University of Cologne short timeframe, in order to inform imminent treatment strategies to bring tangible benefi ts Institute for Pathology therapeutic decisions,” Büttner explains. to all cancer patients, improving prognoses Kerpener Str 62 and saving lives. 50937 Cologne In response to this challenge, the NGM Germany researchers have developed a proprietary data- analysis pipeline, enabling them to fi lter the T +49 221 478 6320 data automatically, using different algorithms PREDICTIVE DIAGNOSTICS E [email protected] that identify the relevant mutations. Although http://bit.ly/InstitutFürPathologie the subsequent clinical interpretation involves www.ngml.de extensive manual work and is hugely time- www.lungcancergroup.de consuming, the NGM has invested signifi cantly in its personnel, meaning that there is a REINHARD BÜTTNER currently serves as the sizeable and robust team of experts on hand to One of the most exciting developments in leading German molecular pathologist at the conduct the analyses. cancer diagnosis is the fi eld of predictive University of Cologne Comprehensive Cancer diagnostics. Through the analysis of CIO Cologne Bonn. With Professor Drs Jürgen tumour tissue specimens, Büttner and A PARADIGM FOR THE FUTURE Wolf and Roman Thomas, he founded the his team are able to classify tumours and Network Genomic Medicine and is steering As the fi rst peripheral healthcare structure use advanced technologies to identify Germany´s leading initiative for personalised in Germany to be fully funded by healthcare the molecular mechanisms that drive the lung cancer medicine. providers, the NGM, steered by Professor Drs malignant growth of a specifi c cancer. Jürgen Wolf and Roman Thomas alongside These fi ndings are signifi cant because they Büttner, is a forward-looking network and enable oncologists to decide when to use a paradigm for the delivery of innovative, therapy to target genomic lesions. comprehensive diagnostics and personalised treatment plans. The researchers are