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DKFZ-HIPO – the Heidelberg Center for Personalised Oncology

The German Cancer Research Center (DKFZ) and the National Center for Tumour Diseases (NCT) have jointly initiated the Heidelberg Center for Personalised Oncology (HIPO) which provides cancer patients with high-throughput genetic and molecular analyses. In anticipation of the upcoming World Cancer Day on 4th February 2013, the potential of high-throughput genetic and molecular analyses in improving cancer therapy was presented at a workshop held in Heidelberg on 17th January 2013.

Genome-wide medulloblastoma RNA expression profile © S. Pfister, DKFZ

“We hope that the National Center for Tumour Diseases (NCT) will be able to offer all cancer patients the genetic profile of their disease in a few years’ time,” said Professor Dr. Christof von Kalle, Director of the NCT in Heidelberg, going on to add, “the basis for being able to do this will be created by the new Heidelberg Center for Personalised Oncology (DKFZ-HIPO) whose researchers have outstanding experience in genome analysis, bioinformatics and translational oncology.” In advance of the 2013 World Cancer Day on 4th February, the German Cancer Research Center (DFKZ) and the NCT Heidelberg invited the press to a presentation event on “Personalised Oncology – the Future of Cancer Medicine?” on 17th January 2013 in order to present and discuss the ideas that have lead to the new initiative. DKFZ-HIPO is financed by the DKFZ.

Towards personalised therapies

Professor Dr. Peter Lichter, spokesperson of the DKFZ-HIPO initiative © DKFZ

Professor Dr. Peter Lichter, head of the Department of Molecular Genetics at the DKFZ and spokesperson of the three-member DKFZ-HIPO board, explained why whole genome sequencing is emerging as a tool for the diagnosis of cancer. Cancer cells display abnormal behaviours due to the accumulation of mutations in key regulatory genes. In addition, patients with superficially the same tumour types might differ in the genetic alterations that have led to their tumour. This is also why far less than 50% of all cancer patients benefit from chemotherapy treatment. “And in the majority of cases we do not even know why some patients respond to chemotherapy and others do not,” said Lichter going on to explain that this is because drug sensitivity is influenced by mutations that occur in the cancer genes. Genome analyses can therefore provide treating doctors with information on the drugs that might or might not be effective. In many cases, such analyses enable doctors to identify the molecular causes of the broad range of different disease outcomes and prescribe drugs that target the genomic aberrations responsible for certain tumours.

In his presentation, Professor Dr. Otmar Wiestler, Chairman and Scientific Director of the DKFZ, spoke about the drug Herceptin, a monoclonal antibody that targets a specific epidermal growth factor receptor (EGFR; HER2) on the surface of cancer cells which plays a pivotal role in growth factor signal transduction, and hence tumour growth. Herceptin has been shown to be highly effective in treating breast cancer; the antibody binds to the receptor, thereby preventing circulating growth factor from binding, and stimulating the breast cancer cells to grow. Around 25% of breast cancer patients overexpress this particular receptor. To enable other breast cancer patients to be spared the severe side effects of ineffective chemotherapy, Herceptin should only be used to treat the 25% who respond to Herceptin treatment. Knowing whether a breast cancer patient is positive for this gene or not is therefore a basic requisite for the use of Herceptin. “Knowledge of the genetic profile of the tumour enables the development of treatments that are adapted to individual patients and tumours. This also enables researchers to transform a long-standing medical dream into reality: to be able to offer a patient targeted treatment that is tailored specifically to his or her requirements,” said Wiestler.  In the field of oncology, the future of personalised diagnosis and treatment is already here.

Assessing the benefits and costs of stratified therapies

Professor Dr. Hagen Pfundner, CEO of Roche Pharma AG and Managing Director of Roche Deutschland Holding GmbH, discussed the drug Zelboraf, which was approved by the American FDA in 2011 for the treatment of malignant melanomas that carry a specific point mutation in the BRAF gene. He saw the approval of this drug as the first major progress in efforts to find an effective treatment for melanoma over the last 30 years. Pfunderer also discussed his belief that the pharmaceutical industry is not as interested in tailoring drug therapies to the requirements of an individual patient as it is in what is known as “drug stratification”, i.e. the identification of entire groups of patients who benefit specifically from a particular drug therapy or who must not be treated with a certain drug because they develop far too severe adverse effects. Pfunderer also highlighted that the development of drugs for smaller groups of patients is associated with higher costs for the drug developer, but that society and healthcare systems benefit largely from personalised medicine as it helps prevent false and ineffective treatment. However, Pfunderer pointed out that what is most important is that the patient benefits from a particular treatment and that government has the responsibility to create conditions that enable the functional interaction of all stakeholders – patients, pharmaceutical companies, healthcare providers, etc. – in the healthcare system.

Professor Dr. Michael Schlander, economist, founder and chairman of the Institute of Innovation and Valuation in Health Care, pointed out that the society’s resources are not unlimited, and insights into the health economy are ultimately no substitute for social discourse in cases where extremely expensive cancer therapies are on the limits of “social willingness to pay”. These issues will become increasingly important with the growing availability of “personalised” and “stratified” treatment options.

Whole genome analysis of tumours will become routine

In the Heidelberg Center for Personalised Oncology, Prof. Lichter will be in charge of carrying out whole genome analyses. He pointed out that knowledge of the genetic alterations of tumours not only enables the development of novel anti-cancer drugs, but also enables existing drugs to be used for the treatment of tumours which were previously not known to harbour a particular mutation.

Immunohistochemical staining (HDAC) of a medulloblastoma © DKFZ

It has long been known that chronic myeloid leukaemia (CML) is associated with the fusion of genes. Such fusion genes are formed when, due to genetic accidents, two particular genes are fused together and new proteins occur as a result. CML can be effectively treated with a drug that specifically targets the protein resulting from the fusion product. The genomes of medulloblastomas have since been sequenced and similar fusion genes identified. Medulloblastoma is the most malignant brain tumour in children. The specific search for drugs similar to those used for the treatment of CML therefore seems to be highly promising.

The medulloblastoma genomes are sequenced by PedBrain, a tumour research project coordinated by the DKFZ. The project is part of the International Genome Consortium and focuses on paediatric brain tumours (see also DKFZ press release: “Genome analysis of brain tumors showing the way to new treatment strategies”). PedBrain is jointly coordinated by Prof. Lichter and Prof. Roland Eils (Head of the Department of Theoretical Bioinformatics at the DKFZ and Director of the Department of Bioinformatics and Functional Genomics at the University of Heidelberg). Eils, one of the DKFZ-HIPO directors who is also in charge of information storage and analysis, is currently establishing one of the largest life sciences data storage units at the university’s BioQuant centre. The final unit will have a storage capacity of as much as six petabytes. Such a high storage capacity is required as the amount of data arising from whole genome sequencing is enormous: a human DNA sequence with 3 billion base pairs requires a storage capacity of 3 terabytes; the same capacity is needed to store the data arising from the sequencing of the RNA, microRNA and the methylome. (One petabyte = 1000 terabyte = 1 million gigabyte; an iPhone has a storage capacity of around 32 gigabytes, a normal laptap around 80 gigabytes.)

NCT Heidelberg © Heidelberg University Hospital

The initiative DKFZ-HIPO – the Heidelberg Center for Personalised Oncology – was established with the objective of bringing the sequencing of whole tumour genomes into the clinic and to infer from the information about a person’s genome the therapy that is best suited for treating a particular patient’s tumour. The field of clinical oncology at the NCT in Heidelberg therefore constitutes a major part of the initiative’s concept. The Department of Translational Oncology at the NCT under the leadership of Professor Christof von Kalle carries out patient-specific research and diagnostics and also translates the analytical results into recommendations on how to effectively treat individual cancer patients. The DKFZ-HIPO has already initiated projects on breast cancer, pancreatic cancer, brain tumours and childhood tumours as well as studies on unexpected therapy responses of patients with different tumours.

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