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Not all patients respond equally well to drug-based cancer therapies. Together with international colleagues, researchers from the European Molecular Biology Laboratory (EMBL), the German Cancer Research Center (DKFZ), the Heidelberg University Hospital (UKHD) and the National Center for Tumor Diseases (NCT) have now investigated in a large study which mechanisms underlie the therapeutic response. In the process, they found that mutations have a much greater impact on drug effects than previously thought.

The NCT Heidelberg is a joint institution of the German Cancer Research Center (DKFZ), the Heidelberg University Hospital (UKHD) and the German Cancer Charity.

Due to the possibility of sequencing the genetic material, in more and more cancer patients gene alterations can be identified against which targeted drugs are available. In the treatment of leukemias and lymphomas, physicians are increasingly turning to therapies that target specific features of the cancer cell. But in spite of these precisely fitting points of attack, the drugs do not work the same way in all patients. In some cases, resistance occurs in the course of treatment.

"If the success of a therapy could be predicted in a better way, many patients would be spared unnecessary treatment and we could switch to more effective therapies earlier - which also reduces costs," says Thorsten Zenz, researcher at the German Cancer Consortium at the DKFZ, NCT Heidelberg and the University Hospital Zurich. But the physicians still lack the key features that indicate the response to a therapy.

Together with international colleagues, scientists from Heidelberg have now systematically investigated the mechanisms responsible for a different therapeutic response in chronic lymphocytic leukemia (CLL) in a large-scale study. To do so, they investigated the effects of 63 drugs on 246 tumor samples from patients with leukemia and lymphoma. The effect of the drugs on the tumor cells were tested in a petri dish. The results were analyzed together with information on gene alteration of the cancer cells of each individual patient as well as the molecular properties of the tumor samples. "We wanted to understand the mechanisms behind treatment response", says Sascha Dietrich, physician and scientist at Heidelberg University Hospital and the European Molecular Biology Laboratory (EMBL).

The scientists found out that in 62% of the tested drugs two or more mutations affect the response to treatment. Using the important cellular pathways that were mutagenic, researchers were able to divide the CLLs into three groups: CLLs with mutations in the BCR, MEK, or mTOR pathway that plays a role in cell survival and growth. Each of these groups is characterized by sensitivity towards specific drugs.
A single cause for therapy failure couldn’t be identified by scientists. Rather, a particular pattern of genetic and molecular properties is always critical – with a different emphasis depending on the drug.

Now, scientists want to divide patients into groups based on these patterns that indicate a response to treatment. Samples even indicate that a combination of more treatments might be effective.
The international study could show that mutations affect the effectiveness of a targeted therapy in CLL patients. “We want to improve these types of analysis with more samples from patients with the goal to generate a variety of new biomarkers and hypothesis that contribute to better treatment options for leukemia diseases”, explains Thorsten Zenz.

S. Dietrich, M. Oleś, J. Lu et al. (2017) Drug-perturbation-based stratification of blood cancer. The Journal of Clinical Investigation Dezember 14. DOI: 10.1172/JCI93801

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caption: cells of chronic lymphatic leukemia (CLL).

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The National Center for Tumor Diseases (NCT) Heidelberg
The National Center for Tumor Diseases (NCT) Heidelberg is a joint institution of the German Cancer Research Center, Heidelberg University Hospital and German Cancer Aid. The NCT's goal is to link promising approaches from cancer research with patient care from diagnosis to treatment, aftercare and prevention. The interdisciplinary tumor outpatient clinic is the central element of the NCT. Here the patients benefit from an individual treatment plan prepared in a timely manner in interdisciplinary expert rounds, the so-called tumor boards. Participation in clinical studies provides access to innovative therapies. The NCT thereby acts as a pioneering platform that translates novel research results from the laboratory into clinical practice. The NCT cooperates with self-help groups and supports them in their work. 2015 the NCT Heidelberg established a partner location in Dresden.

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
The German Cancer Research Center (DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.

Heidelberg University Hospital and Medical Faculty Heidelberg
Heidelberg University Hospital is one of the most important medical centers in Germany; Heidelberg University's Medical Faculty is one of Europe's most prestigious biomedical research facilities. Their shared objective is the development of innovative diagnostics and treatments and their prompt implementation for the benefit of the patient. The hospital and faculty employ approximately 12 600 individuals and are involved in training and qualification. Every year approximately 66 000 patients are treated as inpatients or day patients in more than 50 specialized clinical departments with about 1 900 beds, with more than 1 million patients being treated as outpatients. The Heidelberg Curriculum Medicinale (HeiCuMed) is at the forefront of medical training in Germany. At present approx. 3500 prospective physicians are studying in Heidelberg.