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Crossing the valley of death with translational cancer research

It can take many decades before promising research results become therapies that have a positive effect on cancer patients. Most research projects go adrift somewhere between the laboratory and the bedside in the so-called "valley of death". Translational cancer research activities involving clinician scientists who carry out basic research as well as being involved in patient treatment are expected to contribute to the quicker development of successful therapies. Projects carried out at the DKFZ show that translational cancer research actually works.

It may take fifteen, sometimes even thirty years from a new scientific discovery to therapeutic application - far too long for cancer patients and their relatives. "People expect cancer research and cancer medicine to make rapid and tangible progress in the treatment of cancer, and that these improvements should be available regardless of where the patients live. They must also be affordable," said Professor Michael Baumann, Chairman and Scientific Director of the German Cancer Research Center (DKFZ) in Heidelberg at a meeting held on World Cancer Day on February 4, 2018. Baumann referred to the obstacles that lead to the delay or failure of medical progress as the valley of death in medical research, quite a drastic choice of vocabulary. According to Baumann, there are actually two valleys of death – one between preclinical and clinical research and another between the clinical efficacy of drugs as demonstrated by clinical trials and the evidence of real benefits for patients and society.

Crossing the valley of death

Prof. Dr. med. Michael Baumann, Chairman and Scientific Director of the DKFZ. © NCT Dresden / Philipp Benjamin

There is an expectation that translational cancer research will contribute to reducing the time it usually takes to develop cancer therapies. This involves three stages: first, the discovery, invention and elucidation of disease mechanisms; second, the preclinical development and validation of drug candidates and new methods; third, the clinical testing of drugs and methods and their introduction to the health system. Success depends on multidisciplinarity, professionality and communication on all levels. “We need a translational culture and we need communication between cancer researchers and cancer doctors on equal terms,” says Baumann, further highlighting that so-called clinician scientists, i.e. scientists who do basic research as well as treat patients, are currently few and far between in Germany.

Using BAY 1436032, an inhibitor of mutant isocitrate dehydrogenase 1 that is characteristic of a number of tumours, Dr. Stefan Pusch showed how translational research can accelerate the drug development process. The collaboration between basic researchers and clinical researchers at the DKFZ and Heidelberg University Hospital (in the clinical cooperation units Neuropathology, headed up by Professor Andreas von Deimling, and Molecular Haematology/Oncology, headed up by Professor Alwin Krämer) and the pharmaceutical company Bayer has succeeded in bringing the inhibitor from preclinical to clinical testing in the surprisingly short time span of five years. It is highly likely that the inhibitor will be approved for treating certain forms of brain tumour and leukaemias in a relatively short time.

Prof. Dr. med. Klaus Kopka, director of the Division of Radiopharmaceutical Chemistry, DKFZ and DKTK. © DKFZ

Professor Klaus Kopka, a chemist and departmental head at the DKFZ, presented another example of the successful translation of research results into therapies. Kopka succeeded Professor Michael Eisenhut as director of the Division of Radiopharmaceutical Chemistry at the DKFZ in 2013. Eisenhut and colleagues had previously developed PSMA-11, a marker molecule of prostate cancer, which is the most common tumour in men worldwide. The marker molecule is able to specifically attach to a molecule called prostate-specific membrane antigen (PSMA) and can be labelled with a weakly radioactive gallium isotope. When this compound ([68Ga]Ga-PSMA-11) is administered to patients as a tracer, combined positron-emission tomography and computed tomography (PET/CT) imaging can be used to visualise even the smallest metastases and thus detect small secondary tumours in other organs. As 68Ga has a relatively short half-life of approximately one year, the patients that are administered 68Ga will only be exposed to low amounts of radioactivity.

The use of the tracer as a diagnostic agent is being assessed in phase I and II clinical trials. After diagnostic PET/CT scans have been produced, tissue samples of 150 prostate cancer patients scheduled for surgery will be taken and histologically analysed for PSMA overexpression. This multicentre study involves eleven clinical trial centres in three countries. Professor Frederik Giesel from the Department of Nuclear Medicine at Heidelberg University Hospital is the principal investigator of the clinical trial. Together with his team, Kopka coordinates the decentralised production of the tracer [68Ga]Ga-PSMA-11 as a clinical investigational drug in participating centres. The PET/CT scans will subsequently be compared with histological data to confirm the accuracy of the results. The researchers hope that PET/CT scanning will make the removal of tissue more targeted, potentially reducing or even avoiding it. The overall goal is therefore to develop PET/CT as a new non-invasive method for initial or primary diagnosis of prostate carcinoma.

The Society of Nuclear Medicine and Molecular Imaging (Baltimore, MD, USA) "Image of the Year" 2015: Effect of PSMA-617 in a patient with strongly metastasing prostate cancer. The PET image shows the kidneys and salivary glands (large black spots) along with the heart of the tumour and numerous tumour metastases. Treatment with the prostate-specific membrane antigen inhibitor led to tumour remission (picture on the right; red arrows) © DKFZ / Martina Benešová

The compound class not only detects metastatic prostate cancer when bound to a weakly radioactive radionuclide, but can also treat metastases non-invasively (and is therefore called a theranostic drug) when labelled with a strongly radioactive radionuclide. The researchers led by Professor Kopka have developed a variant of the molecule, PSMA-617, that can be labelled with the strongly radiating lutetium isotope 177Lu and used for treating metastases. PSMA-617 emerged from Martina Benešová’s doctoral thesis at the German Cancer Research Center. A pilot study involving 30 men with advanced prostate cancer has shown that the cancer cells bind to the molecule and are destroyed by radiation after they have taken up the radiolabelled molecule. The compound led to a reduction in the PSA (prostate-specific antigen) levels in the majority of patients. The PET image of a patient, in whom the metastases detected with the 68Ga-labelled compound had completely disappeared following treatment with 177Lu-PSMA-617, was chosen as “Image of the Year” in 2015 by the Society of Nuclear Medicine and Molecular Imaging. One year earlier in 2014, the DKFZ licenced PSMA-617 patent rights to the biotech company ABX GmbH, which after the early clinical development phase was completed, transferred a sub-licence to the US company Endocyte in 2017. The latter has now launched a clinical trial for obtaining marketing authorisation for the radiopharmaceutical. The trial will run until spring 2020.

German Consortium for Translational Cancer Research (DKTK)

The imaging technique introduced to the field of nuclear medicine with the [68Ga] tracer (Professor Uwe Haberkorn) and the evaluation study initiated by Giesel and Kopka are being carried out and funded within the framework of the German Consortium for Translational Cancer Research (DKTK).

The DKTK was founded five years ago as a joint initiative of the German Federal Ministry of Education and Research, participating German states and the DKFZ. It is an association of more than twenty academic research institutions and university hospitals at eight partner locations in Germany (Berlin, Dresden, Essen/Düsseldorf, Frankfurt, Freiburg, Heidelberg, Munich, Tübingen). Its objective is to cross the "valley of death" in medical research through interdisciplinary research projects ("VomLaborInDiePraxis”) at the interface between basic research and clinical practice as well as with clinical trials investigating innovative diagnostic and therapeutic procedures. The DKFZ in Heidelberg serves as the DKTK’s core centre. Such structures and networks are required to rapidly transfer results from the laboratory to the patient. “We have achieved quite a lot in recent years,” says Baumann, adding, “translational research works.”

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