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Cancer medicine development as a science and industry partnership

The German Cancer Research Center (DKFZ) and Bayer AG are collaborating on a strategic partnership focusing on the development of innovative cancer therapies. The two partners have developed an active substance which selectively blocks a mutation of a metabolic enzyme that occurs in certain types of cancer. The substance has been successfully tested in preclinical studies and is now also being tested in a clinical trial on patients with brain tumours and leukaemias that carry these mutations.

Model of the IDH1 complex. Two polypeptide chains (brown and light blue) form a dimer between which the substance BAY 1436032 binds. © Stefan Pusch, DKFZ

The development of novel drugs against complex diseases such as cancer is risky, very expensive and takes a long time. It can take ten years or more to turn research results into marketable products, and the cost can rise to over a billion euros. The pharmaceutical industry is therefore increasingly withdrawing from proprietary drug research and early drug discovery phases, and is instead focusing on cooperation models with academic research institutions in an effort to save costs and share risks.

Strategic partnership between the DKFZ and Bayer

An outstanding example of such a collaboration is the strategic partnership between the German Cancer Research Center and the Bayer Group Pharmaceuticals Division. "By combining the strengths of both partners, we are able to pursue highly complex, innovative projects that neither one of us are able to handle on our own,” said the then Scientific Director and Chairman of the DKFZ, Prof. Otmar Wiestler, who initiated the research alliance with Bayer (formerly Bayer HealthCare) in 2009.

Glossary

  • Mutations are any kind of alteration of genetic information (e.g., the exchange of a base; translocation of a DNA section; introduction of additional bases; loss of bases or entire DNA sections). Mutations occur constantly in nature (induced by UV rays, natural radioactivity) and are the basis of evolution.
  • Screening is a systematic test procedure that is used to identify certain characteristics within an array of samples or persons. In molecular biology screening is used to filter a designated clone out of a gen bank, for example.
  • Stem cells are cells from the embryo, fetus or adult that that have the ability to divide for indefinite periods in culture and give rise to specialized cells. In Germany it is illegal to extract the stem cells from embryos.
  • Oncology is the science that deals with cancer. In a more restrictive meaning, oncology is a sector of medicine that attends to the prevention, diagnostics, therapy and aftercare of malignant diseases.
  • A tumour is a swelling of a tissue caused by abnormal cell growth, which can be benign or malignant. Benign tumours are local swellings, whereas malign tumours may seed off and spread into other tissues, causing secondary growths (metastases).
  • Leukaemia is a malign disease (cancer) of the hematopoietic system. It disturbs the generation of blood cells in the bone marrow by increased formation of degenerated white blood cells and their precursor cells. Other components of the blood are displaced. This leads to anaemia, infections and bleedings and finally to the death of the affected person, if leukaemia remains untreated.
  • Neurooncology deals with the diagnostics and therapy of brain tumor diseases.
  • The toxicity is the poisonousness of a substance.
  • In a medical-biological context, degeneration means the decay of cells, tissues or organs.
  • The term metabolism includes the uptake, transport, biochemical conversion and excretion of substances within an organism. These processes are necessary to build up the body mass and to meet the energy demand of the body. The opposed processes of metabolism are called anabolism and catabolism. Effectiveness of several enzymes could be catabol and anabol. Within one biochemical pathway they cannot work in both directions at the same time.
  • Biomolecules which can bind active agents are called targets. They can be receptors, enzymes or ion channels. If agent and target interact with each other the term agent-target-specific effect is used. The identification of targets is very important in biomedical and pharmaceutical research because a specific interaction can help to understand basic biomolecular processes. This is essential to identify new points of application.

The strategic partnership between the DKFZ and Bayer differs from conventional cooperation agreements between academic institutions and industry in that both partners provide equal amounts of financing and material and human resources. The partners decide jointly on project selection and goals and the budget is determined by a joint steering committee comprising of managers from the two institutions. The cooperation involves the entire value creation chain with all its risks – from the discovery of pharmaceutically relevant target molecules (target discovery) to clinical development. If the development is successful, the DKFZ will receive a share of the proceeds.

In 2013, the alliance was extended to include the area of immuno-oncology and has now been extended until 2018. Dr. Ruth Herzog, Head of Technology Transfer at the DKFZ comments: “Between 2014 and 2018, the DKFZ and Bayer are injecting 6 million euros per year into oncological research. Many of the 30 or more projects initiated have already reached important milestones and continued on to the next development phase, namely the screening of substances for identifying new drug candidates. Several advanced projects are already in either preclinical development or early phases of clinical development."

Cancer-specific mutations in a metabolic enzyme

Dr. Stefan Pusch, Department of Neuropathology at the University of Heidelberg and Clinical Neuropathology Cooperation Unit at the German Cancer Research Center and the German Consortium for Translational Cancer Research. © Stefan Pusch/DKFZ

One of the partners’ advanced projects involves a novel drug candidate (BAY 1436032), which highly selectively inhibits mutations of the enzyme isocitrate dehydrogenase 1 (IDH1). These mutations are common in certain brain tumours (astrocytomas and oligodendrogliomas), blood cancer (acute myeloid leukaemia, AML) and some other forms of cancer (bile duct cancer and chondrosarcomas). In contrast to healthy cells, cancer cells carry a point mutation that leads to an amino acid exchange at position 132 of the IDH1 protein. This changes the reaction catalysed by the native enzyme in such a way that a dramatic increase in R-2 hydroxyglutarate occurs. R-2 hydroxyglutarate is a so-called oncometabolite, i.e. a metabolite associated with a cancer.

"This gave us the idea of developing an agent that specifically inhibits the IDH1 enzyme that carries a mutation at position 132 of the enzyme's chain of amino acids. Our goal is a drug that targets cancer cells with mutations of IDH1, but not healthy cells with the normal enzyme," says Dr. Stefan Pusch, first author of a large-scale study that shows that BAY 1436032 has huge potential to become a highly attractive target for inhibitory drugs and thus for brain tumours with IDH1 mutations. The team involving Pusch and his colleagues is headed up by Prof. Dr. Andreas von Deimling who works in the Department of Neuropathology at Heidelberg University Hospital and the DKFZ's Clinical Cooperation Unit Neuropathology.

Together with researchers from Bayer’s Drug Discovery division, the DKFZ scientists have demonstrated that the jointly developed inhibitor is effective against all known mutations at position 132 of the IDH1 enzyme. In preclinical studies, mice carrying human astrocytomas and treated with BAY 1436032 survived significantly longer than untreated animals. The orally administered substance was well tolerated even at high doses. Obviously, the substance was able to overcome the blood-brain barrier and significantly reduce the concentration of the cancer-promoting metabolite R-2-hydroxyglutarate in the astrocytoma. "The cancer cells of the treated mice lost their dangerous stem cell properties and developed into precursors of normal brain cells," explained von Deimling.

How BAY 1436032 (yellow) binds to the mutated enzyme IDH1. © Stefan Pusch/DKFZ

Under his leadership, an international, multidisciplinary clinical study is being conducted as part of the Heidelberg Neurooncology Programme in patients with astrocytomas and other solid tumours with a (R132)-IDH1 mutation. High expectations are pinned on the study, as treatment-resistant astrocytomas often degenerate into particularly aggressive tumours which do not respond to existing cancer drugs.

Another paper published by the DKFZ-Bayer Alliance demonstrates that the pan-mutant IDH1 inhibitor BAY 1436032 is also effective in AML patients whose blood cancer cells carry the R-132 mutation. The team of Prof. Dr. Alwin Krämer, head of the Clinical Cooperation Unit Haematology/Oncology at the University Hospital in Heidelberg and the DKFZ, played an instrumental role in these achievements. A preclinical study performed on mice carrying (R132)-IDH1-mutated human AML cells was also successful: the treated animals lived significantly longer and the number of leukaemia stem cells in the bone marrow decreased significantly. According to Krämer, there is a lot of evidence to show that "BAY 1436032 is not cytotoxic to tumour cells but allows them to mature into normal blood cells". Under Krämer’s leadership, an international clinical trial to evaluate the tolerability and dosage of the inhibitor in AML patients with IDH1 mutations will commence shortly.

Original publications:

Pusch S, Krausert S, Fischer V, Balss J, Ott M, Schrimpf D, Capper D, Sahm F, Eisel J, Beck A-C, Jugold M, Eichwald V, Kaulfuss S, Panknin O, Rehwinkel H, Zimmermann K, Hillig RC, Guenther J, Toschi L, Neuhaus R, Haegebart A, Hess-Stumpp H, Bauser M, Wick W, Unterberg A, Herold-Mende C, Platten M, von Deimling A: Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo. Acta Neuropathologica, 2017, DOI: 10.1007/s00401-017-1677-y

Chaturvedi A, Herbst L, Pusch S, Klett L, Goparaju R, Stichel D, Kaulfuss S, Panknin O, Zimmermann K, Toschi L, Neuhaus R, Haegebarth A, Rehwinkel H, Hess-Stumpp H, Bauser M, Bochtler T, Struys EA, Sharma A, Bakkali A, Geffers R, Araujo-Cruz MM, Thol F, Gabdoulline R, Ganser A, Ho AD, von Deimling A, Rippe K, Heuser M, Krämer A: Pan-mutant-IDH1 inhibitor BAY 1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo. Leukemia, 2017, DOI: 10.1038/leu.2017.46

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