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.

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."

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.

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