Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Blocking cancer-specific mutations in leukemia and brain tumors

30.05.2017

Many malignancies develop as a result of genetic alterations in individual cells. These gene mutations often cause altered proteins that give new, growth-promoting properties to the cell. A prime example for this principle is a cancer-related altered form of the IDH1 enzyme that was initially discovered in certain malignant brain tumors.

Scientists had noticed that mutations in isocitrate dehydrogenase (IDH) 1 almost always occur at position 132 of the enzyme's chain of amino acids. This replacement causes a specific cancer-promoting metabolic product to accumulate in the cells. Non-mutated IDH enzymes in healthy cells do not produce this metabolite.


Candidate drug BAY1436032 (yellow) binds to the mutated enzyme IDH1.

Credit: Stefan Pusch/DKFZ

"This prompted the idea of developing an agent that inhibits position 132-mutant IDH1," said Stefan Pusch from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). He added: "Our goal is to develop a drug that acts on cancer cells while it does not influence healthy cells with the normal enzyme."

In a research alliance with Bayer AG, the researchers from the DKFZ and Bayer jointly succeeded in finding a substance that is presumed to be highly selective. The investigational compound, called BAY1436032, is currently being examined in comprehensive preclinical tests for its safety and effectiveness.

Leukemia and brain cancer in mice slowed down

The 132 mutation of IDH1 has been found by now not only in various types of brain cancer (oligodendroglioma, diffuse astrocytoma and a smaller portion of glioblastomas) but also in approximately ten percent of acute myeloid leukemias (AML) as well as in bile duct cancer and certain malignant bone tumors. In two currently published studies, the Heidelberg researchers have now demonstrated the preclinical activity of BAY1436032 against AML and brain tumors (astrocytoma) in mice.

Under treatment with BAY1436032, mice that had been transplanted human astrocytoma cells survived significantly longer than untreated fellows. The agent, which can be administered with the food, substantially reduced the levels of the cancer-promoting metabolite in the cancer. "Even at high doses the animals tolerated the treatment well," said Andreas von Deimling, who is the head of a Clinical Cooperation Unit at the DKFZ and at Heidelberg University Hospital. "BAY1436032 really seems to act specifically on the mutated IDH1 in the cancer cells."

Tests of the agent against AML were also successful. Mice that had received IDH1-mutant human leukemia cells survived longer when treated with BAY1436032 than untreated animals did. Furthermore, the leukemia stem cells in their bone marrow were significantly reduced.

Cancer cells lose stem-cell properties

"There is evidence to suggest that BAY1436032 does not act cytotoxic, but may cause tumor cells to mature into normal blood cells instead," stated hemato-oncologist and scientist Alwin Krämer, who leads a Clinical Cooperation Unit of the German Cancer Research Center and Heidelberg University Hospital. Von Deimling, who led the preclinical study in gliomas, confirmed this observation: "The cancer cells in the mice under investigation lost their dangerous stem-cell characteristics and developed into precursors of normal brain cells".

As a couple of different mutations at amino acid position 132 of IDH1 are known, the research team also tested the effectiveness of the investigational compound against these mutational variants. In biochemical and cell culture assays, they could show that BAY1436032 is effective against all known mutational variants at position 132. In addition, there are indications that BAY1436032 may be able to cross the blood-brain barrier.

Following these promising preclinical results, a first clinical trial is currently being conducted at the Neurology Department of Heidelberg University Hospital. The trial comprises patients with glioma and other solid tumors with proven IDH1 mutation. The goal is to determine the tolerability of BAY1436032 and the appropriate dose. "Innovative therapies are greatly needed here," von Deimling said, "because therapy-resistant astrocytomas often turn into highly aggressive tumors that cannot be treated effectively with the drugs that are available at the present time."

In addition, an international clinical trial led by Alwin Krämer will shortly be launched to study the tolerability and the appropriate dose of BAY1436032 against IDH1 mutant AML.

###

A Chaturvedi, L Herbst, S Pusch, L Klett, R Goparaju, D, Stichel, S Kaulfuss, O Panknin, K Zimmermann, L Toschi, R Neuhaus, A, Haegebarth, H Rehwinkel, H Hess-Stumpp, M Bauser, T Bochtler, E A Struys, A, Sharma, A Bakkali, R Geffers, M M Araujo-Cruz, F Thol, R Gabdoulline, A, Ganser, A D Ho, A von Deimling, K Rippe, M Heuser, A Krämer: Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo. Leukemia, 2017; DOI: 10.1038/leu.2017.46.

Stefan Pusch, Sonja Krauser, Viktoria Fischer, Jörg Balss, Martina Ott, Daniel Schrimpf, David Capper, Felix Sahm, Jessica Eisel, Ann-Christin Beck, Manfred Jugold, Viktoria Eichwald, Stefan Kaulfuss, Olaf Panknin, Hartmut Rehwinkel, Katja Zimmermann, Roman C. Hillig, Judith Guenther, Luisella Toschi, Roland Neuhaus, Andrea Haegebart, Holger Hess-Stumpp, Markus Bauser, Wolfgang Wick, Andreas Unterberg, Christel Herold-Mende, Michael Platten, Andreas von Deimling: 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

The German Cancer Research Center (Deutsches Krebsforschungszentrum, 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.

Media Contact

Dr. Sibylle Kohlstädt
S.kohlstaedt@dkfz.de

 @DKFZ

http://www.dkfz.de 

Dr. Sibylle Kohlstädt | EurekAlert!

Further reports about: AML CANCER DKFZ IDH1 brain cancer brain tumors cancer cells healthy cells leukemia metabolite tumors

More articles from Health and Medicine:

nachricht Using fragment-based approaches to discover new antibiotics
21.06.2018 | SLAS (Society for Laboratory Automation and Screening)

nachricht Scientists learn more about how gene linked to autism affects brain
19.06.2018 | Cincinnati Children's Hospital Medical Center

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Temperature-controlled fiber-optic light source with liquid core

In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.

Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...

Im Focus: Overdosing on Calcium

Nano crystals impact stem cell fate during bone formation

Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

Towards universal influenza vaccines – is Neuraminidase underrated?

22.06.2018 | Life Sciences

Thermal Radiation from Tiny Particles

22.06.2018 | Physics and Astronomy

Polar ice may be softer than we thought

22.06.2018 | Earth Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>