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Hope for more effective brain tumour therapy

Glioblastoma is the most common and most aggressive type of brain tumour in humans. It has a tendency to recur and it carries a bad prognosis. Intensive research into the molecular reaction chains involved in its pathogenesis has led to promising and effective treatment strategies.

Primary brain tumours account for around two per cent of all tumours; compared with lung and breast cancer, they are therefore quite rare. The German Cancer Society estimates show that around 7,000 people every year in Germany develop brain tumours and the even rarer cancer of the spinal spinal cord. This estimate does not include patients with metastases that originate from primary tumours nor does it include the large number of deaths resulting from brain tumours.

Unclear causes, bad prognoses

The causes of the development of primary or intrinsic (arising in the brain) tumours are still largely unknown. A genetic disposition for brain tumours appears to be rare; neither have lifestyle and diet or environmental factors, known to be contributory factors for many other types of cancer, been identified as factors that contribute to the development of brain cancers. The majority of brain tumours occur in people between 50 and 70 years of age; they are also quite frequent in young children, representing the second most frequent type of tumour in children after leukaemia.

Magnetic resonance image of a recurrent glioblastoma © German Cancer Society

The biomodal frequency distribution of brain tumours is most likely due to different causes. While elderly people are mainly affected by malignant gliomas (originating from glial cells) and benign meningeomas (tumours of the meninges), children are mainly affected by benign gliomas and malignant medulloblastomas (which occur mainly in the cerebellum).

Malignant gliomas are the most frequent type and growth forms of intrinsic brain tumours in adults, and more than 50 per cent of these are glioblastomas. They pose a particular health threat due to their aggressive growth and frequent relapses. For this reason, the development of more efficient strategies for the treatment of glioblastoma is a prime role of the molecular biology and neurooncology research and development projects outlined below:

Angiogenesis blockers

The name glioblastoma multiforme, which is no longer used, relates to a major problem associated with this cancer, namely the huge variation in shape. The treatment of glioblastoma using maximally safe surgery, radiotherapy and chemotherapy is always associated with the risk that tumour cells will survive in seemingly healthy brain tissue and form the starting point for a tumour relapse. With a one-year-survival rate of only 20 per cent once a glioblastoma relapse has been discovered, the prognosis for these patients is very bad. The drug cilengitide developed by Darmstadt-based Merck KgaA could potentially improve this situation. Cilengitide is an integrin inhibitor that is currently being tested in a clinical Phase III trial. The results of the preceding Phase II trial suggest that the drug improves the survival rate of patients undergoing primary tumour treatment (subgroup determined from molecular analyses). The results of the ongoing Phase III trial, for which the required number of patients has been recruited, are expected for 2014. Integrins are a large family of receptor proteins on cell membranes that are mainly responsible for making cells and the extracellular matrix interact. In addition, they also play a role in the survival of tumour cells, tumour angiogenesis (the formation of blood vessels required to supply the tumour with oxygen and nutrients) and metastasis. Cilengitide is a cyclic pentapeptide that binds to the integrins ανβ3 and ανβ5, which also occur in glioblastoma. This prevents the formation of blood vessels and hence the supply of nutrients to the tumour resulting in the tumours being starved and destroyed.

The monoclonal antibody bevacizumab (Avastin®) marketed by Roche/Genentech also has promising effects when used for the treatment of primary and recurrent tumours. The antibody is directed against the vascular endothelial growth factor, thereby improving therapy by targeting the same tumour compartment as cilengitide. In addition, important feasibility studies are currently being carried out with an anti-angiogenic substance (temsirolismus, Torisel® developed by Pfizer) and a low-molecular inhibitor of a transforming growth factor receptor (Eli Lilly).

Different functions of the CD95 receptor

Apogenix GmbH is pursuing another promising approach for the treatment of glioblastoma. The Heidelberg-based biopharmaceutical company, a spin-off of the German Cancer Research Center (DKFZ), develops novel protein drugs based on the targeted modulation of interleukin-4 and CD95 receptor-mediated signalling pathways. These signalling pathways play an important role in a variety of malignant and inflammatory diseases. The company’s lead compound, APG101, is a soluble fusion protein consisting of the extracellular domain of CD95 and the Fc portion of immunoglobulin G1. APG101 blocks CD95-mediated signalling pathways by binding to the ligand, thereby blocking activation of the CD95 system and preventing the CD95-mediated apoptosis of healthy cells.

Prof. Dr. Ana Martin-Villalba © DKFZ

CD95 is a receptor with pleiotropic functions transmitting apoptotic and non-apoptotic signals such as migration and invasion of tumour cells, which is triggered by the CD95 ligand. CD95 acts as a death receptor that induces programmed cell death (apoptosis) following its activation through the CD95L death ligand. APG101 addresses a variety of disease indications that are characterised by an excess of apoptosis, such as acute "graft-versus-host disease" (aGvHD). Prof. Dr. Ana Martin-Villalba and her research group at the DKFZ in cooperation with scientists from the University of Heidelberg and Apogenix have shown that the situation is different in glioblastoma.

Suppression of invasive growth

Glioblastoma cells induce the expression of CD95L in the surrounding nervous tissue, thereby activating the CD95 receptor on the plasma membrane of tumour cells. However, this does not initiate apoptosis in glioblastoma cells, but triggers the release of enzymes that favour the migration of tumour cells into the surrounding brain tissue. By blocking the CD95L ligand, APG101 also suppresses the further invasive growth of the glioblastomas, which is the major cause of the recurrences associated with this disease. Apogenix has received two patents from the European Patent Office, one for APG101’s composition of matter and the second one for the medical use of CD95 ligand inhibitors such as APG101 for the treatment of cerebral injuries. In addition, Apogenix was also granted orphan drug status in Europe and the USA for APG101 for the treatment of glioblastoma.

APG101 is currently undergoing a clinical Phase II trial for the treatment of glioblastoma. The trial is being conducted at 21 study centres in Germany and 11 additional sites in Austria and Russia. Primary endpoint of the trial is the 6-month rate of progression-free survival (PFS6) of patients treated for first or second relapse of glioblastoma. Patients are either being treated with APG101 and radiotherapy or with radiotherapy alone. Clinical data show that APG101 is safe and well tolerated by the patients. In January 2011, the independent “Data Safety Monitoring Board” (DSMB) recommended the unchanged continuation of the trial on the basis of 25 patients treated.

Prof. Dr. Wolfgang Wick © University Hospital of Heidelberg

Professor Dr. Wolfgang Wick, medical director of the Department of Neurooncology established at the Neurocentre of the University Hospital of Heidelberg and the National Centre for Tumour Diseases, is the principal investigator of the trial. This is the first independent academic department in Germany focusing on the treatment and research of tumour diseases of the nervous system. The department is financially supported by the Hertie Foundation. Working in close cooperation with other hospitals and institutes at the University of Heidelberg, the department is treating patients with brain tumours according to state-of-the-art therapy standards and through medical trials to test the efficacy of new drugs. Professor Wick is also head of the Clinical Cooperation Neurooncology Unit at the DKFZ which focuses on the biology of malignant gliomas and the preclinical development of new strategies for their treatment. Prof. Wick regards the cooperation between DKFZ, Apogenix, NCT and Heidelberg University, which has led to the ongoing APG101 trial, as an excellent model for the effective translation of basic research into clinical application.

Invasion as resistance mechanism to brain tumour therapy

Prof. Wick’s research group is also investigating experimental strategies for the treatment of malignant brain tumours with the goal of uncovering resistances to therapies involving anti-angiogenic drugs and irradiation as well as deciphering specific resistance and survival strategies of glioma cells under hypoxic conditions. In a project funded by the German Ministry of Education and Research (BMBF), the researchers are investigating novel invasion-associated molecular target molecules for the treatment of glioblastoma with the goal of quickly transferring the laboratory results into clinical concepts. Other BMBF-funded projects carried out in cooperation with numerous research groups from Heidelberg focus on the development of new prognostic and predictive factors in large controlled studies using different high-throughput methods with the aim of defining relevant glioblastoma subgroups according to specific molecular characteristics.

Further information:
Prof. Dr. Wolfgang Wick
Department of Neurooncology
Hospital of Neurology and National Tumour Centre
University Hospital Heidelberg
Im Neuenheimer Feld 400
69120 Heidelberg
E-mail: wolfgang.wick(at)med.uni-heidelberg.de
Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/hope-for-more-effective-brain-tumour-therapy