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Glioblastoma is the most common and aggressive brain tumor. Due to the fact that in humans it is well-supplied with blood, this tumor grows very fast and affected individuals die within a few months of diagnosis. In several clinical trials in the USA and Germany, clinical researchers are using different approaches to prevent the creation of new blood vessels initiated by the tumor itself in an attempt to literally "starve" the tumor. Professor Peter Vajkoczy of the University Clinic in Mannheim which belongs to University of Heidelberg, Germany, presented his latest results from a clinical pilot study at the Brain Tumor 2006 conference of the Max Delbrück Center of Molecular Medicine (MDC) in Berlin-Buch. Rather than administering high dose chemotherapy at several intervals, the team treated glioblastomas with low dose but continuously administered chemo-therapy in combination with an anti-inflammatory inhibitor to indirectly block blood vessel growth. "Of the thirty patients with glioblastoma, the average survival time was 17 months with a very good compliance. This is positive compared to other studies", Professor Vajkoczy said in Berlin.
Angiogenesis, the creation of tiny new blood vessels, plays an important role in tumor growth as the tumors take nutrients and oxygen from the blood stream. In order to ensure that they will not starve, tumors of a certain size send signals in the form of messengers molecules to the surrounding blood vessels which trigger the creation of new blood vessels which, in turn, grow and connect to the tumor. More than 25 of such messenger molecules are known today. One of the most important is VEGF (Vascular Endothelial Growth Factor), considered to be the central factor of new vessel formation.
To prevent the tumor from growing, scientists and clincians are attempting to block either the factors themselves or their creation. This idea of anti-angiogenesis was originally presented thirty years ago in the USA by Prof. Judah Folkman. Nevertheless, it was not until this year (2006) that the first anti-angiogenic drug was approved in the USA. The drug works by cutting the blood supply in cases of renal cell carcinoma and in a rare form of gastrointestinal stromal tumor (GIST). The idea of starving tumors is now being tested as a possible therapy for glioblastomas in both the USA and in Germany.
Glioblastomas arise from the glial cells in the brain. They are the most common and most aggressive form of brain tumor. In addition, in humans they are the tumors with the best blood supply, according to Professor Vajkoczy. After having connected with the new blood vessels, these tumors experience a "growth spurt". Therefore, researchers consider anti-angiogenesis to be very important for the treatment of glioblastomas.
Yet the mechanisms of vessel formation are complicated and not fully elucidated. Thus, Professor Vajkoczy is using an indirect approach to induce anti-angiogenesis in gliomas. "It has been shown that some drugs which are being used in conventional chemo-therapy have an anti-angiogenic effect." One of those drugs is the cancer-drug temozolomide. Professor Vajkoczy and his collaborators combined this drug with an anti-inflammatory inhibitor which also blocks the growth of blood vessels and applied it in a pilot study in Mannheim involving thirty glioblastoma patients. The results of this three-year study (2002 through 2005) have been published in part.*
As he reported in Berlin, the patients in the different subgroups received low dose temozolomide up to twice a day over a maximum period of 22 months. This metronomic therapy was designed to improve upon traditional tumor therapy. Normally, patients receive high doses of anti-cancer drugs over a fixed period of time followed by a period without medication to allow for the body to recover. However, in this therapy-free period, the tumor likewise "recovers" and starts to induce new vessel growth. Using low-dose chemotherapy that is steadily administered over weeks, the researchers aim to keep the tumor in check and prevent the growth of new blood vessels.
In addition, the clinicians from Mannheim combined the cancer drug with the inflammation-inhibitor rofexocib. This drug was replaced by celebrex, another inflammation-inhibitor, following the removal of rofexocib from the market in the fall of 2004 due to reasons unrelated to this therapy. Both drugs have anti-angiogenic effects and prevent an extended formation of the growth factor VEGF in tumor cells. These drugs block the enzyme cyclooxigenase-2 (COX-2) which is detectable in large amounts in gliomas.
"This combined approach is safe with only few side-effects. The quality of life of the patients remains good" reported Professor Vajkoczy in Berlin. The average time of survival was seventeen months and, even in patients with aggressive tumor angiogenesis, as high as 22 months. "[The survival rates are]? very favorable compared to conventional therapies", he said. Yet he emphasized that further examinations are necessary to gain better insight into the mechanisms and strategies of resistance toward this new technique which such tumors could possibly develop with the aim of optimizing the therapy.
* Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme
Jochen Tuettenberg1, Rainer Grobholz2, Tobias Korn1, Frederik Wenz3, Ralf Erber1, Peter Vajkoczy1
1, Department of Neurosurgery, Klinikum Mannheim, Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany., E-mail: peter.vajkoczy@nch.ma.uni-heidelberg.de 2, Department of Pathology, Medical Faculty of the University of Heidelberg,Mannheim, Germany 3, Department of Radiation Oncology, Medical Faculty of the University of Heidelberg,Mannheim, Germany
Journal of Cancer Research and Clinical Oncology. 2005 Jan;131(1):31-40.
Barbara Bachtler
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Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
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http://www.mdc-berlin.de/englisch/about_the_mdc/public_relations/e_index.htm
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