Making Glioblastomas Starve – First Clinical Trials In The USA And Germany

Glioblastoma is the most common and aggressive brain tumour. Due to the fact that in humans it is well-supplied with blood, this tumour 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 tumour itself in an attempt to literally "starve" the tumour. 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 Tumour 2006 conference of the Max Delbruck Centre 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 tumour growth as the tumours take nutrients and oxygen from the blood stream. In order to ensure that they will not starve, tumours 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 tumour. 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 tumour from growing, scientists and clinicians 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 tumour (GIST). The idea of starving tumours 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 tumour. In addition, in humans they are the tumours with the best blood supply, according to Professor Vajkoczy. After having connected with the new blood vessels, these tumours 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 tumour 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 tumour 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 tumour 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 tumour 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 tumour angiogenesis, as high as 22 months. "[The survival rates are] … very favourable 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 tumours could possibly develop with the aim of optimizing the therapy.(Source: Max Delbruck Centre of Molecular Medicine: December 2006.)