Forsøksdyr: Determening the role of lactate dehydrogenase (LDH) in glioblastoma

Godkjenningsdato 25.05.2018

Godkjenningsperiode 01.06.2018-01.06.2019

Current treatment for malignant brain tumors (Glioblastoma, GBM) include surgery followed by combined radio-and chemotherapy, yet the average survival rate is still only 12-15 months. Therefore, there is a need for new innovative treatment strategies. As GBMs are highly hypoxic and angiogenic, they have been considered as good candidates for anti-angiogenic therapy. Recent results from our laboratory have shown that targeting the Vascular Endothelial Growth Factor (VEGF) pathway, using the drug Avastin (bevacizumab), show antitumor effects in animal models as well as high initial radiological response rates in patients. Yet, in the clinic, anti-angiogenic therapy for GBMs has not yet shown any overall survival benefit. Recent preclinical results from our laboratory show that anti-vascular therapy leads to a metabolic switch towards anaerobic glycolysis and the data indicate that lactate dehydrogenase (LDH), the enzyme that convert pyruvate into lactate, represents a promising target for therapy. In this proposal, we hypothesize that blocking both angiogenesis and anaerobic respiration we will cause a suppression of tumor growth and invasion, thereby improving survival. This application represents a focused initiative, developing a new treatment principle based on new biological knowledge generated in our laboratory showing how tumors develop metabolic escape mechanisms towards anti-angiogenic therapy. This knowledge represents thus, a biological rationale that will be used to design new therapeutic strategies for GBMs.

In total we will use 36 nod/scid mice for this experiment. As animal models reflect 3D-structural behavior and physiological conditions that in vitro experiments cannot, we will use animals to obtain our aim.
The procedures will be carried out by at least two well-trained persons, with significant experience with similar procedures. The biological effect, human error and variation will therefore be minimal. We will monitor the animals carefully after implantation of the tumor. We will follow the tumor growth by non-invasive imaging, in addition to observation of the animals’ behavior, and measuring their body weight regularly. Animals will be euthanised when they develop symptoms identified by using a score sheet. We have classified the burden of this experiment as moderate for the animals.