Analysis of CD95L and TRAIL apoptotic pathways in glioma. [ 2001 - 2003 ]

Research Grant

Researchers: A/Pr Christine Hawkins (Principal investigator) ,  Prof David Ashley

Brief description Most patients with the brain cancer malignant glioma die within two years of diagnosis, thus innovative approaches to treatment are desperately needed. Mutations which prevent the precancerous cells from responding to suicide (apoptotic) signals can contribute to tumourigenesis. As standard treatment regimes act by inducing this cellular suicide machinery, tumour cells with apoptotic pathway alterations can be resistant to conventional therapies. Malignant gliomas are typically resistant to chemo- and radiotherapy, and therefore may have altered apoptotic pathways. By identifying the components of apoptotic pathways in glioma cells, rational design of either novel drugs, or treatments which will restore-enable susceptibility of the tumour cells to currently available therapies will be feasible. Here we will focus on the suicide pathways triggered by the molecules CD95L and TRAIL. We will characterise the sensitivity of glioma cells to CD95L and TRAIL, chemotherapeutic drugs and irradiation. We will then systematically survey the molecules implicated in CD95L and TRAIL-mediated cell death, based on studies in other cell types, to determine the relevant components of the molecular pathways which lead to apoptosis following CD95L-TRAIL exposure. We will also assess the roles played by known inhibitors, in determining resistance to CD95L and-or TRAIL, and will perform screens for novel inhibitors of these pathways. This study will elucidate the molecules responsible for the CD95L-TRAIL-mediated apoptosis seen in some glioma cells, and the molecules which confer resistance to these treatments in others. We will also learn whether the typical resistance to chemo- and radiotherapy observed in gliomas is mechanistically linked to resistance to CD95 and-or TRAIL resistance. This knowledge will be valuable for the rational design of diagnostic and therapeutic agents for glioma, and potentially for other diseases.

Funding Amount $AUD 423,055.08

Funding Scheme NHMRC Project Grants

Notes Standard Project Grant