Grant: Project Grant

We have identified a new class agents designed to block protein called EGFR and EGFRvIII that are found in stem cells and believed to be responsible for drug resistance and recurrencein glioblastoma multiforme (GBM). We also armed this agent with a chemical function that allows it to damage DNA in cancer cells. This led to a molecule with one-two punch function that is fatal to these robustly resistant cells. Recent studies showed that this type of molecules is capable of crossing the blood barrier and inducing significant tumour delay in an aggressive tumour model of mouse intracranially implanted with these cells called stem cells take from human brain tumours that are resistant to temodal, the drug used in the clinic . We now understand what makes this compound damage DNA: a very small thing on the structure that we call chloroethylamino. Therefore, we are ready to improve it and test it in GBM.The unique strength of the activity that we see in petri dishes does not translate into the expected full blown activity in mice carrying human tumours. Recently we found that this is because the liver abundantly transforms the drug into something that is not strong enough to kill the tumour cells. The purpose of this proposal is to produce new drugs to make sure that the liver does not remove too much of what it takes for the molecule to have full blown action: this chloroethylamino group, which is responsible for damaging the DNA of tumour cells. We also want to test how they can improve outcome in combination with radiation therapy. To perform this work, we have assembled a team of experts in radio-oncology who treat patients with brain cancers and who established experimental disease models in animal and a neurosurgeon who will provide real samples from human. Dr. Jean-Jacques Lebrun a well-renowned expert in genetic engineering will engineer GBM cells to serve as clinically relevant experimental models.