Grant: Project Grant

A promising class of drugs has recently emerged that recruits the patient's own immune system to fight cancer, fulfilling a long-held belief that 'immunotherapy' can help in the treatment of cancer. The drugs called "immune checkpoint inhibitors", or ICIs, are significantly extending the life of patients with advanced stages of cancer, such as melanoma, a disease once thought to be incurable. ICIs are poised to improve survival rates for many other forms of cancer. However, these drugs have significant side effects and there remains much room for improvement. I recently discovered that a family of experimental drugs called Smac mimetics, which have been proven safe in Phase I/II cancer trials, can also make use of the immune system to dramatically increase the effectiveness of ICIs in animal models of cancer. I discovered that the combination of Smac mimetics with ICIs can cure mice with glioblastoma, a highly fatal brain cancer seen in adults and children. In this proposal, I seek to understand the broad-based nature of this combination and to decipher the ways that Smac mimetics improve the activity of ICIs against glioblastoma. These studies will improve our understanding of this specific deadly brain cancer and help justify the initiation of combination trials using Smac mimetics and ICIs for cancer patients who are in dire need of more effective therapies.