Grant: Operating Grant

The cellular inhibitor of apoptosis (IAP) gene family, which includes the proteins cIAP1, cIAP2 and XIAP, was discovered by our group nearly 20 years ago. Since then, the IAPs have been proven to be important cancer causing genes because they can suppress cancer cell death induced by multiple therapeutic and physiological insults, such as chemo- and radio-therapy, and cell death signals from the host's own immune system. Experimental drugs, which target cIAP1, cIAP2 and XIAP, have been in the clinic for several years and have been proven safe. However, the effectiveness of these anti-cancer drugs, known as SMCs, is limited by the fact that they need a death signal, such as tumor necrosis factor alpha (TNF-alpha), from the host to kill the cancer cell. Unfortunately, TNF-alpha is too toxic to be given directly to the patient. However, we devised and tested ways by which experimental hosts (i.e. mice) can generate their own TNF-alpha response in a controlled and safe manner that can then kill tumors in combination with SMCs. We found that co-treatment of mice with SMCs and infection with certain tumor-killing ("oncolytic") viruses results in a powerful death response of cancer cells. Furthermore, the oncolytic virus can be substituted by various non-viral immune stimulants to produce the same potent combination therapy effect. We are proposing to continue the investigation of this co-treatment approach in order to ultimately bring this promising and novel anti-cancer treatment procedure into the clinic.