Understanding protein interactions to develop new cancer treatments

Based at the Central Clinical School, our laboratory works closely with clinicians at the Alfred Hospital to study mechanisms of cancer development and metastasis. One of our key objectives is to understand how the histone methyltransferase EZH2 drives cancer growth and metastases. EZH2, a master epigenetic regulator in mammals, is also a driver of cancers in the prostate, breast, brain, ovary and melanoma. Because of this, more than 10 different types of EZH2 inhibitors have been developed by pharmaceutical companies, almost all focusing on its well known methyltransferase activity. Unfortunately, none of these inhibitors has been very successful. Our recent work has shed a light on this perplexing phenomenon. We demonstrated that EZH2 can drive cancer growth via a newly discovered mechanism, which is independent of its methyltransferase activity and dependent on interacting with at least 2 other proteins, IMPDH2 and KLC1. With a long-term goal of translating our preliminary finding into drug discovery efforts, we will be using highly sophisticated biochemical techniques to confirm and understand the exact sites of these protein interactions, which can be targeted in cancer. This project will first confirm EZH2-IMPDH2 interactions and subsequently identify their interaction. Based on these findings, we will develop new ways to inhibit those interactions, and test its effects in cancer growth and metastasis.