Control of Immune Checkpoints by the Ubiquitin Ligase RNF5: Implications for Melanoma
Abstract
I am a postdoctoral researcher in the lab of Dr. Ze ev Ronai at the Sanford Burnham Prebys Medical Discovery Institute. Support by the Peer Reviewed Cancer Research Program s Horizon Award will enable me to answer fundamental questions in melanoma management and conduct research with clinical significance. The award comes at a critical stage in my training to move me toward my goal, which is to establish an independent laboratory in academia. These studies will allow me to define biochemical components of one of the most important pathways in cancer research today, namely the one that governs the immune checkpoint. I am dedicating my career to cancer research, and in this application focus my efforts to identify novel therapeutic targets for melanoma, the most devastating form of skin cancer. Since I joined the lab in 2014, I have studied exciting new approaches applicable to melanoma treatment, some recognized as the most important discoveries of the past decade. Currently, there is intense interest in how tumors, including melanoma, block immune responses, allowing tumors to develop unchecked. This proposal addresses approaches to strengthen the immune response. Melanoma often develops following extensive and prolonged sun exposure, and strong evidence suggests that sun exposure in individuals aged 16-25 constitutes a more significant risk than it does in older individuals. As a result, this work is highly applicable to young individuals in the military: exposure of our troops to sun in the Middle East and other hot countries -- particularly in contexts in which protective measures or sun exposure treatments are impractical -- puts young men and women at major risk for developing melanoma after they leave the Service, potentially impacting not only their health but the well-being of families that depend on them. The so-called "immune checkpoint mechanism" is analogous to a brake, which slows the immune system s ability to attack and eradicate tumor cells. The success of immune checkpoint-targeted therapies in recent years is recognized as one of the most significant advances in cancer therapy, with melanoma being the leading paradigm. Our lab discovered a component of that pathway potentially responsible for melanoma growth. We identified a factor whose inhibition restricts melanoma growth in mouse models of melanoma. Specifically, we found that a gene named RNF5 (for Ring Finger 5) functions in the pathway and that mice engineered to lack this gene showed decreased melanoma tumor growth relative to mice with intact RNF5. Our data also showed that mice lacking RNF5 exhibited enhanced anti-tumor immune responses, suggesting that RNF5 loss inhibits the immune checkpoint. Biochemically, RNF5 acts to modify ("ubiquitinate") proteins in a manner that destabilizes them, implicating these interacting factors as players in the immune checkpoint. The research I plan to conduct with support of this Horizon Award will define targets of RNF5 in this context and test whether their activity, or that of RNF5, can be manipulated as part of immune response-based therapies for melanoma. If successful, this work could provide new drugs for preclinical and later clinical evaluation, within the next 3 to 5 years. This outcome would increase treatment options for patients, both in and out of the military, with this highly invasive cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610517
Entities
People
- Yan Li
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army