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    Carl Novina, MD, PhD

    Associate Professor of Medicine, Harvard Medical School
     
     

    About Novina Lab

    Engineering epigenetic cancer immunotherapy

    The Novina lab combines basic science and advanced technologies to accelerate the translation of biological discoveries into novel therapies. Areas of focus in the lab include the role of non-coding RNAs in oncogenesis and epigenetic engineering of disease relevant loci – especially genes relevant for cancer immunotherapy – using our programmable DNA methyltransferase.

    Long non-coding RNAs (lncRNAs) are emerging as important regulators of tissue physiology and disease processes, especially cancers. Although dysregulated lncRNA expression has been associated with cancer progression, the contribution of lncRNAs to oncogenesis is poorly understood because their molecular and biological functions are obscure. We recently identified a novel lncRNA and its interacting proteins important for melanoma invasion. We are currently studying how this lncRNA functions at the molecular level, which may be important for determining why more males than females die from melanomas.

    More broadly, the Novina lab is attempting to understand lncRNA biology and its roles in oncogenesis by systematically identifying lncRNA-associated proteins. It is virtually impossible to bioinformatically predict lncRNA function (or interacting proteins) by sequence analysis because (1) lncRNAs are poorly conserved and (2) proteins bind to RNAs by a poorly understood combination of RNA sequence and secondary structure. We are beginning to systematically define lncRNA-dependent interactomes through development of a lncRNA-based yeast three hybrid (Y3H) platform.

    Regulatory RNAs are just one of many regulatory mechanisms that coordinate gene expression in normal and disease contexts. MicroRNA and lncRNA genes themselves are developmentally regulated and demonstrate altered epigenetic marks such as aberrant promoter hypo- and hyper-methylation, especially in cancers. Altered microRNA expression has been correlated with the tissue of origin, prognosis, and drug sensitivity of cancers and other diseases.

    We recently described a novel tool for targeted DNA methylation by tethering a “split-fusion” methyltransferase to an endonuclease-deficient mutant Cas9. Our split-fusion approach minimizes off-target effects by ensuring that enzyme activity is specifically reconstituted at the targeted locus. We are also developing gRNA screening strategies to fine-tune targeting within each locus. How are epigenetic marks set, maintained, spread and inherited? How do establishing DNA marks relate to establishing histone marks? These fundamentally important questions must be answered to realize the full potential of epigenetic engineering in the clinic.

    To develop this tool as a future epigenetic therapy, we are attempting to target DNA methylation to genes important for cancer immunotherapy. Specifically, we would like to repress checkpoint inhibitor genes which would increase T cell-mediated tumor killing. Additionally, we would like to repress “M2” polarizing genes in tumor-associated macrophages. Increasing “M1” polarization is expected to increase anti-tumor immune responses.