• Researcher Profile

    Carl Novina, MD, PhD

     
    Carl Novina, MD, PhD
     
    Associate Professor, Dana-Farber Cancer Institute & Harvard Medical School
    Associate Member, Broad Institute of Harvard and MIT


    Office phone: 617-582-7961
    Fax: 617-582-7962
    Email: carl_novina@dfci.harvard.edu
    Website: Novina Lab Website

    Preferred contact method: email
     
     

    Research Department

    Cancer Immunology and Virology

    Area of Research

    Engineering Epigenetic Cancer Immunotherapy


    Dana-Farber Cancer Institute
    450 Brookline Avenue
    Smith 552
    Boston, MA 02215

    Biography

     Carl D. Novina MD, PhD is an Associate Professor of Medicine at the Dana-Farber Cancer Institute & Harvard Medical School and an Associate Member of the Broad Institute of Harvard and MIT. He received his M.D. from Columbia University, College of Physicians and Surgeons and his Ph.D. from Tufts University, Sackler School of Graduate Biomedical Sciences. He completed his postdoctoral fellowship at the Massachusetts Institute of Technology in the laboratory of Nobel Laureate Dr. Phillip Sharp.

    Dr. Novina’s laboratory has made several important discoveries into the biology of noncoding RNAs, their dysregulation in cancers, and their development as biomedical tools. More recently, his laboratory has developed tools for cellular engineering, including tools that enable targeted DNA methylation and T cell-directed immunotherapy. He has established many collaborations between industry partners and physicians to facilitate his goal of bringing biomedical innovations from bench to bedside.

    Dr. Novina is the recipient of numerous awards and honors including the Doris Duke Clinical Scientist Development Award, American Cancer Society Research Scholar Award, W.M. Keck Distinguished Young Scholars Award, Department of Defense Idea Award, The NCI Director’s Provocative Questions Award, and the National Science Foundation Collaborative Research Project Award. He is also the recipient of the prestigious NIH Director’s Pioneer Award, which funds high-risk research with transformative potential.

    Research

    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.

    (1) Discovering lncRNA-dependent interactomes in cancers

    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 (Schmidt 2016). 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.

    (2) Molecular pathogenesis of the ribosomopathies SDS and DBA

    We found that reduced expression of ribosomal protein genes selectively increased translation of microRNA-targeted mRNAs by a mechanism involving the p53 pathway (Janas 2012). Our data suggest that RPGs as a class globally regulated microRNA-mediated repression of translation initiation. This led us to analysis of bone marrow failure syndromes (e.g. Shwachman Diamond Syndrome (SDS) and Diamond Blackfan Anemia DBA)) characterized by germline mutations in genes mediating ribosome biogenesis and function.

    Dysfunction in rare or heterogeneous cell types contributes to human disease. Recent technological advancements have enabled robust analysis of single eukaryotic cells. Single cell RNA-sequencing on primary CD34+ hematopoietic progenitors from normal and SDS bone marrows identified dysregulation of TGF-beta target genes in SDS hematopoietic stem cells and multipotent progenitors, but not in lineage committed progenitors. Proteomic analysis of primary SDS patient plasma identified increased TGF-beta family ligand production. Treatment of SDS patient bone marrows with a TGFBR1 inhibitor increased hematopoietic colony formation, supporting a causative role for TGF-beta signaling through its receptor as a mechanism of SDS pathogenesis. We are planning to perturb specific effectors in the TGF-beta signaling network in selected cell populations in SDS bone marrows, especially through epigenetic engineering. These studies might enable translation of insights from single cell biology into a novel SDS therapy.

    (3) Targeted DNA methylation and epigenetic regulation of gene expression

    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 (Xiong 2017). 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.

    (4) Engineering T cells for immunotherapy

    T cells play a central role in our immune system’s responses to infections. Recent clinical studies have shown tremendous promise that the immune system can be “taught” to reject tumors as if the tumors were infections. One way to teach T cells is to “engineer” them to bind specific proteins found on the surface of tumors. An especially exciting example of this strategy is the use of “chimeric antigen receptor” (CAR) T cells. Clinical trials have shown that CAR T cells can selectively bind to a protein found on only antibody producing cells (B cells) and on B cell cancers (leukemias). However, patients who receive such CAR T cells often show complete remission of their leukemia as well as a dramatic loss of their normal B cells. This approach is limited and therefore not used to treat patients with solid tumors partly because few proteins are found only on tumors but not on normal tissues.

    The Novina Lab is developing technologies that broaden the application of CAR T cell technology to attack solid tumors by selectively unmasking artificial antigens on tumors or through direct engineering of T cell receptors. We are working with clinical and industry collaborators to engineer CAR T cells that mount robust immune responses at tumors with minimal effects on normal tissues. We are attempting to engineer autologous T cells for ovarian cancer, neuroendocrine and brain cancer immunotherapy. We are also exploring the use of RNA-based strategies to engineer T cells to resist the anti-inflammatory environment which limits immune responses to tumors.

    Trainees

    • Joyce, Cailin, PhD
    • Neier, Steven, PhD
    • Nobili, Alberto, PhD
    • Thomas, Dolly, PhD
View Physician Directory

Find a Clinical Trial

Support Cancer
Research

Give Now