The overarching goal of the Bedogni lab is to understand tumor-specific traits that make cancer therapeutically challenging, with a focus on melanoma, the deadliest type of skin cancer, whose trend has been persistently on the rise. One of the main projects in the lab is to understand the role of Notch1 and ERBB3 in the pathogenesis of melanoma. Notch1 and ERBB3 are embryonic developmental proteins that also play an essential role in melanocyte stem and precursor cells. While mature melanocytes express very little, if none, levels of both, we have discovered that Notch1 and ERBB3 are concomitantly reactivated in up to 70% of melanoma, regardless of their oncogenic drivers. Pharmacological inhibition of these cascades leads to melanoma tumor regression. The goals are to understand the underlying mechanisms of the cooperation of Notch1 and ERBB3 in sustaining melanoma and to design better targeted therapies, devoid of the side effects associated with pan ERBB and Notch inhibitors. To this end we have designed novel anti Notch1 and anti ERBB3 selective inhibitors to test their efficacy in melanoma models of disease.
These models encompass classic xenograft models to study human melanoma cell lines responses; as well as patient derived xenografts; and syngeneic and transgenic mouse melanoma models to address the effects of these novel therapies on the immune component of the tumor and host. Another line of research focuses on understanding how the interplay between the extracellular matrix (ECM) and the tumor affects responses to therapy. In particular, we are dissecting the role of the metalloproteinase MT1-MMP in modulating tumor cell responses to chemo- radio- and targeted therapy. Evidence suggests MT1-MMP mediated processing of ECM components activates survival signaling pathways inside the cells that allow tumors to survive treatment and to eventually relapse. Ongoing research is assessing the efficacy of a novel, selective MT1-MMP inhibitor in combination with conventional therapies in several cancer models, including melanoma, glioblastoma and breast cancer. Additionally, we are looking into the mechanisms whereby MT1-MMP activates an outside-in survival signaling cascades utilized by cancer cells to thrive.
Another interest of the lab is to understand how certain oncogenic pathways contribute to melanoma immune escape. For example, we have recently discovered that Notch1 favors an immune suppressive tumor microenvironment through the recruitment of immune suppressive cells, such as MDSCs and Tregs. Inhibition of Notch1, reduces the number of tumor infiltrating MDSCs and Tregs while increasing that of cytotoxic CD8 T cells. The overall results is an improvement of melanoma responses to immune-checkpoint inhibitors when Notch1 is depleted. Ongoing research is elucidating the mechanisms regulating Notch1 dependent immune suppressive properties; assessing the role of other pathways involved in melanoma pathogenesis such as ERBB signaling and MT1-MMP; and is assessing the efficacy of novel, specific inhibitors of these factors in immunotherapy. Overall, the Bedogni lab utilizes several models of disease, with an emphasis on melanoma, to understand the mechanisms dictating tumor cell survival and dissemination, in order to develop novel therapies capable of delivering effective and durable responses.