报告题目:Evolution of therapeutic resistance in melanoma
报告人：Willy Hugo博士
报告时间：2018年6月6日（周三）10:00
报告地点：逸夫楼C座314会议室
摘要：
My work has been focused on the resistance mechanisms of melanoma treated with MAPKi such as BRAF and MEK kinase inhibitors (BRAFi and MEKi, respectively). Based on genomic analyses on patient matched tumors pre- and post-MAPKi resistance, I reported the first genomic landscape of resistance mechanisms to BRAFi6 and dual BRAFi and MEKi inhibition. I subsequently reported that genomic alterations do not adequately explain the BRAF V600E melanoma’s resistance to MAPKi therapy and that transcriptomic and epigenomic alterations play an important role in the emergence of such resistance. Importantly, MAPK inhibitor (MAPKi) resistant melanoma showed an increased number of intratumoral, immunesuppressive M2-macrophages, presumably leading to the eventual loss of intratumoral T cells. In my most recent work, I reported a set of tumor intrinsic processes implicated in intrinsic resistance to therapy using antibody against PD-1 (aPD-1). These processes, termed the IPRES (Innate Anti-PD-1 Resistance) signatures, consist of known immunesuppressive biological processes such as angiogenesis, mesenchymal transition and wound healing. Importantly, I confirmed that the inhibition of IPRES significantly improved anti-tumor T-cell activity and delayed BRAFi resistance in mouse melanoma model. This observation indicates a converging immune evasion mechanism as a resistance mechanism to both MAPK and immune checkpoint inhibition.
报告人简介：
Dr. Willy Hugo, an Assistant Professor at the Department of Medicine, UCLA. I came from a Computer Science background and I did my bachelor study and PhD study in computational biology at the National University of Singapore. Subsequently, I did my postdoctoral research in cancer with Dr. Roger Lo at UCLA where I studied the mechanism of therapeutic resistance in melanoma. My research work has been centered on exploiting high throughput omic data from patient-derived tumor tissues and cancer models to understand the evolution of therapeutic resistance in cancer. I studied melanoma resistance to MAPK pathway inhibition, immune checkpoint blockade based immunotherapy, such as anti PD-1 antibody therapy, and their combination. Currently, we are actively looking for ways to combine these treatment approaches. Our current data and experiments strongly hinted that the combination of MAPK inhibition, checkpoint immunotherapies and suppression of additional immunesuppressive pathways can cause prolonged tumor suppression in multiple preclinical models.