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      Prostate cancer research: The next generation; report from the 2019 Coffey‐Holden Prostate Cancer Academy Meeting

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          Abstract

          The 2019 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, “Prostate Cancer Research: The Next Generation,” was held 20 to 23 June, 2019, in Los Angeles, California. The CHPCA Meeting is an annual conference held by the Prostate Cancer Foundation, that is uniquely structured to stimulate intense discussion surrounding topics most critical to accelerating prostate cancer research and the discovery of new life-extending treatments for patients. The 7th Annual CHPCA Meeting was attended by 86 investigators and concentrated on many of the most promising new treatment opportunities and next-generation research technologies. The topics of focus at the meeting included: new treatment strategies and novel agents for targeted therapies and precision medicine, new treatment strategies that may synergize with checkpoint immunotherapy, next-generation technologies that visualize tumor microenvironment (TME) and molecular pathology in situ, multi-omics and tumor heterogeneity using single cells, 3D and TME models, and the role of extracellular vesicles in cancer and their potential as biomarkers. This meeting report provides a comprehensive summary of the talks and discussions held at the 2019 CHPCA Meeting, for the purpose of globally disseminating this knowledge and ultimately accelerating new treatments and diagnostics for patients with prostate cancer.

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          CTLA-4 and PD-1 Pathways

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            Epigenome editing by a CRISPR/Cas9-based acetyltransferase activates genes from promoters and enhancers

            Technologies that facilitate the targeted manipulation of epigenetic marks could be used to precisely control cell phenotype or interrogate the relationship between the epigenome and transcriptional control. Here we have generated a programmable acetyltransferase based on the CRISPR/Cas9 gene regulation system, consisting of the nuclease-null dCas9 protein fused to the catalytic core of the human acetyltransferase p300. This fusion protein catalyzes acetylation of histone H3 lysine 27 at its target sites, corresponding with robust transcriptional activation of target genes from promoters, proximal enhancers, and distal enhancers. Gene activation by the targeted acetyltransferase is highly specific across the genome. In contrast to conventional dCas9-based activators, the acetyltransferase effectively activates genes from enhancer regions and with individual guide RNAs. The core p300 domain is also portable to other programmable DNA-binding proteins. These results support targeted acetylation as a causal mechanism of transactivation and provide a new robust tool for manipulating gene regulation.
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              Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-Cell Analyses

              To guide the design of immunotherapy strategies for patients with early stage lung tumors, we developed a multiscale immune profiling strategy to map the immune landscape of early lung adenocarcinoma lesions to search for tumor-driven immune changes. Utilizing a barcoding method that allows a simultaneous single cell analysis of the tumor, non-involved lung and blood cells together with multiplex tissue imaging to assess spatial cell distribution, we provide a detailed immune cell atlas of early lung tumors. We show that stage I lung adenocarcinoma lesions already harbor significantly altered T cell and NK cell compartments. Moreover, we identified changes in tumor infiltrating myeloid cell (TIM) subsets that likely compromise anti-tumor T cell immunity. Paired single cell analyses thus offer valuable knowledge of tumor-driven immune changes, providing a powerful tool for the rational design of immune therapies. Comparing single tumor cells with adjacent normal tissue and blood from patients with lung adenocarcinoma charts early changes in tumor immunity and provides insights to guide immunotherapy design.
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                Author and article information

                Journal
                The Prostate
                Prostate
                Wiley
                0270-4137
                1097-0045
                December 03 2019
                February 2020
                December 11 2019
                February 2020
                : 80
                : 2
                : 113-132
                Affiliations
                [1 ]Science DepartmentProstate Cancer FoundationSanta Monica California
                [2 ]Division of Clinical StudiesInstitute of Cancer ResearchLondon UK
                [3 ]Department of MedicineThe Royal Marsden NHS Foundation TrustLondon UK
                [4 ]Department of Oncologic PathologyDana‐Farber Cancer InstituteBoston Massachusetts
                [5 ]Department of Pathology, Brigham and Women's HospitalHarvard Medical SchoolBoston Massachusetts
                [6 ]The Broad Institute of MIT and Harvard UniversityCambridge Massachusetts
                [7 ]National Cancer Institute, Center for Cancer ResearchNational Institutes of HealthBethesda Maryland
                [8 ]Department of MedicineBaylor College of MedicineHouston Texas
                [9 ]Division of Immunology, Department of PathologyThe Johns Hopkins School of MedicineBaltimore Maryland
                [10 ]Helen Diller Family Comprehensive Cancer CenterUniversity of California San FranciscoSan Francisco California
                [11 ]Department of Epidemiology & BiostatisticsUniversity of California San FranciscoSan Francisco California
                [12 ]Department of PathologyUniversity of California Los AngelesLos Angeles California
                [13 ]Department of UrologyUniversity of California Los AngelesLos Angeles California
                [14 ]Department of Oncology, Sidney Kimmel Comprehensive Cancer CenterThe Johns Hopkins School of MedicineBaltimore Maryland
                [15 ]Department of UrologyThe James Buchanan Brady Urological InstituteBaltimore Maryland
                [16 ]Department of Pharmacology and Molecular SciencesThe Johns Hopkins School of MedicineBaltimore Maryland
                Article
                10.1002/pros.23934
                7301761
                31825540
                8a0f2cf0-cbc0-4305-86dd-deb6da50a35d
                © 2020

                http://onlinelibrary.wiley.com/termsAndConditions#vor

                http://doi.wiley.com/10.1002/tdm_license_1.1

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