Browsing by Author "Blagg, Brian S. J."

Now showing 1 - 4 of 4
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    Hsp90β inhibition upregulates interferon response and enhances immune checkpoint blockade therapy in murine tumors
    (Frontiers Media, 2022-10-20) Rahmy, Sharif; Mishra, Sanket J.; Murphy, Sean; Blagg, Brian S. J.; Lu, Xin; Medicine, School of Medicine
    Response resistance to the immune checkpoint blockade (ICB) immunotherapy remains a major clinical challenge that may be overcome through the rational combination of ICB and specific targeted therapeutics. One emerging combination strategy is based on sensitizing ICB-refractory tumors with antagonists of 90kD heat shock protein (Hsp90) that target all four isoforms. However, pan-Hsp90 inhibitors are limited by the modest efficacy, on-target and off-tumor toxicities, and induction of the heat shock response (HSR) that overrides the effect of Hsp90 inhibition. Recently, we developed Hsp90β-selective inhibitors that were cytotoxic to cancer cells but did not induce HSR in vitro. Here, we report that the Hsp90β inhibitor NDNB1182 downregulated CDK4 (an Hsp90β-dependent client protein) and induced the expression of endogenous retroviral elements and interferon-stimulated genes. In syngeneic mouse models of prostate cancer and breast cancer, NDNB1182 significantly augmented the efficacy of ICB therapy. Furthermore, NDNB1182 showed superior tolerability to the pan-Hsp90 inhibitor Ganetespib in mice. Our findings provide evidence that Hsp90β inhibition is a potentially effective and safe regimen to combine with ICB to treat immunotherapy-refractory solid tumors.
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    Hsp90β inhibition upregulates interferon response and enhances immune checkpoint blockade therapy in murine tumors
    (Frontiers, 2022-10-19) Rahmy, Sharif; Mishra, Sanket J.; Murphy, Sean; Blagg, Brian S. J.; Lu, Xin; Biology, School of Science
    Response resistance to the immune checkpoint blockade (ICB) immunotherapy remains a major clinical challenge that may be overcome through the rational combination of ICB and specific targeted therapeutics. One emerging combination strategy is based on sensitizing ICB-refractory tumors with antagonists of 90kD heat shock protein (Hsp90) that target all four isoforms. However, pan-Hsp90 inhibitors are limited by the modest efficacy, on-target and off-tumor toxicities, and induction of the heat shock response (HSR) that overrides the effect of Hsp90 inhibition. Recently, we developed Hsp90β-selective inhibitors that were cytotoxic to cancer cells but did not induce HSR in vitro. Here, we report that the Hsp90β inhibitor NDNB1182 downregulated CDK4 (an Hsp90β-dependent client protein) and induced the expression of endogenous retroviral elements and interferon-stimulated genes. In syngeneic mouse models of prostate cancer and breast cancer, NDNB1182 significantly augmented the efficacy of ICB therapy. Furthermore, NDNB1182 showed superior tolerability to the pan-Hsp90 inhibitor Ganetespib in mice. Our findings provide evidence that Hsp90β inhibition is a potentially effective and safe regimen to combine with ICB to treat immunotherapy-refractory solid tumors.
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    Second international symposium on the chaperone code, 2023
    (Elsevier, 2024) Buchner, Johannes; Alasady, Milad J.; Backe, Sarah J.; Blagg, Brian S. J.; Carpenter, Richard L.; Colombo, Giorgio; Gelis, Ioannis; Gewirth, Daniel T.; Gierasch, Lila M.; Houry, Walid A.; Johnson, Jill L.; Kang, Byoung Heon; Kao, Aimee W.; LaPointe, Paul; Mattoo, Seema; McClellan, Amie J.; Neckers, Leonard M.; Prodromou, Chrisostomos; Rasola, Andrea; Sager, Rebecca A.; Theodoraki, Maria A.; Truman, Andrew W.; Truttman, Matthias C.; Zachara, Natasha E.; Bourboulia, Dimitra; Mollapour, Mehdi; Woodford, Mark R.; Biochemistry and Molecular Biology, School of Medicine
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    Targeting the chromatin effector Pygo2 promotes cytotoxic T cell responses and overcomes immunotherapy resistance in prostate cancer
    (American Association for the Advancement of Science, 2023) Zhu, Yini; Zhao, Yun; Wen, Jiling; Liu, Sheng; Huang, Tianhe; Hatial, Ishita; Peng, Xiaoxia; Al Janabi, Hawraa; Huang, Gang; Mittlesteadt, Jackson; Cheng, Michael; Bhardwaj, Atul; Ashfeld, Brandon L.; Kao, Kenneth R.; Maeda, Dean Y.; Dai, Xing; Wiest, Olaf; Blagg, Brian S. J.; Lu, Xuemin; Cheng, Liang; Wan, Jun; Lu, Xin; Medical and Molecular Genetics, School of Medicine
    The noninflamed microenvironment in prostate cancer represents a barrier to immunotherapy. Genetic alterations underlying cancer cell-intrinsic oncogenic signaling are increasingly appreciated for their role in shaping the immune landscape. Recently, we identified Pygopus 2 (PYGO2) as the driver oncogene for the amplicon at 1q21.3 in prostate cancer. Here, using transgenic mouse models of metastatic prostate adenocarcinoma, we found that Pygo2 deletion decelerated tumor progression, diminished metastases, and extended survival. Pygo2 loss augmented the activation and infiltration of cytotoxic T lymphocytes (CTLs) and sensitized tumor cells to T cell killing. Mechanistically, Pygo2 orchestrated a p53/Sp1/Kit/Ido1 signaling network to foster a microenvironment hostile to CTLs. Genetic or pharmacological inhibition of Pygo2 enhanced the antitumor efficacy of immunotherapies using immune checkpoint blockade (ICB), adoptive cell transfer, or agents inhibiting myeloid-derived suppressor cells. In human prostate cancer samples, Pygo2 expression was inversely correlated with the infiltration of CD8+ T cells. Analysis of the ICB clinical data showed association between high PYGO2 level and worse outcome. Together, our results highlight a potential path to improve immunotherapy using Pygo2-targeted therapy for advanced prostate cancer.