Browsing by Author "Wei, Zhi"

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    Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy.
    (Molecular systems biology, 2019-03-11) Sahu, Avinash Das; S Lee, Joo; Wang, Zhiyong; Zhang, Gao; Iglesias-Bartolome, Ramiro; Tian, Tian; Wei, Zhi; Miao, Benchun; Nair, Nishanth Ulhas; Ponomarova, Olga; Friedman, Adam A; Amzallag, Arnaud; Moll, Tabea; Kasumova, Gyulnara; Greninger, Patricia; Egan, Regina K; Damon, Leah J; Frederick, Dennie T; Jerby-Arnon, Livnat; Wagner, Allon; Cheng, Kuoyuan; Park, Seung Gu; Robinson, Welles; Gardner, Kevin; Boland, Genevieve; Hannenhalli, Sridhar; Herlyn, Meenhard; Benes, Cyril; Flaherty, Keith; Luo, Ji; Gutkind, J Silvio; Ruppin, Eytan
    Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (the rescuer). Here, we perform a genome-wide in silico prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients' response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers.
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    Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.
    (Nature communications, 2021-01-13) Gromeier, Matthias; Brown, Michael C; Zhang, Gao; Lin, Xiang; Chen, Yeqing; Wei, Zhi; Beaubier, Nike; Yan, Hai; He, Yiping; Desjardins, Annick; Herndon, James E; Varn, Frederick S; Verhaak, Roel G; Zhao, Junfei; Bolognesi, Dani P; Friedman, Allan H; Friedman, Henry S; McSherry, Frances; Muscat, Andrea M; Lipp, Eric S; Nair, Smita K; Khasraw, Mustafa; Peters, Katherine B; Randazzo, Dina; Sampson, John H; McLendon, Roger E; Bigner, Darell D; Ashley, David M
    Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10-20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.