Browsing by Author "Dry, Jonathan R."

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    A pan-cancer organoid platform for precision medicine
    (Elsevier, 2021) Larsen, Brian M.; Kannan, Madhavi; Langer, Lee F.; Leibowitz, Benjamin D.; Bentaieb, Aicha; Cancino, Andrea; Dolgalev, Igor; Drummond, Bridgette E.; Dry, Jonathan R.; Ho, Chi-Sing; Khullar, Gaurav; Krantz, Benjamin A.; Mapes, Brandon; McKinnon, Kelly E.; Metti, Jessica; Perera, Jason F.; Rand, Tim A.; Sanchez-Freire, Veronica; Shaxted, Jenna M.; Stein, Michelle M.; Streit, Michael A.; Tan, Yi-Hung Carol; Zhang, Yilin; Zhao, Ende; Venkataraman, Jagadish; Stumpe, Martin C.; Borgia, Jeffrey A.; Masood, Ashiq; Catenacci, Daniel V. T.; Mathews, Jeremy V.; Gursel, Demirkan B.; Wei, Jian-Jun; Welling, Theodore H.; Simeone, Diane M.; White, Kevin P.; Khan, Aly A.; Igartua, Catherine; Salahudeen, Ameen A.; Medicine, School of Medicine
    Patient-derived tumor organoids (TOs) are emerging as high-fidelity models to study cancer biology and develop novel precision medicine therapeutics. However, utilizing TOs for systems-biology-based approaches has been limited by a lack of scalable and reproducible methods to develop and profile these models. We describe a robust pan-cancer TO platform with chemically defined media optimized on cultures acquired from over 1,000 patients. Crucially, we demonstrate tumor genetic and transcriptomic concordance utilizing this approach and further optimize defined minimal media for organoid initiation and propagation. Additionally, we demonstrate a neural-network-based high-throughput approach for label-free, light-microscopy-based drug assays capable of predicting patient-specific heterogeneity in drug responses with applicability across solid cancers. The pan-cancer platform, molecular data, and neural-network-based drug assay serve as resources to accelerate the broad implementation of organoid models in precision medicine research and personalized therapeutic profiling programs.
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    DeePaN: deep patient graph convolutional network integrating clinico-genomic evidence to stratify lung cancers for immunotherapy
    (Nature, 2021) Fang, Chao; Xu, Dong; Su, Jing; Dry, Jonathan R.; Linghu, Bolan; Biostatistics, School of Public Health
    Immuno-oncology (IO) therapies have transformed the therapeutic landscape of non-small cell lung cancer (NSCLC). However, patient responses to IO are variable and influenced by a heterogeneous combination of health, immune, and tumor factors. There is a pressing need to discover the distinct NSCLC subgroups that influence response. We have developed a deep patient graph convolutional network, we call “DeePaN”, to discover NSCLC complexity across data modalities impacting IO benefit. DeePaN employs high-dimensional data derived from both real-world evidence (RWE)-based electronic health records (EHRs) and genomics across 1937 IO-treated NSCLC patients. DeePaN demonstrated effectiveness to stratify patients into subgroups with significantly different (P-value of 2.2 × 10−11) overall median survival of 20.35 months and 9.42 months post-IO therapy. Significant differences in IO outcome were not seen from multiple non-graph-based unsupervised methods. Furthermore, we demonstrate that patient stratification from DeePaN has the potential to augment the emerging IO biomarker of tumor mutation burden (TMB). Characterization of the subgroups discovered by DeePaN indicates potential to inform IO therapeutic insight, including the enrichment of mutated KRAS and high blood monocyte count in the IO beneficial and IO non-beneficial subgroups, respectively. Our work has proven the concept that graph-based AI is feasible and can effectively integrate high-dimensional genomic and EHR data to meaningfully stratify cancer patients on distinct clinical outcomes, with potential to inform precision oncology.