A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma.
A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma.
复制标题
功能性精准医学管道结合了比较转录组学和肿瘤类器官建模，以确定胶质母细胞瘤的定制治疗策略。
DOI：
10.3390/cells10123400
复制
发表时间：
2021-12-02
期刊：
影响因子：
6
通讯作者：
Rodriguez A
中科院分区：
文献类型：
--
作者：
Reed MR;Lyle AG;De Loose A;Maddukuri L;Learned K;Beale HC;Kephart ET;Cheney A;van den Bout A;Lee MP;Hundley KN;Smith AM;DesRochers TM;Vibat CRT;Gokden M;Salama S;Wardell CP;Eoff RL;Vaske OM;Rodriguez A
Li Fraumeni综合征（LFS）是一种遗传性癌症易感综合征，由TP 53的生殖系突变引起。TP 53是人类癌症中最常见的突变基因，发生在30-50%的胶质母细胞瘤（GBM）中。在这里，我们强调了一个精准医学平台，以确定LFS GBM患者的潜在目标。我们使用比较转录组学方法来鉴定相对于12，747个肿瘤RNA测序数据集（包括200个GBM）的癌症概要，在LFS GBM患者中独特过表达的基因。STAT 1和STAT 2被鉴定为在LFS患者中显著过表达，表明鲁索利替尼（一种Janus激酶1和2抑制剂）是一种潜在的治疗方法。LFS患者在45例高级别胶质瘤患者中具有最高水平的STAT 1和STAT 2表达，进一步支持癌症概要结果。为了从经验上验证比较转录组学管道，我们使用了贴壁和类器官细胞培养技术的组合，包括来自四种患者来源的细胞系（包括LFS患者）的离体患者来源的类器官（PDO）。四种患者来源的细胞中的STAT 1和STAT 2表达水平与在各自的母体肿瘤中鉴定的水平相关。在贴壁培养和类器官培养中，与STAT 1和STAT 2表达水平较低的患者来源细胞相比，来自LFS患者的细胞对ruxolitinib最敏感。进行基于球体的药物筛选测定（3D-PREDICT）并用于鉴定进一步的治疗靶点。为目标患者选择了两种靶向治疗，并导致放射学疾病稳定。该手稿支持使用比较转录组学在恶性脑肿瘤的功能性精准医学平台中识别个性化治疗靶点。
Li Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer, occurring in 30–50% of glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets for a GBM patient with LFS. We used a comparative transcriptomics approach to identify genes that are uniquely overexpressed in the LFS GBM patient relative to a cancer compendium of 12,747 tumor RNA sequencing data sets, including 200 GBMs. STAT1 and STAT2 were identified as being significantly overexpressed in the LFS patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitors, as a potential therapy. The LFS patient had the highest level of STAT1 and STAT2 expression in an institutional high-grade glioma cohort of 45 patients, further supporting the cancer compendium results. To empirically validate the comparative transcriptomics pipeline, we used a combination of adherent and organoid cell culture techniques, including ex vivo patient-derived organoids (PDOs) from four patient-derived cell lines, including the LFS patient. STAT1 and STAT2 expression levels in the four patient-derived cells correlated with levels identified in the respective parent tumors. In both adherent and organoid cultures, cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. A spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. Two targeted therapies were selected for the patient of interest and resulted in radiographic disease stability. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors.
登录
查看更多内容
影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
影响因子：
4.4
作者：
Jin, Yueling;Xiao, Weizhong;Dai, Zhensheng
通讯作者：
Dai, Zhensheng
影响因子：
5.9
作者：
Phan, Nhan;Hong, Jenny J.;Soragni, Alice
通讯作者：
Soragni, Alice
影响因子：
64.8
作者：
Chin, L.;Meyerson, M.;Aldape, K.;Bigner, D.;Mikkelsen, T.;VandenBerg, S.;Kahn, A.;Penny, R.;Ferguson, M. L.;Gerhard, D. S.;Getz, G.;Brennan, C.;Taylor, B. S.;Winckler, W.;Park, P.;Ladanyi, M.;Hoadley, K. A.;Verhaak, R. G. W.;Hayes, D. N.;Spellman, Paul T.;Absher, D.;Weir, B. A.;Ding, L.;Wheeler, D.;Lawrence, M. S.;Cibulskis, K.;Mardis, E.;Zhang, Jinghui;Wilson, R. K.;Donehower, L.;Wheeler, D. A.;Purdom, E.;Wallis, J.;Laird, P. W.;Herman, J. G.;Schuebel, K. E.;Weisenberger, D. J.;Baylin, S. B.;Schultz, N.;Yao, Jun;Wiedemeyer, R.;Weinstein, J.;Sander, C.;Gibbs, R. A.;Gray, J.;Kucherlapati, R.;Lander, E. S.;Myers, R. M.;Perou, C. M.;McLendon, Roger;Friedman, Allan;Van Meir, Erwin G;Brat, Daniel J;Mastrogianakis, Gena Marie;Olson, Jeffrey J;Lehman, Norman;Yung, W. K. Alfred;Bogler, Oliver;Berger, Mitchel;Prados, Michael;Muzny, Donna;Morgan, Margaret;Scherer, Steve;Sabo, Aniko;Nazareth, Lynn;Lewis, Lora;Hall, Otis;Zhu, Yiming;Ren, Yanru;Alvi, Omar;Yao, Jiqiang;Hawes, Alicia;Jhangiani, Shalini;Fowler, Gerald;San Lucas, Anthony;Kovar, Christie;Cree, Andrew;Dinh, Huyen;Santibanez, Jireh;Joshi, Vandita;Gonzalez-Garay, Manuel L.;Miller, Christopher A.;Milosavljevic, Aleksandar;Sougnez, Carrie;Fennell, Tim;Mahan, Scott;Wilkinson, Jane;Ziaugra, Liuda;Onofrio, Robert;Bloom, Toby;Nicol, Rob;Ardlie, Kristin;Baldwin, Jennifer;Gabriel, Stacey;Fulton, Robert S.;McLellan, Michael D.;Larson, David E.;Shi, Xiaoqi;Abbott, Rachel;Fulton, Lucinda;Chen, Ken;Koboldt, Daniel C.;Wendl, Michael C.;Meyer, Rick;Tang, Yuzhu;Lin, Ling;Osborne, John R.;Dunford-Shore, Brian H.;Miner, Tracie L.;Delehaunty, Kim;Markovic, Chris;Swift, Gary;Courtney, William;Pohl, Craig;Abbott, Scott;Hawkins, Amy;Leong, Shin;Haipek, Carrie;Schmidt, Heather;Wiechert, Maddy;Vickery, Tammi;Scott, Sacha;Dooling, David J.;Chinwalla, Asif;Weinstock, George M.;O'Kelly, Michael;Robinson, Jim;Alexe, Gabriele;Beroukhim, Rameen;Carter, Scott;Chiang, Derek;Gould, Josh;Gupta, Supriya;Korn, Josh;Mermel, Craig;Mesirov, Jill;Monti, Stefano;Nguyen, Huy;Parkin, Melissa;Reich, Michael;Stransky, Nicolas;Garraway, Levi;Golub, Todd;Protopopov, Alexei;Perna, Ilana;Aronson, Sandy;Sathiamoorthy, Narayan;Ren, Georgia;Kim, Hyunsoo;Kong, Sek Won;Xiao, Yonghong;Kohane, Isaac S.;Seidman, Jon;Cope, Leslie;Pan, Fei;Van Den Berg, David;Van Neste, Leander;Yi, Joo Mi;Li, Jun Z.;Southwick, Audrey;Brady, Shannon;Aggarwal, Amita;Chung, Tisha;Sherlock, Gavin;Brooks, James D.;Jakkula, Lakshmi R.;Lapuk, Anna V.;Marr, Henry;Dorton, Shannon;Choi, Yoon Gi;Han, Ju;Ray, Amrita;Wang, Victoria;Durinck, Steffen;Robinson, Mark;Wang, Nicholas J.;Vranizan, Karen;Peng, Vivian;Van Name, Eric;Fontenay, Gerald V.;Ngai, John;Conboy, John G.;Parvin, Bahram;Feiler, Heidi S.;Speed, Terence P.;Socci, Nicholas D.;Olshen, Adam;Lash, Alex;Reva, Boris;Antipin, Yevgeniy;Stukalov, Alexey;Gross, Benjamin;Cerami, Ethan;Wang, Wei Qing;Qin, Li-Xuan;Seshan, Venkatraman E.;Villafania, Liliana;Cavatore, Magali;Borsu, Laetitia;Viale, Agnes;Gerald, William;Topal, Michael D.;Qi, Yuan;Balu, Sai;Shi, Yan;Wu, George;Bittner, Michael;Shelton, Troy;Lenkiewicz, Elizabeth;Morris, Scott;Beasley, Debbie;Sanders, Sheri;Sfeir, Robert;Chen, Jessica;Nassau, David;Feng, Larry;Hickey, Erin;Schaefer, Carl;Madhavan, Subha;Buetow, Ken;Barker, Anna;Vockley, Joseph;Compton, Carolyn;Vaught, Jim;Fielding, Peter;Collins, Francis;Good, Peter;Guyer, Mark;Ozenberger, Brad;Peterson, Jane;Thomson, Elizabeth
通讯作者：
Thomson, Elizabeth
影响因子：
64.5
作者：
Jacob F;Salinas RD;Zhang DY;Nguyen PTT;Schnoll JG;Wong SZH;Thokala R;Sheikh S;Saxena D;Prokop S;Liu DA;Qian X;Petrov D;Lucas T;Chen HI;Dorsey JF;Christian KM;Binder ZA;Nasrallah M;Brem S;O'Rourke DM;Ming GL;Song H
通讯作者：
Song H