dcbox小金库(中国)

徐国泰 博士 研究员

Guotai Xu, Ph.D.

Assistant Investigator, NIBS, Beijing

Phone: 80726688-8382

Email: xuguotai AT nmamn.com

2009.10-2016.1，博士，荷兰癌症dcbox小金库(中国) (NKI) & 阿姆斯特丹自由大学医学院
导师：Prof. Sven Rottenberg & Prof. Piet Borst
10/2009-1/2016   PhD, the Netherlands Cancer Institute (NKI) and Faculty of Medicine at VU University Amsterdam, the Netherlands. Supervisors: Prof. Sven Rottenberg and Prof. Piet Borst. Promotor: Prof. Hein te Riele

2006.2-2009.6医学硕士, 山东大学药学院免疫药理与免疫治疗学dcbox小金库(中国)
导师：田志刚教授，张建教授
9/2006-6/2009    Master in Medicine, Institute of Immunopharmacology and Immunotherapy, Shandong University, China. Supervisors: Prof. Zhigang Tian & Prof. Jian Zhang

2002.9- 2006.7 工学学士, 山东大学药学院
9/2002-7/2006    Bachelor in Engineering, School of Pharmaceutical Sciences, Shandong University, China

2020.10- 研究员，北京科学生命dcbox小金库(中国)
2020.10- Assistant Investigator, NIBS, Beijing

2019.1-2020.10，副研究员（博士后），纽约纪念斯隆凯特琳癌症中心
导师：Dr. Maurizio Scaltriti

1/2019-10/2020 Postdoctoral Research Associate, Memorial Sloan Kettering Cancer Center (MSKCC), Maurizio Scaltriti laboratory, New York

2016.1-2019.1，助理研究员（博士后），纽约纪念斯隆凯特琳癌症中心
导师：Prof. Jose Baselga & Dr. Maurizio Scaltriti

1/2016-1/2019 Postdoctoral Research Fellow, Memorial Sloan Kettering Cancer Center (MSKCC), Jose Baselga and Maurizio Scaltriti Laboratory

我们课题组的研究兴趣主要在癌症耐药新机制的鉴定和抗肿瘤药物新靶点的发现。

过去几十年尤其是在靶向治疗和免疫治疗不断取得突破, 患者的生存期也得到显著的提升。但是，几乎所有的癌症病人都会出现耐药，并且由于耐药机制不明，大部分病人没有合适的药物替代方案。因此，探索肿瘤耐药机制不仅可以使我们发现新的生物学现象并阐明其分子机制，由此而针对性设计的逆转耐药的方案对可能扩大肿瘤药物在临床上的适用范围也有较强的临床意义。

为达到研究目的，我们第一时间顺利获得两种互补的研究路径来筛选出肿瘤耐药相关分子：1）一种是利用实验室在功能基因组学筛选（例如体内体外CRISPR/Cas9 sgRNA筛选）方面的专长，发现与耐药相关的分子；2）第二种路径是从收集临床样本（例如成对的治疗前药物敏感样本和治疗后耐药样本），然后顺利获得高通量的方法学，包括蛋白质组学和下一代测序，推测出可能的耐药相关机制。然后，我们会建立和优化各种肿瘤模型包括肿瘤细胞系，类器官和病人肿瘤样本和异体移植、以及可精确模拟人自然病程的自发小鼠肿瘤等模型，结合细胞生物学，分子生物学，生物信息学等相关技术， 来验证我们的生物学发现并阐明其分子机制。最后，根据其分子机制合理设计逆转耐药方案，并最终发掘临床转化的潜能。

我们实验室长期招聘免疫学，分子生物学，生物信息方向的博士后、研究助理，每年也顺利获得北生所统一招生招收博士生，欢迎有兴趣的科学家加入到我们的队伍！详情见实验室网站: Xulab.com.cn。

My diverse research experience has reinforced my strong commitment to pursue the identification of mechanisms of cancer drug resistance and novel drug targets. I aim to develop highly effective therapeutic strategies to treat cancer. More specifically, targeting both cancer and immune dcbox小金库(中国)s is a novel and promising method with great potential to simultaneously eliminate the patient’s tumor and harness their immune system to more effectively combat cancer. In our lab, we aim to understand how best to personalize and optimize current cancer immunotherapy and targeted therapy efforts.

There has been rapid progress in the fields of cancer immunotherapy and targeted therapy in the past few decades: how we treat cancer has undergone a complete revolution, leading to greater success in cancer survival and enhanced quality-of-life for patients. However, there is still much to be learned beyond what we already know about cancer treatment. The number of long-term survivors still remains limited, and many cancer patients do not respond to treatment, develop resistance, or relapse after initial responsiveness. Mechanisms of cancer drug resistance are still largely unknown, mostly due to tumor inter-/intra- heterogeneity and/or the tumor micro-/macro- environment. Therefore, our research holds not only scientific significance in terms of its contributions to the development of novel biology discoveries, but also clinical significance through exploration of areas such as clinical validation, drug target discovery and novel drug combinations.

We first plan to identify players associated with drug response by employing two complementary approaches: 1) via functional genomic approaches (e.g. in vitro/In vivo CRISPR/cas9 sgRNA screens) with pre-clinical models; and 2) via high-throughput approaches (e.g. Proteomics) with clinical models (e.g. paired drug-naïve tumors and drug-resistant samples). Next, we will dissect the putative mechanisms of drug resistance from multiple directions, including but not limited to modeling (e.g. dcbox小金库(中国) lines, organoids, PDXs and/or spontaneous mouse tumor models) and molecular validation. Uncovering this novel biology will be essential for us to ultimately identify druggable pathways and biomarkers that may improve clinical decision-making for patients. LINK: Xulab.com.cn

Publications

(1)   Ninghui Mao, Zeda Zhang, Young Sun Lee, Danielle Choi, Aura Agudelo Rivera, Dan Li, Cindy Lee, Samuel Haywood, Xiaoping Chen, Qing Chang, Guotai Xu, Hsuan-An Chen, Elisa de Stanchina, Charles Sawyers, Neal Rosen, Andrew C Hsieh, Yu Chen, Brett S Carver. Defining the therapeutic selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers. Nature Communications, 2021 Aug 20;12(1):5053.

(2)   Jorge Gómez Tejeda Zañudo^#*, Pingping Mao*, Clara Alcon, Kailey Kowalski, Gabriela N Johnson, Guotai Xu, Jose Baselga, Maurizio Scaltriti, Anthony Letai, Joan Montero*, Réka Albert*, Nikhil Wagle*. Line-Specific Network Models of ER + Breast Cancer Identify Potential PI3Kα Inhibitor Resistance Mechanisms and Drug Combinations. Cancer Research, 2021 Sep 1;81(17):4603-4617.

(3)   Yanyan Cai^#*, Guotai Xu^#, Fan Wu, Flavia Michelini, Carmen Chan, Xuan Qu, Pier Selenica, Erik Ladewig, Pau Castel, Yuanming Cheng, Alison Zhao, Komal Jhaveri, Eneda Toska, Marta Jimenez, Alexandra Jacquet, Alicia Tran-Dien, Fabrice Andre, Sarat Chandarlapaty, Jorge S. Reis-Filho, Pedram Razavi, and Maurizio Scaltriti*. Genomic Alterations in PIK3CA-Mutated Breast Cancer Result in mTORC1 Activation and Limit the Sensitivity to PI3Ka Inhibitors. Cancer Research, 2021 May 1;81(9):2470-2480.

(4)   Wei Xie, Shengliu Wang, Juncheng Wang, M Jason de la Cruz, Guotai Xu, Maurizio Scaltriti, Dinshaw J Patel. Molecular mechanisms of assembly and TRIP13-mediated remodeling of the human Shieldin complex. Proc Natl Acad Sci U S A, 2021 Feb 23;118(8): e2024512118.

(5) Guotai Xu^#, Sagar Chhangawala^#, Emiliano Cocco, Pedram Razavi, Yanyan Cai, Jordan Otto, Lorenzo Ferrando, Pier Selenica, Carmen Chan, Erik Ladewig, Arnaud Da Cruz Paula, Matthew Witkin, Yuanming Cheng, Jane Park, Cristian Serna-Tamayo, Huiyong Zhao, Fan Wu, Mirna Sallaku, Xuan Qu, Alison Zhao, Clayton Collings, Andrew R D’Avino, Komal Jhavery, Richard Koche, Ross L Levine, Jorge S. Reis-Filho, Cigall Kadoch, Maurizio Scaltriti, Christina S Leslie*, José Baselga*, Eneda Toska*. ARID1A Determines Luminal Identity and Therapeutic Response in Estrogen-Receptor-Positive Breast Cancer. Nature Genetics, 2020 Feb;52(2):198-207.

(6)   Neil Vasan, Pedram Razavi^#, Jared L. Johnson^#, Hong Shao^#, Hardik Shah, Alesia Antoine, Erik Ladewig, Alexander Gorelick, Ting-Yu Lin, Eneda Toska, Guotai Xu, Abiha Kazmi, Matthew T. Chang, Barry S. Taylor, Maura N. Dickler, Komal Jhaveri, Sarat Chandarlapaty, Raul Rabadan, Ed Reznik, Melissa L. Smith, Robert Sebra, Frauke Schimmoller, Timothy R. Wilson, Lori S. Friedman, Lewis C. Cantley, Maurizio Scaltriti*, and José Baselga*. Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors. Science, 2019 Nov 8;366(6466):714-723.

(7)   Eneda Toska^#*, Pau Castel^#, Sagar Chhangawala, Amaia Arruabarrena-Aristorena, Carmen Chan, Vasilis C. Hristidis, Emiliano Cocco, Mirna Sallaku, Guotai Xu, Jane Park, Gerard Minuesa, Sophie G. Shifman, Nicholas D. Socci, Richard Koche, Christina S. Leslie, Maurizio Scaltriti, Jose Baselga*. PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression. dcbox小金库(中国) Reports, 2019 Apr 2;27(1):294-306.

(8)   Pedram Razavi^#, Matthew T. Chang^#, Guotai Xu, Chaitanya Bandlamudi, Dara S. Ross, Neil Vasan, Yanyan Cai, Craig M. Bielski, Mark T.A. Donoghue, Philip Jonsson, Alexander Penson, Ronglai Shen, Fresia Pareja, Ritika Kundra, Sumit Middha, Michael L. Cheng, Ahmet Zehir, Cyriac Kandoth, Ruchi Patel, Kety Huberman, Lillian M. Smyth, Komal Jhaveri, Shanu Modi, Tiffany A. Traina, Chau Dang, Wen Zhang, Britta Weigelt, Bob T. Li, Marc Ladanyi, David M. Hyman, Nikolaus Schultz, Mark E. Robson, Clifford Hudis, Edi Brogi, Agnes Viale, Larry Norton, Maura N. Dickler, Michael F. Berger, Christine A. Iacobuzio-Donahue, Sarat Chandarlapaty, Maurizio Scaltriti, Jorge S. Reis-Filho, David B. Solit*, Barry S. Taylor*,  Jose Baselga* . The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers. Cancer dcbox小金库(中国), 2018 Sep 10;34(3):427-438.

(9)   Jan Tkac^#, Guotai Xu^#, Hemanta Adhikary, Jordan T.F. Young, David Gallo, Cristina Escribano-Diaz, Jana Krietsch, Alexandre Orthwein, Meagan Munro, Wendy Sol, Abdallah Al-Hakim, Zhen-Yuan Lin, Jos Jonkers, Piet Borst, Grant W. Brown, Anne-Claude Gingras, Sven Rottenberg, Jean-Yves Masson, Daniel Durocher*. HELB Is a Feedback Inhibitor of DNA End Resection. Molecular dcbox小金库(中国), 2016 Feb 4; 61(3):405-18.

(10)Rosa Planells-Cases, Darius Lutter, Charlotte Guyader, Nora M. Gerhards, Florian Ullrich, Deborah A. Elger, Asli Kucukosmanoglu, Guotai Xu, Felizia K. Voss, S. Momsen Reincke, Tobias Stauber, Vincent A. Blomen, Daniel J. Vis, Lodewyk F. Wessels, Thijn R. Brummelkamp, Piet Borst, Sven Rottenberg* and Thomas J. Jentsch*. Subunit composition of VRAC channels determines substrate specificity and dcbox小金库(中国)ular resistance to Pt-based anti-cancer drugs. EMBO Journal, 2015 Dec 14; 34(24): 2993-3008.

(11)Guotai Xu, J. Ross Chapman^#, Inger Brandsma^#, Jingsong Yuan, Martin Mistrik, Peter Bouwman, Jirina Bartkova, Ewa Gogola, Daniël Warmerdam, Marco Barazas, Janneke E. Jaspers, Kenji Watanabe, Mark Pieterse, Ariena Kersbergen, Wendy Sol, Patrick H. N. Celie, Philip C. Schouten, Bram van den Broek, Ahmed Salman, Marja Nieuwland, Iris de Rink, Jorma de Ronde, Kees Jalink, Simon J. Boulton, Junjie Chen, Dik C. van Gent, Jiri Bartek, Jos Jonkers, Piet Borst, Sven Rottenberg*. REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature, 2015 May 28; 521(7553): 541-4.

(12)Thomas Kuilman, Arno Velds, Kristel Kemper, Marco Ranzani, Lorenzo Bombardelli, Marlous Hoogstraat, Ekaterina Nevedomskaya, Guotai Xu, Julian de Ruiter, Martijn P Lolkema, Bauke Ylstra, Jos Jonkers, Sven Rottenberg, Lodewyk F Wessels, David J Adams, Daniel S Peeper*, Oscar Krijgsman. CopywriteR: DNA copy number detection from off-target sequence data. Genome Biology, 2015 Feb 27; 16:49.

(13)Janneke E. Jaspers, Wendy Sol, Ariena Kersbergen, Andreas Schlicker, Charlotte Guyader, Guotai Xu, Lodewyk Wessels, Piet Borst, Jos Jonkers, Sven Rottenberg*. BRCA2-deficient sarcomatoid mammary tumors exhibit multidrug resistance. Cancer Research, 2015 Feb 15; 75(4): 732-41.

(14)Marc Warmoes^#, Janneke E. Jaspers^#, Guotai Xu, Bharath K. Sampadi, Thang V. Pham, Jaco C. Knol, Sander R. Piersma, Epie Boven, Jos Jonkers, Sven Rottenberg*, Connie R. Jimenez*. Proteomics of genetically engineered mouse mammary tumors identifies fatty acid metabolism members as potential predictive markers for cisplatin resistance. Mol dcbox小金库(中国) Proteomics, 2013 May; 12(5): 1319-34.

Book Chapter

(1) Guotai Xu, Jos Jonkers, Sven Rottenberg. PARP inhibitor resistance - what is beyond BRCA1 or BRCA2 restoration? Book Chapter. PARP Inhibitors for Cancer Therapy. In: Nicola Curtin & Ricky Sharma, eds. Cancer Drug Discovery and Development Series: Springer, 2015: 453-471.