PO.CL07.01 · 临床研究

针对胶质母细胞瘤微小残留病灶的候选治疗药物的计算机模拟筛选

In silico screening of therapeutics candidates targeting minimal residual disease in glioblastoma

编号 2496 展板 3 时间 4/20 09:00–12:00 区域 Section 43 主讲 Jianzhong Zhang, PhD

分会场 Data-Driven Approaches to Precision Oncology

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作者与单位 Authors & Affiliations

Harrshavasan Congivaram¹, Shashwat Tripathi¹, Mateo Gomez¹, Katy McCortney¹, Ching Man Wai², Ruochen Du¹, Thomas K. Sears¹, Jianzhong Zhang¹, Daniel J. Brat³, Craig M. Horbinski⁴, Mark W. Youngblood¹, Jared T. Ahrendsen⁵, Adam M. Sonabend¹, Stephen T. Magill¹, Matthew C. Tate¹, Maciej S. Lesniak¹, Sean Sachdev⁶, Timothy Sita⁶, Priya Kumthekar⁷, Karan Dixit⁷, Robin Buerki⁷, Ditte Primdahl⁷, Mustafa Khasraw⁸, John de Groot⁹, David A. Reardon¹⁰, Rimas V. Lukas⁷, Roger Stupp⁷, Amy B. Heimberger¹

¹Neurological Surgery, Northwestern Univ. Feinberg School of Medicine, Chicago, IL,²Biochemistry and Molecular Genetics, Northwestern Univ. Feinberg School of Medicine, Chicago, IL,³Professor, Dept. of Path. & Lab Med., Northwestern University - Evanston, IL, Chicago, IL,⁴Department of Laboratory Medicine and Pathology, Mayo Clinic Jacksonville, Chicago, IL,⁵Pathology, Northwestern Univ. Feinberg School of Medicine, Chicago, IL,⁶Radiation Oncology, Northwestern Univ. Feinberg School of Medicine, Chicago, IL,⁷Neurology, Northwestern Univ. Feinberg School of Medicine, Chicago, IL,⁸Duke Cancer Institute, Durham, NC,⁹Neuro-Oncology, University of California San Francisco, San Franscisco, CA,¹⁰Ctr. for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA

摘要 Abstract

中文摘要

背景：尽管对增强（CE）肿瘤进行了积极的手术切除，胶质母细胞瘤的复发仍不可避免。与CE胶质母细胞瘤经过深入分子表征不同，代表微小残留病灶（MRD）的未切除浸润性肿瘤尚未得到充分研究。越来越多针对胶质母细胞瘤患者MRD情况开展的临床试验，使得理解未切除浸润性肿瘤对于靶向治疗药物开发变得十分必要。方法：采用Visium HD空间转录组学对一组新诊断、未经治疗、接受了超最大程度切除的胶质母细胞瘤患者队列进行分析，同时包含核心和浸润性原位组分。空间谱生成了浸润性和CE肿瘤的表达特征。为了对靶向MRD的治疗药物进行计算机模拟预测，将浸润性和CE肿瘤的表达特征与NIH L1000数据库中的药物扰动特征进行比较，使用sRGES方法预测疾病表达模式的逆转。人类细胞系的IC50数据汇总自癌症药物敏感性基因组学数据库或单项研究数据，同时使用CNS-MPO方法预测血脑屏障（BBB）穿透性。发现：浸润性肿瘤表达谱富集于对应神经和少突胶质细胞前体样细胞的基因。相比之下，CE胶质母细胞瘤显示间充质和星形胶质细胞程序，提示胶质母细胞瘤状态在MRD和CE肿瘤中的空间集中。对于CE胶质母细胞瘤，蛋白酶体抑制剂和糖皮质激素受体激动剂被预测具有最高的抗肿瘤活性。相比之下，组蛋白脱乙酰酶抑制剂（HDACi）对MRD排名很高，但在CE肿瘤中预测疗效较低。对候选药物的协同作用分析为CE和MRD情况均提供了多种双药治疗选择。结论：综上所述，这些数据表明切除的肿瘤并不反映MRD状态，从而阐明了为何针对胶质母细胞瘤的靶向治疗药物一直未能取得特别成功。对MRD的空间分析显示其对独特药物靶点的易感性，若在正确的情况下加以利用，可带来更大的生存获益。

查看英文原文 English abstract

Background : Glioblastoma recurrence is inevitable despite aggressive surgical resection of contrast enhancing (CE) tumor. Unlike the deep molecular characterization of CE glioblastoma, unresected infiltrating tumor, representing minimal residual disease (MRD) has not been well profiled. Increasingly, clinical trials are being conducted in the MRD setting for glioblastoma patients, necessitating understanding of unresected infiltrating tumor for targeted therapeutic development. Methods : Visium HD spatial transcriptomics was used to profile a cohort of newly diagnosed, treatment-naïve glioblastoma patients that underwent supramaximal resection, with both core and infiltrating in situ components. Spatial profiles generated expression signatures of infiltrative and CE tumor. For i n silico prediction of therapeutics targeting the MRD, expression signatures of infiltrative and CE tumor were compared with drug perturbation signatures from the NIH L1000 database using the sRGES method to predict reversal of disease expression patterns. IC 50 data from human cell lines were aggregated from the Genomics of Drug Sensitivity in Cancer or individual study data while blood-brain barrier (BBB) penetrance was predicted using the CNS-MPO approach. Findings : Infiltrative tumor expression profiles were enriched for genes corresponding to neural and oligodendrocyte progenitor like cells. In contrast CE glioblastoma displayed mesenchymal and astrocytic programs, suggesting spatial concentration of glioblastoma states within MRD and CE tumor. For CE glioblastoma, proteasome inhibitors and glucocorticoid receptor agonists were predicted to have the highest antitumor activity. In contrast, histone deacetylase inhibitors (HDACi) were highly ranked for MRD while exhibiting low predicted efficacy in CE tumor. Synergy analysis of drug candidates provided multiple dual treatment options for both the CE and MRD contexts. Conclusions : Cumulatively, these data indicate that the resected tumor does not reflect the MRD state, providing clarity on why targeted therapeutics for glioblastoma have not been particularly successful. Spatial profiling of the MRD demonstrates vulnerability to unique drug targets, which if utilized in the correct setting could confer greater survival benefit.

利益披露 Disclosure

H. Congivaram, Lunaphore ). S. Tripathi, None.. M. Gomez, None.. K. McCortney, None.. C. Wai, None.. R. Du, None.. T. K. Sears, None.. J. Zhang, None.. C. M. Horbinski, None.. M. W. Youngblood, None.. J. T. Ahrendsen, None.. A. M. Sonabend, None. S. T. Magill, Stryker ). Black Forest Medical Group ). Stanford University Other, honoraria. M. C. Tate, None.. M. S. Lesniak, None. S. Sachdev, Servier g., Board of Directors, non-salaried role), ). T. Sita, None. P. Kumthekar, Belay Diagnostics ). Plus Therapeutics ). EnClear Therapeutics ). Biocept ). FYR Diagnostics ). Mirati ). Novocure ). Telix ). Biodexa ). Bioclinica ). Janssen ). Exelixis ). Autem ). Orbus ). Pfizer (Seagen) Other, honoraria. Servier Other, honoraria. K. Dixit, Servier Other, honoraria. R. Buerki, Guidepoint ). Techspert ). Servier ). Sapience Pharmeceuticals Other, honoraria. Monteris Medical Other, honoraria. D. Primdahl, Servier g., Board of Directors, non-salaried role). Catalyst g., Board of Directors, non-salaried role). M. Khasraw, Bristol Myers Squibb ). AbbVie ). Daiichi Sankyo ). BioNTech ). Celldex ). Astellas ). Immvira ). Personalis ). CNS Pharmeceuticals ). Immorna Therapeutics ). Jakscon Laboratory honoraria. Johnson and Johnson Other, honoraria. Voyager Therapeutics Other, honoraria. George Clinical Other, honoraria. Novocure ), honoraria. Servier ), honoraria. Daiichi Sankyo ), honoraria. Siren Therapeutics honoraria. Menarini Therapeutics honoraria. J. de Groot, Kintara ). Kazia ). Mundipharma ). Monteris Medical ). Samus ). Sapience Pharmeceuticals ). DSP Pharma ). Telix ). Servier ). Alpha Pharmeceuticals ). Capital One ). Nuvation ). Ariceum ). Nerviano ). Stoked Bio ). GBM AGILE Agent Selection Committee ). D. A. Reardon, Agenus ). Ashvattha Therapeutics ). Boehringer Ingelheim ). Bristol Myers Squibb ). Corbus Pharmeceuticals ). EMD Serono ). Enterome ). InvivO Therapeutics ). Medicenna Therapeutics ). Mogling Bio ). NeoTx ). Numiera Therapeutics ). Sapience Pharmeceuticals ). SphereBio ). Vaccinex ). AnHeart Pharmeceuticals ). BlueRock Therapeutics ). CeCaVa GmbH & Co. KG ). Neuvogen ). Putnam Inizio Associates ). R. V. Lukas, Merck g., Board of Directors, non-salaried role). Novocure g., Board of Directors, non-salaried role), Other, honoraria. Servier g., Board of Directors, non-salaried role), Other, honoraria. Telix g., Board of Directors, non-salaried role). Bristol Myers Squibb ). Novocure ), Other, honoraria. EBSCO Other, honoraria. Elsevier ), Other, honoraria. Medlink Neurology ), Other, honoraria. Oxford University Press ), Other, honoraria. R. Stupp, Agenus ). Bristol Myers Squibb ). Carthera ). Alpheus ). Carthera ). G Medical ). Novocure Other, honoraria. ZaiLab Other, honoraria. Sapience Pharmeceuticals g., Board of Directors, non-salaried role). Ipsen g., Board of Directors, non-salaried role). AiMED Bio g., Board of Directors, non-salaried role). Hemispherian g., Board of Directors, non-salaried role). Carthera Stock, Stock Option. Alpheus Stock, Stock Option. Modifi Bio Stock. A. B. Heimberger, WCG Oncology g., Board of Directors, non-salaried role). Moleculin ). AbbVie ). Alnylam ). Caris Life Sciences g., Board of Directors, non-salaried role). ImmunoGenesis g., Board of Directors, non-salaried role).

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