PO.CL06.02 · 临床研究

CDK4/6抑制剂与TMZ和放疗联合可改变细胞状态，在原位DIPG模型中产生协同反应

Combining CDK4/6 inhibitor with TMZ and radiation alters cell states for synergistic responses in orthotopic DIPG models

编号 1150 展板 3 时间 4/19 02:00–05:00 区域 Section 45 主讲 Zilu Huang, MD

分会场 Mechanistic Insights for Targeted Therapies in Pediatric Cancer

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作者与单位 Authors & Affiliations

Zilu Huang¹, Tongchao Jiang², Milagros M. Suarez Palacios², Tommy Ouyang², Aalaa Abdallah², Long Niu², Jinnan Chen², Xin Zhai², Emily Ciolak², Wenan Qiang², Runxin Wu³, Nitin Wadhwani⁴, Alicia Lenzen⁴, Michael DeCuypere⁴, Sandi Lam³, Shi-Yuan Cheng⁵, Ching Man Wai⁶, Brian Wray⁶, Matthew John Schipma⁶, Xinkun Wang⁴, Wan-Yee Teo⁷, Daniel J. Brat⁸, Yuchen Du⁴, Yunfei Xia¹, Xiao-Nan Li⁴, John Kalapurakal⁹

¹Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China,²Pediatrics, Northwestern Univ. Feinberg School of Medicine, Chicago, IL,³Northwestern Univ. Feinberg School of Medicine, Chicago, IL,⁴Ann & Robert H. Lurie Children's Hosp. of Chicago, Chicago, IL,⁵Professor, Northwestern University, Chicago, IL,⁶NUSeq Core Facility, Center for Genetic Medicine, Northwestern Univ. Feinberg School of Medicine, Chicago, IL,⁷National Cancer Center, Singapore, Singapore,⁸Professor, Dept. of Path. & Lab Med., Northwestern University, Chicago, IL,⁹Department of Radiation Oncology, Northwestern Univ. Feinberg School of Medicine, Chicago, IL

摘要 Abstract

中文摘要

背景：为开发针对不同临床阶段DIPG的有效疗法，我们在两个患者来源的原位异种移植（PDOX）模型中考察了一种联合疗法——abemaciclib（一种CDK4/6抑制剂）、temozolomide（TMZ）和放疗（XRT）——的疗效和作用机制，这两个模型分别源自未经治疗（IBs-9119DIPG）和尸检（IBs-A0317DIPG）的肿瘤。方法：在肿瘤类器官中考察体外协同抗肿瘤活性，并在PDOX模型中考察单用及联用abemaciclib（75 mg/Kg × 14天）、TMZ（50 mg/Kg × 5天）和XRT（2 Gy/天 × 5天）的体内疗效（每组n=10，每个模型60只小鼠）。采用log-rank分析评估动物生存时间的变化。通过免疫组织化学和scRNA-seq分析阐明治疗反应和耐药的机制。结果：三联疗法在类器官中产生协同抗肿瘤效应，并显著延长了两个PDOX模型的生存时间（P<0.05），尽管它们存在显著的细胞状态差异。scRNAseq鉴定出在两个模型中少突胶质前体样（OPC样）细胞减少，以及IBs-A0317DIPG中星形胶质细胞样（AC样）细胞减少，作为反应介导因素；并揭示IBs-A0317DIPG中神经前体样（NPC样）细胞扩增，以及IBs-9119DIPG中间充质样（MES样）和有丝分裂样细胞扩增，作为耐药促成因素。拟时序轨迹分析揭示，在未经治疗的IBs-9119DIPG中，少突胶质前体样（OPC样）细胞从干性退出进入分化是一种新的耐药机制，这与复发模型IBs-A0317DIPG中干细胞样细胞富集形成对比。此外还发现了一个具有新候选靶点（NPAS3、TBC1D5、INPP4B）的放疗耐药亚群。结论：本研究证明了三联疗法通过作用于不同的细胞和分子靶点，在未经治疗和复发的DIPG肿瘤中均具有强大的抗DIPG能力，并鉴定出此前未被认识的DIPG治疗反应和耐药的潜在机制。

查看英文原文 English abstract

Background: To develop effective therapies for DIPG at different clinical stages, we examined efficacy and mechanisms of action of a combination therapy-abemaciclib (a CDK4/6 inhibitor), temozolomide (TMZ), and radiation (XRT)-in two patient-derived orthotopic xenograft (PDOX) models derived from treatment-naïve (IBs-9119DIPG) and autopsied (IBs-A0317DIPG) tumors. Methods: In vitro synergistic anti-tumor activities were examined in tumor organoids, and in vivo efficacy in the PDOX models treated with abemaciclib (75 mg/Kg × 14 days), TMZ (50 mg/Kg × 5 days) and XRT (2 Gy/day × 5 days) alone and in combination (n=10/group, 60 mice/model). Changes of animal survival times were analyzed with log-rank analysis. Mechanisms of treatment response and resistance were elucidated by immunohistochemistry and scRNA-seq analysis. Results: The triple therapy generated synergistic anti-tumor effects in organoids and significantly extended survival times in both PDOX models ( P <0.05) despite their strong cellular state differences. scRNAseq identified reduction of oligodendrocyte-progenitor-like (OPC-like) cells in both models and astrocyte-like (AC-like) cells in IBs-A0317DIPG as response mediators; and revealed expansion of neural progenitor-like (NPC-like) cells in IBs-A0317DIPG and of mesenchymal-like (MES-like) and mitotic-like cells in IBs-9119DIPG as resistance contributors. Pseudotime trajectory analysis uncovered the exit of stemness into differentiation in oligodendrocyte-progenitor-like (OPC-like) cells as a novel mechanism of resistance in the treatment-naïve IBs-9119DIPG, in contrast to the enrichment of stem-like cells in the recurrent model IBs-A0317DIPG. A radiation-resistant subpopulation with novel candidate targets ( NPAS3, TBC1D5, INPP4B ) was also discovered. Conclusions: This study demonstrated strong anti-DIPG capacities of the triple therapy in both untreated and recurrent DIPG tumors by acting on distinct cellular and molecular targets, and identifies previously unrecognized mechanisms underlying DIPG therapy response and resistance.

利益披露 Disclosure

Z. Huang, None.. T. Jiang, None.. M. M. Suarez Palacios, None.. T. Ouyang, None.. A. Abdallah, None.. L. Niu, None.. J. Chen, None.. X. Zhai, None.. E. Ciolak, None.. W. Qiang, None.. R. Wu, None.. S. Lam, None.. C. Wai, None.. B. Wray, None.. M. J. Schipma, None.. Y. Xia, None.. J. Kalapurakal, None.

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