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1
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Stockwell CA, Thang M, Kram DE, Satterlee AB, Hingtgen S. Therapeutic approaches for targeting the pediatric brain tumor microenvironment. Drug Deliv Transl Res 2025:10.1007/s13346-025-01839-3. [PMID: 40257744 DOI: 10.1007/s13346-025-01839-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2025] [Indexed: 04/22/2025]
Abstract
Central nervous system (CNS) tumors are the most frequent solid malignant tumors in pediatric patients and are the leading cause of tumor-related death in children. Treatment for this heterogeneous group of tumors consists of various combinations of safe maximal surgical resection, chemotherapy, and radiation therapy which offer a cure for some children but often cause debilitating adverse late effects in others. While therapies targeting the tumor microenvironment (TME) like immune checkpoint inhibition (ICI) have been successful in treating some cancers, these therapies failed to exhibit treatment efficacy in the majority of pediatric brain tumors in the clinic. Importantly, the pediatric TME is unique and distinct from adult brain tumors and designing therapies to effectively target these tumors requires understanding the unique biology of pediatric brain tumors and the use of translational models that recapitulate the TME. Here we describe the TME of medulloblastoma (MB) and diffuse midline glioma (DMG), specifically diffuse intrinsic pontine glioma (DIPG), and further present the current drug delivery approaches and clinical administration routes targeting the TME in these tumors, including preclinical and clinical studies.
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Affiliation(s)
- Caroline A Stockwell
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Morrent Thang
- Neuroscience Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - David E Kram
- Division of Pediatric Hematology-Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Andrew B Satterlee
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Eshelman Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Shawn Hingtgen
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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2
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Mann B, Artz N, Darawsheh R, Kram DE, Hingtgen S, Satterlee AB. Opportunities and challenges for patient-derived models of brain tumors in functional precision medicine. NPJ Precis Oncol 2025; 9:47. [PMID: 39953052 PMCID: PMC11828933 DOI: 10.1038/s41698-025-00832-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 02/03/2025] [Indexed: 02/17/2025] Open
Abstract
Here, we review a growing paradigm shift from genomics-based precision medicine toward functional precision medicine, which evaluates therapeutic efficacy by directly treating living patient tumors ex vivo to better predict patient-specific responses to treatment. We discuss several classes of patient-derived models of central nervous system tumors, highlighting unique features of each. Each class of models holds promise to improve treatment selection, prolong survival, and enhance patient outcomes.
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Affiliation(s)
- Breanna Mann
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Eshelman Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Nichole Artz
- Division of Pediatric Hematology-Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Rami Darawsheh
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - David E Kram
- Division of Pediatric Hematology-Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Shawn Hingtgen
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Andrew B Satterlee
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Eshelman Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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3
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Shen G, Jia X, Qi T, Hu Z, Xiao A, Liu Q, He K, Guo W, Zhang D, Li W, Cao G, Li G, Tian J, Huang X, Hu Y. Data-Driven Design of Triple-Targeted Protein Nanoprobes for Multiplexed Imaging of Cancer Lymphatic Metastasis. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2405877. [PMID: 38889909 DOI: 10.1002/adma.202405877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 06/06/2024] [Indexed: 06/20/2024]
Abstract
Targeted imaging of cancer lymphatic metastasis remains challenging due to its highly heterogeneous molecular and phenotypic diversity. Herein, triple-targeted protein nanoprobes capable of specifically binding to three targets for imaging cancer lymphatic metastasis, through a data-driven design approach combined with a synthetic biology-based assembly strategy, are introduced. Specifically, to address the diversity of metastatic lymph nodes (LNs), a combination of three targets, including C-X-C motif chemokine receptor 4 (CXCR4), transferrin receptor protein 1 (TfR1), and vascular endothelial growth factor receptor 3 (VEGFR3) is identified, leveraging machine leaning-based bioinformatics analysis and examination of LN tissues from patients with gastric cancer. Using this identified target combination, ferritin nanocage-based nanoprobes capable of specifically binding to all three targets are designed through the self-assembly of genetically engineered ferritin subunits using a synthetic biology approach. Using these nanoprobes, multiplexed imaging of heterogeneous metastatic LNs is successfully achieved in a polyclonal lymphatic metastasis animal model. In 19 freshly resected human gastric specimens, the signal from the triple-targeted nanoprobes significantly differentiates metastatic LNs from benign LNs. This study not only provides an effective nanoprobe for imaging highly heterogeneous lymphatic metastasis but also proposes a potential strategy for guiding the design of targeted nanomedicines for cancer lymphatic metastasis.
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Affiliation(s)
- Guodong Shen
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiaohua Jia
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
- Department of Ultrasound, Shuozhou Grand Hospital of Shanxi Medical University, Shuozhou, 036000, China
| | - Tianyi Qi
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Zhenhua Hu
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Anqi Xiao
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Qiqi Liu
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Keyu He
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Weihong Guo
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Dan Zhang
- Center of Biomedical Analysis, Tsinghua University, Beijing, 100084, China
| | - Wanjun Li
- Department of Pathology, Affiliated 3201 Hospital of Xi'an Jiaotong University, Hanzhong, 723000, China
| | - Genmao Cao
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, 030000, China
| | - Guoxin Li
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jie Tian
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine and Engineering, Beihang University, Beijing, 100191, China
| | - Xinglu Huang
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Yanfeng Hu
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
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4
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Zhang X, Taylor H, Valdivia A, Dasari R, Buckley A, Bonacquisti E, Nguyen J, Kanchi K, Corcoran DL, Herring LE, Steindler DA, Baldwin A, Hingtgen S, Satterlee AB. Auto-loaded TRAIL-exosomes derived from induced neural stem cells for brain cancer therapy. J Control Release 2024; 372:433-445. [PMID: 38908756 PMCID: PMC11283351 DOI: 10.1016/j.jconrel.2024.06.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 06/04/2024] [Accepted: 06/19/2024] [Indexed: 06/24/2024]
Abstract
Transdifferentiation (TD), a somatic cell reprogramming process that eliminates pluripotent intermediates, creates cells that are ideal for personalized anti-cancer therapy. Here, we provide the first evidence that extracellular vesicles (EVs) from TD-derived induced neural stem cells (Exo-iNSCs) are an efficacious treatment strategy for brain cancer. We found that genetically engineered iNSCs generated EVs loaded with the tumoricidal gene product TRAIL at nearly twice the rate of their parental fibroblasts, and TRAIL produced by iNSCs was naturally loaded into the lumen of EVs and arrayed across their outer membrane (Exo-iNSC-TRAIL). Uptake studies in ex vivo organotypic brain slice cultures showed that Exo-iNSC-TRAIL selectively accumulates within tumor foci, and co-culture assays demonstrated that Exo-iNSC-TRAIL killed metastatic and primary brain cancer cells more effectively than free TRAIL. In an orthotopic mouse model of brain cancer, Exo-iNSC-TRAIL reduced breast-to-brain tumor xenografts by approximately 3000-fold compared to treatment with free TRAIL, with all Exo-iNSC-TRAIL treated animals surviving through 90 days post-treatment. In additional in vivo testing against aggressive U87 and invasive GBM8 glioblastoma tumors, Exo-iNSC-TRAIL also induced a statistically significant increase in survival. These studies establish a novel, easily generated, stable, tumor-targeted EV to efficaciously treat multiple forms of brain cancer.
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Affiliation(s)
- Xiaopei Zhang
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Hannah Taylor
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Alain Valdivia
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Rajaneekar Dasari
- Eshelman Institute for Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Andrew Buckley
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Emily Bonacquisti
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Juliane Nguyen
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Krishna Kanchi
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - David L Corcoran
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Laura E Herring
- Michael Hooker Proteomics Core, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Dennis A Steindler
- Eshelman Institute for Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Steindler Consulting, Boston, MA, USA
| | - Albert Baldwin
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Shawn Hingtgen
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Andrew Benson Satterlee
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Eshelman Institute for Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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5
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Zhang X, Taylor H, Valdivia A, Dasari R, Buckley A, Bonacquisti E, Nguyen J, Kanchi K, Corcoran DL, Herring LE, Steindler DA, Baldwin A, Hingtgen S, Satterlee AB. Auto-loaded TRAIL-exosomes derived from induced neural stem cells for brain cancer therapy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.24.595724. [PMID: 38854085 PMCID: PMC11160660 DOI: 10.1101/2024.05.24.595724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
Transdifferentiation (TD), a somatic cell reprogramming process that eliminates pluripotent intermediates, creates cells that are ideal for personalized anti-cancer therapy. Here, we provide the first evidence that extracellular vesicles (EVs) from TD-derived induced neural stem cells (Exo-iNSCs) are an efficacious treatment strategy for brain cancer. We found that genetically engineered iNSCs generated EVs loaded with the tumoricidal gene product TRAIL at nearly twice the rate as their parental fibroblasts, and the TRAIL produced by iNSCs were naturally loaded into the lumen of EVs and arrayed across their outer membrane (Exo-iNSC-TRAIL). Uptake studies in ex vivo organotypic brain slice cultures showed Exo-iNSC-TRAIL selectively accumulates within tumor foci, and co-culture assays showed that Exo-iNSC-TRAIL killed metastatic and primary brain cancer cells more effectively than free TRAIL. In an orthotopic mouse model of brain cancer, Exo-iNSC-TRAIL reduced breast-to-brain tumor xenografts around 3000-fold greater than treatment with free TRAIL, with all Exo-iNSC-TRAIL treated animals surviving through 90 days post-treatment. In additional in vivo testing against aggressive U87 and invasive GBM8 glioblastoma tumors, Exo-iNSC-TRAIL also induced a statistically significant increase in survival. These studies establish a new easily generated, stable, tumor-targeted EV to efficaciously treat multiple forms of brain cancer.
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6
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Shen Y, Thng DKH, Wong ALA, Toh TB. Mechanistic insights and the clinical prospects of targeted therapies for glioblastoma: a comprehensive review. Exp Hematol Oncol 2024; 13:40. [PMID: 38615034 PMCID: PMC11015656 DOI: 10.1186/s40164-024-00512-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 04/08/2024] [Indexed: 04/15/2024] Open
Abstract
Glioblastoma (GBM) is a fatal brain tumour that is traditionally diagnosed based on histological features. Recent molecular profiling studies have reshaped the World Health Organization approach in the classification of central nervous system tumours to include more pathogenetic hallmarks. These studies have revealed that multiple oncogenic pathways are dysregulated, which contributes to the aggressiveness and resistance of GBM. Such findings have shed light on the molecular vulnerability of GBM and have shifted the disease management paradigm from chemotherapy to targeted therapies. Targeted drugs have been developed to inhibit oncogenic targets in GBM, including receptors involved in the angiogenic axis, the signal transducer and activator of transcription 3 (STAT3), the PI3K/AKT/mTOR signalling pathway, the ubiquitination-proteasome pathway, as well as IDH1/2 pathway. While certain targeted drugs showed promising results in vivo, the translatability of such preclinical achievements in GBM remains a barrier. We also discuss the recent developments and clinical assessments of targeted drugs, as well as the prospects of cell-based therapies and combinatorial therapy as novel ways to target GBM. Targeted treatments have demonstrated preclinical efficacy over chemotherapy as an alternative or adjuvant to the current standard of care for GBM, but their clinical efficacy remains hindered by challenges such as blood-brain barrier penetrance of the drugs. The development of combinatorial targeted therapies is expected to improve therapeutic efficacy and overcome drug resistance.
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Affiliation(s)
- Yating Shen
- The N.1 Institute for Health (N.1), National University of Singapore, Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Dexter Kai Hao Thng
- The N.1 Institute for Health (N.1), National University of Singapore, Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Andrea Li Ann Wong
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Department of Haematology-Oncology, National University Hospital, Singapore, Singapore
| | - Tan Boon Toh
- The N.1 Institute for Health (N.1), National University of Singapore, Singapore, Singapore.
- The Institute for Digital Medicine (WisDM), National University of Singapore, Singapore, Singapore.
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7
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Cheng X, An J, Lou J, Gu Q, Ding W, Droby GN, Wang Y, Wang C, Gao Y, Anand JR, Shelton A, Satterlee AB, Mann B, Hsiao YC, Liu CW, Lu K, Hingtgen S, Wang J, Liu Z, Miller CR, Wu D, Vaziri C, Yang Y. Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma. Nat Commun 2024; 15:1957. [PMID: 38438348 PMCID: PMC10912752 DOI: 10.1038/s41467-024-45979-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 02/08/2024] [Indexed: 03/06/2024] Open
Abstract
Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides an aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of O6mG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM.
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Affiliation(s)
- Xing Cheng
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA
- Department of Neuro-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Jing An
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA
- Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, China
| | - Jitong Lou
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 27599, USA
- Eli Lilly and Company, Indianapolis, IN, 46285, USA
| | - Qisheng Gu
- Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
- Department of Immunology, Université Paris Cité, Paris, France
| | - Weimin Ding
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Gaith Nabil Droby
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA
- Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC, 27599, USA
| | - Yilin Wang
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA
| | - Chenghao Wang
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 27599, USA
| | - Yanzhe Gao
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA
| | - Jay Ramanlal Anand
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA
| | - Abigail Shelton
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA
| | - Andrew Benson Satterlee
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, NC, 27599, USA
| | - Breanna Mann
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, NC, 27599, USA
| | - Yun-Chung Hsiao
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Chih-Wei Liu
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Kun Lu
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Shawn Hingtgen
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, NC, 27599, USA
| | - Jiguang Wang
- Division of Life Science, Department of Chemical and Biological Engineering, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong SAR, China
- Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong SAR, China
| | - Zhaoliang Liu
- Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, China
| | - C Ryan Miller
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA
- Department of Pathology, Division of Neuropathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Di Wu
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA
- Division of Oral and Craniofacial Health Science, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Cyrus Vaziri
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA.
| | - Yang Yang
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA.
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Liu W, Zhao Y, Liu Z, Zhang G, Wu H, Zheng X, Tang X, Chen Z. Therapeutic effects against high-grade glioblastoma mediated by engineered induced neural stem cells combined with GD2-specific CAR-NK. Cell Oncol (Dordr) 2023; 46:1747-1762. [PMID: 37420122 DOI: 10.1007/s13402-023-00842-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2023] [Indexed: 07/09/2023] Open
Abstract
PURPOSE High-grade glioblastoma is extremely challenging to treat because of its aggressiveness and resistance to conventional chemo- and radio-therapies. On the contrary, genetic and cellular immunotherapeutic strategies based on the stem and immune cells are emerging as promising treatments against glioblastoma (GBM). We aimed to developed a novel combined immunotherapeutic strategy to improve the treatment efficacy using genetically engineered PBMC-derived induced neural stem cells (iNSCs) expressing HSV-TK and second-generation CAR-NK cells against GBM. METHODS iNSCs cells expressing HSV-TK (iNSCsTK) and GD2-specific CAR-NK92 (GD2NK92) were generated from PBMC-derived iNSCs and NK92 cell lines, respectively. The anti-tumor effect of iNSCsTK and the combinational therapeutics of iNSCsTK and GD2NK92 were evaluated by GBM cell line using in vitro and in vivo experiments. RESULTS PBMC-derived iNSCsTK possessed tumor-tropism migration ability in vitro and in vivo, which exhibited considerable anti-tumor activity via bystander effect in the presence of ganciclovir (GCV). iNSCsTK/GCV could slow GBM progression and prolong median survival in tumor-bearing mice. However, the anti-tumor effect was limited to single therapy. Therefore, the combinational therapeutic effect of iNSCsTK/GCV and GD2NK92 against GBM was investigated. This approach displayed a more significant anti-tumor effect in vitro and in xenograft tumor mice. CONCLUSIONS PBMC-derived iNSCsTK showed a significant tumor-tropic migration and an effective anti-tumor activity with GCV in vitro and in vivo. In addition, combined with GD2NK92, iNSCsTK therapeutic efficacy improved dramatically to prolong the tumor-bearing animal model's median survival.
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Affiliation(s)
- Weihua Liu
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Yu Zhao
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Zhongfeng Liu
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Guangji Zhang
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Huantong Wu
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Xin Zheng
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Xihe Tang
- Neurosurgery Center of Aeronautical General Hospital, Beijing, 100012, China
| | - Zhiguo Chen
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China.
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China.
- , Beijing, China.
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9
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Cheng X, An J, Lou J, Gu Q, Ding W, Droby G, Wang Y, Wang C, Gao Y, Shelton A, Satterlee AB, Mann BE, Hsiao YC, Liu CW, Liu K, Hingtgen S, Wang J, Liu Z, Miller R, Wu D, Vaziri C, Yang Y. Trans-Lesion Synthesis and Mismatch Repair Pathway Crosstalk Defines Chemoresistance and Hypermutation Mechanisms in Glioblastoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.16.562506. [PMID: 37905107 PMCID: PMC10614844 DOI: 10.1101/2023.10.16.562506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/02/2023]
Abstract
Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides a new aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of O6mG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define novel molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM.
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Affiliation(s)
- Xing Cheng
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Neuro-Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
| | - Jing An
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
- Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, China
| | - Jitong Lou
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Qisheng Gu
- Unit of Immunity and Pediatric Infectious Diseases, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
- Department of Immunology, Université Paris Cité, Paris, France
| | - Weimin Ding
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Gaith Droby
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
- Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599
| | - Yilin Wang
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Chenghao Wang
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Yanzhe Gao
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Abigail Shelton
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Andrew Benson Satterlee
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, NC 27599
| | - Breanna Elizabeth Mann
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, NC 27599
| | - Yun-Chung Hsiao
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Chih-Wei Liu
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Kun Liu
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Shawn Hingtgen
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, NC 27599
| | - Jiguang Wang
- Division of Life Science, Department of Chemical and Biological Engineering, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong SAR, China
- Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong SAR, China
| | - Zhaoliang Liu
- Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, China
| | - Ryan Miller
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Pathology, Division of Neuropathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Di Wu
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Division of Oral and Craniofacial Health Science, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Cyrus Vaziri
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Yang Yang
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
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10
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Cheng X, An J, Lou J, Gu Q, Ding W, Droby G, Wang Y, Wang C, Gao Y, Shelton A, Satterlee AB, Mann BE, Hsiao YC, Liu CW, Liu K, Hingtgen S, Wang J, Liu Z, Miller R, Wu D, Vaziri C, Yang Y. Trans-Lesion Synthesis and Mismatch Repair Pathway Crosstalk Defines Chemoresistance and Hypermutation Mechanisms in Glioblastoma. RESEARCH SQUARE 2023:rs.3.rs-2367368. [PMID: 37886584 PMCID: PMC10602147 DOI: 10.21203/rs.3.rs-2367368/v1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/28/2023]
Abstract
Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides a new aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of O6mG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define novel molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM.
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Affiliation(s)
- Xing Cheng
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Neuro-Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
| | - Jing An
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
- Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, China
| | - Jitong Lou
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Qisheng Gu
- Unit of Immunity and Pediatric Infectious Diseases, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
- Department of Immunology, Université Paris Cité, Paris, France
| | - Weimin Ding
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Gaith Droby
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
- Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599
| | - Yilin Wang
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Chenghao Wang
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Yanzhe Gao
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Abigail Shelton
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Andrew Benson Satterlee
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, NC 27599
| | - Breanna Elizabeth Mann
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, NC 27599
| | - Yun-Chung Hsiao
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Chih-Wei Liu
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Kun Liu
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Shawn Hingtgen
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, NC 27599
| | - Jiguang Wang
- Division of Life Science, Department of Chemical and Biological Engineering, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong SAR, China
- Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong SAR, China
| | - Zhaoliang Liu
- Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, China
| | - Ryan Miller
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Pathology, Division of Neuropathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Di Wu
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Division of Oral and Craniofacial Health Science, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Cyrus Vaziri
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Yang Yang
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
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11
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Mann B, Zhang X, Bell N, Adefolaju A, Thang M, Dasari R, Kanchi K, Valdivia A, Yang Y, Buckley A, Lettry V, Quinsey C, Rauf Y, Kram D, Cassidy N, Vaziri C, Corcoran DL, Rego S, Jiang Y, Graves LM, Dunn D, Floyd S, Baldwin A, Hingtgen S, Satterlee AB. A living ex vivo platform for functional, personalized brain cancer diagnosis. Cell Rep Med 2023; 4:101042. [PMID: 37192626 PMCID: PMC10313921 DOI: 10.1016/j.xcrm.2023.101042] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 03/08/2023] [Accepted: 04/19/2023] [Indexed: 05/18/2023]
Abstract
Functional precision medicine platforms are emerging as promising strategies to improve pre-clinical drug testing and guide clinical decisions. We have developed an organotypic brain slice culture (OBSC)-based platform and multi-parametric algorithm that enable rapid engraftment, treatment, and analysis of uncultured patient brain tumor tissue and patient-derived cell lines. The platform has supported engraftment of every patient tumor tested to this point: high- and low-grade adult and pediatric tumor tissue rapidly establishes on OBSCs among endogenous astrocytes and microglia while maintaining the tumor's original DNA profile. Our algorithm calculates dose-response relationships of both tumor kill and OBSC toxicity, generating summarized drug sensitivity scores on the basis of therapeutic window and allowing us to normalize response profiles across a panel of U.S. Food and Drug Administration (FDA)-approved and exploratory agents. Summarized patient tumor scores after OBSC treatment show positive associations to clinical outcomes, suggesting that the OBSC platform can provide rapid, accurate, functional testing to ultimately guide patient care.
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Affiliation(s)
- Breanna Mann
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Xiaopei Zhang
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Noah Bell
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Adebimpe Adefolaju
- Eshelman Institute for Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Morrent Thang
- Department of Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Rajaneekar Dasari
- Eshelman Institute for Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Krishna Kanchi
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Alain Valdivia
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Yang Yang
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Andrew Buckley
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Vivien Lettry
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Carolyn Quinsey
- Department of Neurosurgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Yasmeen Rauf
- Department of Neurosurgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - David Kram
- Division of Pediatric Hematology-Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Noah Cassidy
- School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Cyrus Vaziri
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - David L Corcoran
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Stephen Rego
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Yuchao Jiang
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Lee M Graves
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Denise Dunn
- Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA
| | - Scott Floyd
- Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA
| | - Albert Baldwin
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Shawn Hingtgen
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Andrew B Satterlee
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Eshelman Institute for Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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12
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Sun Y, Wang X, Ming GL, Song H. Brain tumors on slice: A novel platform for personalized therapeutic screening. Cell Rep Med 2023; 4:101059. [PMID: 37343520 DOI: 10.1016/j.xcrm.2023.101059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/08/2023] [Accepted: 05/08/2023] [Indexed: 06/23/2023]
Abstract
Mann and Zhang et al. developed a robust ex vivo slice culture platform consisting of resected patient high- and low-grade glioma tissue engrafted onto rat organotypic brain slices, and interrogated tumor responses to clinically relevant therapeutics with a novel treatment-response algorithm.
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Affiliation(s)
- Yusha Sun
- Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Xin Wang
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Guo-Li Ming
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Hongjun Song
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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13
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Satterlee AB, Dunn DE, Valdivia A, Malawsky D, Buckley A, Gershon T, Floyd S, Hingtgen S. Spatiotemporal analysis of induced neural stem cell therapy to overcome advanced glioblastoma recurrence. Mol Ther Oncolytics 2022; 26:49-62. [PMID: 35784402 PMCID: PMC9217992 DOI: 10.1016/j.omto.2022.06.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 06/01/2022] [Indexed: 12/03/2022] Open
Abstract
Genetically engineered neural stem cells (NSCs) are a promising therapy for the highly aggressive brain cancer glioblastoma (GBM); however, treatment durability remains a major challenge. We sought to define the events that contribute to dynamic adaptation of GBM during treatment with human skin-derived induced NSCs releasing the pro-apoptotic agent TRAIL (iNSC-TRAIL) and develop strategies that convert initial tumor kill into sustained GBM suppression. In vivo and ex vivo analysis before, during, and after treatment revealed significant shifts in tumor transcriptome and spatial distribution as the tumors adapted to treatment. To address this, we designed iNSC delivery strategies that increased spatiotemporal TRAIL coverage and significantly decreased GBM volume throughout the brain, reducing tumor burden 100-fold as quantified in live ex vivo brain slices. The varying impact of different strategies on treatment durability and median survival of both solid and invasive tumors provides important guidance for optimizing iNSC therapy.
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Affiliation(s)
- Andrew B. Satterlee
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Denise E. Dunn
- Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27704, USA
| | - Alain Valdivia
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Daniel Malawsky
- Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
| | - Andrew Buckley
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Timothy Gershon
- Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
- UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
| | - Scott Floyd
- Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27704, USA
| | - Shawn Hingtgen
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
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14
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Current Opportunities for Targeting Dysregulated Neurodevelopmental Signaling Pathways in Glioblastoma. Cells 2022; 11:cells11162530. [PMID: 36010607 PMCID: PMC9406959 DOI: 10.3390/cells11162530] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 08/06/2022] [Accepted: 08/09/2022] [Indexed: 11/29/2022] Open
Abstract
Glioblastoma (GBM) is the most common and highly lethal type of brain tumor, with poor survival despite advances in understanding its complexity. After current standard therapeutic treatment, including tumor resection, radiotherapy and concomitant chemotherapy with temozolomide, the median overall survival of patients with this type of tumor is less than 15 months. Thus, there is an urgent need for new insights into GBM molecular characteristics and progress in targeted therapy in order to improve clinical outcomes. The literature data revealed that a number of different signaling pathways are dysregulated in GBM. In this review, we intended to summarize and discuss current literature data and therapeutic modalities focused on targeting dysregulated signaling pathways in GBM. A better understanding of opportunities for targeting signaling pathways that influences malignant behavior of GBM cells might open the way for the development of novel GBM-targeted therapies.
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Attia N, Mashal M, Pemminati S, Omole A, Edmondson C, Jones W, Priyadarshini P, Mughal T, Aziz P, Zenick B, Perez A, Lacken M. Cell-Based Therapy for the Treatment of Glioblastoma: An Update from Preclinical to Clinical Studies. Cells 2021; 11:116. [PMID: 35011678 PMCID: PMC8750228 DOI: 10.3390/cells11010116] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/08/2021] [Accepted: 12/14/2021] [Indexed: 01/12/2023] Open
Abstract
Glioblastoma (GB), an aggressive primary tumor of the central nervous system, represents about 60% of all adult primary brain tumors. It is notorious for its extremely low (~5%) 5-year survival rate which signals the unsatisfactory results of the standard protocol for GB therapy. This issue has become, over time, the impetus for the discipline of bringing novel therapeutics to the surface and challenging them so they can be improved. The cell-based approach in treating GB found its way to clinical trials thanks to a marvelous number of preclinical studies that probed various types of cells aiming to combat GB and increase the survival rate. In this review, we aimed to summarize and discuss the up-to-date preclinical studies that utilized stem cells or immune cells to treat GB. Likewise, we tried to summarize the most recent clinical trials using both cell categories to treat or prevent recurrence of GB in patients. As with any other therapeutics, cell-based therapy in GB is still hampered by many drawbacks. Therefore, we highlighted several novel techniques, such as the use of biomaterials, scaffolds, nanoparticles, or cells in the 3D context that may depict a promising future when combined with the cell-based approach.
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Affiliation(s)
- Noha Attia
- The American University of Antigua-College of Medicine, Coolidge 1451, Antigua and Barbuda; (S.P.); (A.O.); (C.E.); (W.J.); (P.P.); (T.M.); (P.A.); (B.Z.); (A.P.); (M.L.)
- Laboratory of Pharmaceutics, NanoBioCel Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain
- Histology and Cell Biology Department, Faculty of Medicine, University of Alexandria, Alexandria 21561, Egypt
| | - Mohamed Mashal
- The American University of Antigua-College of Medicine, Coolidge 1451, Antigua and Barbuda; (S.P.); (A.O.); (C.E.); (W.J.); (P.P.); (T.M.); (P.A.); (B.Z.); (A.P.); (M.L.)
- Laboratory of Pharmaceutics, NanoBioCel Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain
| | - Sudhakar Pemminati
- The American University of Antigua-College of Medicine, Coolidge 1451, Antigua and Barbuda; (S.P.); (A.O.); (C.E.); (W.J.); (P.P.); (T.M.); (P.A.); (B.Z.); (A.P.); (M.L.)
| | - Adekunle Omole
- The American University of Antigua-College of Medicine, Coolidge 1451, Antigua and Barbuda; (S.P.); (A.O.); (C.E.); (W.J.); (P.P.); (T.M.); (P.A.); (B.Z.); (A.P.); (M.L.)
| | - Carolyn Edmondson
- The American University of Antigua-College of Medicine, Coolidge 1451, Antigua and Barbuda; (S.P.); (A.O.); (C.E.); (W.J.); (P.P.); (T.M.); (P.A.); (B.Z.); (A.P.); (M.L.)
| | - Will Jones
- The American University of Antigua-College of Medicine, Coolidge 1451, Antigua and Barbuda; (S.P.); (A.O.); (C.E.); (W.J.); (P.P.); (T.M.); (P.A.); (B.Z.); (A.P.); (M.L.)
| | - Priyanka Priyadarshini
- The American University of Antigua-College of Medicine, Coolidge 1451, Antigua and Barbuda; (S.P.); (A.O.); (C.E.); (W.J.); (P.P.); (T.M.); (P.A.); (B.Z.); (A.P.); (M.L.)
| | - Temoria Mughal
- The American University of Antigua-College of Medicine, Coolidge 1451, Antigua and Barbuda; (S.P.); (A.O.); (C.E.); (W.J.); (P.P.); (T.M.); (P.A.); (B.Z.); (A.P.); (M.L.)
| | - Pauline Aziz
- The American University of Antigua-College of Medicine, Coolidge 1451, Antigua and Barbuda; (S.P.); (A.O.); (C.E.); (W.J.); (P.P.); (T.M.); (P.A.); (B.Z.); (A.P.); (M.L.)
| | - Blesing Zenick
- The American University of Antigua-College of Medicine, Coolidge 1451, Antigua and Barbuda; (S.P.); (A.O.); (C.E.); (W.J.); (P.P.); (T.M.); (P.A.); (B.Z.); (A.P.); (M.L.)
| | - Ambar Perez
- The American University of Antigua-College of Medicine, Coolidge 1451, Antigua and Barbuda; (S.P.); (A.O.); (C.E.); (W.J.); (P.P.); (T.M.); (P.A.); (B.Z.); (A.P.); (M.L.)
| | - Morgan Lacken
- The American University of Antigua-College of Medicine, Coolidge 1451, Antigua and Barbuda; (S.P.); (A.O.); (C.E.); (W.J.); (P.P.); (T.M.); (P.A.); (B.Z.); (A.P.); (M.L.)
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16
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Sevastre AS, Costachi A, Tataranu LG, Brandusa C, Artene SA, Stovicek O, Alexandru O, Danoiu S, Sfredel V, Dricu A. Glioblastoma pharmacotherapy: A multifaceted perspective of conventional and emerging treatments (Review). Exp Ther Med 2021; 22:1408. [PMID: 34676001 PMCID: PMC8524703 DOI: 10.3892/etm.2021.10844] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 09/21/2021] [Indexed: 12/13/2022] Open
Abstract
Due to its localisation, rapid onset, high relapse rate and resistance to most currently available treatment methods, glioblastoma multiforme (GBM) is considered to be the deadliest type of all gliomas. Although surgical resection, chemotherapy and radiotherapy are among the therapeutic strategies used for the treatment of GBM, the survival rates achieved are not satisfactory, and there is an urgent need for novel effective therapeutic options. In addition to single-target therapy, multi-target therapies are currently under development. Furthermore, drugs are being optimised to improve their ability to cross the blood-brain barrier. In the present review, the main strategies applied for GBM treatment in terms of the most recent therapeutic agents and approaches that are currently under pre-clinical and clinical testing were discussed. In addition, the most recently reported experimental data following the testing of novel therapies, including stem cell therapy, immunotherapy, gene therapy, genomic correction and precision medicine, were reviewed, and their advantages and drawbacks were also summarised.
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Affiliation(s)
- Ani-Simona Sevastre
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Alexandra Costachi
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Ligia Gabriela Tataranu
- Department of Neurosurgery, ‘Bagdasar-Arseni’ Emergency Clinical Hospital, 041915 Bucharest, Romania
| | - Corina Brandusa
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Stefan Alexandru Artene
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Olivian Stovicek
- Department of Pharmacology, Faculty of Nursing Targu Jiu, Titu Maiorescu University of Bucharest, 210106 Targu Jiu, Romania
| | - Oana Alexandru
- Department of Neurology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Suzana Danoiu
- Department of Pathophysiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Veronica Sfredel
- Department of Physiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Anica Dricu
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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17
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Zhang GL, Wang CF, Qian C, Ji YX, Wang YZ. Role and mechanism of neural stem cells of the subventricular zone in glioblastoma. World J Stem Cells 2021; 13:877-893. [PMID: 34367482 PMCID: PMC8316865 DOI: 10.4252/wjsc.v13.i7.877] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/16/2021] [Accepted: 06/18/2021] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma multiforme (GBM), the most frequently occurring malignant brain tumor in adults, remains mostly untreatable. Because of the heterogeneity of invasive gliomas and drug resistance associated with the tumor microenvironment, the prognosis is poor, and the survival rate of patients is low. Communication between GBMs and non-glioma cells in the tumor microenvironment plays a vital role in tumor growth and recurrence. Emerging data have suggested that neural stem cells (NSCs) in the subventricular zone (SVZ) are the cells-of-origin of gliomas, and SVZ NSC involvement is associated with the progression and recurrence of GBM. This review highlights the interaction between SVZ NSCs and gliomas, summarizes current findings on the crosstalk between gliomas and other non-glioma cells, and describes the links between SVZ NSCs and gliomas. We also discuss the role and mechanism of SVZ NSCs in glioblastoma, as well as the interventions targeting the SVZ and their therapeutic implications in glioblastoma. Taken together, understanding the biological mechanism of glioma-NSC interactions can lead to new therapeutic strategies for GBM.
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Affiliation(s)
- Gui-Long Zhang
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
| | - Chuan-Fang Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
| | - Cheng Qian
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
| | - Yun-Xiang Ji
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
| | - Ye-Zhong Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
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18
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Biserova K, Jakovlevs A, Uljanovs R, Strumfa I. Cancer Stem Cells: Significance in Origin, Pathogenesis and Treatment of Glioblastoma. Cells 2021; 10:cells10030621. [PMID: 33799798 PMCID: PMC8000844 DOI: 10.3390/cells10030621] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/27/2021] [Accepted: 03/09/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer stem cells (CSCs), known also as tumor-initiating cells, are quiescent, pluripotent, self-renewing neoplastic cells that were first identified in hematologic tumors and soon after in solid malignancies. CSCs have attracted remarkable research interest due to their role in tumor resistance to chemotherapy and radiation treatment as well as recurrence. Extensive research has been devoted to the role of CSCs in glioblastoma multiforme (GBM), the most common primary brain tumor in adults, which is characterized by a dismal prognosis because of its aggressive course and poor response to treatment. The aim of the current paper is to provide an overview of current knowledge on the role of cancer stem cells in the pathogenesis and treatment resistance of glioblastoma. The six regulatory mechanisms of glioma stem cells (GSCs)—tumor microenvironment, niche concept, metabolism, immunity, genetics, and epigenetics—are reviewed. The molecular markers used to identify GSCs are described. The role of GSCs in the treatment resistance of glioblastoma is reviewed, along with future treatment options targeting GSCs. Stem cells of glioblastoma thus represent both a driving mechanism of major treatment difficulties and a possible target for more effective future approaches.
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Affiliation(s)
- Karina Biserova
- Faculty of Residency, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia
- Correspondence:
| | - Arvids Jakovlevs
- Department of Pathology, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia; (A.J.); (R.U.); (I.S.)
| | - Romans Uljanovs
- Department of Pathology, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia; (A.J.); (R.U.); (I.S.)
| | - Ilze Strumfa
- Department of Pathology, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia; (A.J.); (R.U.); (I.S.)
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19
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Generation and Profiling of Tumor-Homing Induced Neural Stem Cells from the Skin of Cancer Patients. Mol Ther 2020; 28:1614-1627. [PMID: 32402245 DOI: 10.1016/j.ymthe.2020.04.022] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 03/13/2020] [Accepted: 04/23/2020] [Indexed: 12/22/2022] Open
Abstract
The conversion of human fibroblasts into personalized induced neural stem cells (iNSCs) that actively seek out tumors and deliver cytotoxic agents is a highly promising approach for treating various types of cancer. However, the ability to generate iNSCs from the skin of cancer patients has not been explored. Here, we take an important step toward clinical application by generating iNSCs from skin biopsies of human patients undergoing treatment for the aggressive brain cancer, glioblastoma (GBM). We then utilized a panel of functional and genomic studies to investigate the efficacy and tumor-homing capacity of these patient-derived cells, as well as genomic analysis, to characterize the impact of interpatient variability on this personalized cell therapy. From the skin-tissue biopsies, we established fibroblasts and transdifferentiated the cells into iNSCs. Genomic and functional testing revealed marked variability in growth rates, therapeutic agent production, and gene expression during fibroblast-to-iNSC conversion among patient lines. In vivo testing showed patient-derived iNSCs home to tumors, yet rates and expression of homing-related pathways varied among patients. With the use of surgical-resection mouse models of invasive human cluster of differentiation 133+ (CD133+) GBM cells and serial kinetic imaging, we found that "high-performing" patient-derived iNSC lines reduced the volume of GBM cells 60-fold and extended survival from 28 to 45 days. Treatment with "low-performing" patient lines had minimal effect on tumor growth, but the anti-tumor effect could be rescued by increasing the intracavity dose. Together, these data show, for the first time, that tumor-homing iNSCs can be generated from the skin of cancer patients and efficaciously suppress tumor growth. We also begin to define genetic markers that could be used to identify cells that will contain the most effective attributes for tumor homing and kill in human patients, including high gene expression of the semaphorin-3B (SEMA3B), which is known to be involved in neuronal cell migration. These studies should serve as an important guide toward clinical GBM therapy, where the personalized nature of optimized iNSC therapy has the potential to avoid transplant rejection and maximize treatment durability.
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