|
1
|
Li YA, Zhao C, Ge JJ, Li C, Xue FJ, Qi SP, Zhao C, Kong CC, Zhang JP. Apatinib combined with temozolomide in diffuse midline glioma: a novel and effective therapy. BMC Cancer 2024; 24:754. [PMID: 38907215 PMCID: PMC11193221 DOI: 10.1186/s12885-024-12373-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 05/10/2024] [Indexed: 06/23/2024] Open
Abstract
PURPOSE Diffuse midline glioma (DMG), H3 K27M-mutant is a type of diffuse high-grade glioma that occurs in the brain midline carrying an extremely poor prognosis under the best efforts of surgery, radiation, and other therapies. For better therapy, we explored the efficacy and toxicity of a novel therapy that combines apatinib and temozolomide in DMG. METHODS A retrospective analysis of 32 patients with DMG who underwent apatinib plus temozolomide treatment was performed. Apatinib was given 500 mg in adults, 250 mg in pediatric patients once daily. Temozolomide was administered at 200 mg/m2/d according to the standard 5/28 days regimen. The main clinical data included basic information of patients, radiological and pathological characteristics of tumors, treatment, adverse reactions, prognosis. RESULTS The objective response rate was 24.1%, and the disease control rate was 79.3%. The median PFS of all patients was 5.8 months, and median OS was 10.3 months. A total of 236 cycles of treatment were available for safety assessment and the toxicity of the combination therapy was relatively well tolerated. The most common grade 3 toxicities were myelosuppression including leukopenia (5.08%), neutropenia (4.24%), lymphopenia (2.12%), thrombocytopenia (1.69%) and anemia (1.27%). Grade 4 toxicities included neutropenia (2.12%), thrombocytopenia (2.12%) and proteinuria (1.69%). All the adverse events were relieved after symptomatic treatment or dose reduction. CONCLUSIONS Apatinib plus temozolomide could be an effective regimen with manageable toxicities and favorable efficacy and may outperform temozolomide monotherapy, particularly in newly diagnosed adults with tumors located outside the pons. The novel therapy deserves further investigation in adult DMG patients.
Collapse
Affiliation(s)
- Yu-An Li
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Chuan Zhao
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Jing-Jing Ge
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Cheng Li
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Feng-Jun Xue
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Shao-Pei Qi
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Chi Zhao
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Chen-Chen Kong
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Jun-Ping Zhang
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China.
| |
Collapse
|
|
2
|
Ghosh D, Pryor B, Jiang N. Cellular signaling in glioblastoma: A molecular and clinical perspective. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 386:1-47. [PMID: 38782497 DOI: 10.1016/bs.ircmb.2024.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
Glioblastoma multiforme (GBM) is the most aggressive brain tumor with an average life expectancy of less than 15 months. Such high patient mortality in GBM is pertaining to the presence of clinical and molecular heterogeneity attributed to various genetic and epigenetic alterations. Such alterations in critically important signaling pathways are attributed to aberrant gene signaling. Different subclasses of GBM show predominance of different genetic alterations and therefore, understanding the complex signaling pathways and their key molecular components in different subclasses of GBM is extremely important with respect to clinical management. In this book chapter, we summarize the common and important signaling pathways that play a significant role in different subclasses and discuss their therapeutic targeting approaches in terms of preclinical studies and clinical trials.
Collapse
Affiliation(s)
- Debarati Ghosh
- McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, United States.
| | - Brett Pryor
- McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Nancy Jiang
- Wellesley College, Wellesley, MA, United States
| |
Collapse
|
|
3
|
Dewdney B, Jenkins MR, Best SA, Freytag S, Prasad K, Holst J, Endersby R, Johns TG. From signalling pathways to targeted therapies: unravelling glioblastoma's secrets and harnessing two decades of progress. Signal Transduct Target Ther 2023; 8:400. [PMID: 37857607 PMCID: PMC10587102 DOI: 10.1038/s41392-023-01637-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/29/2023] [Accepted: 09/07/2023] [Indexed: 10/21/2023] Open
Abstract
Glioblastoma, a rare, and highly lethal form of brain cancer, poses significant challenges in terms of therapeutic resistance, and poor survival rates for both adult and paediatric patients alike. Despite advancements in brain cancer research driven by a technological revolution, translating our understanding of glioblastoma pathogenesis into improved clinical outcomes remains a critical unmet need. This review emphasises the intricate role of receptor tyrosine kinase signalling pathways, epigenetic mechanisms, and metabolic functions in glioblastoma tumourigenesis and therapeutic resistance. We also discuss the extensive efforts over the past two decades that have explored targeted therapies against these pathways. Emerging therapeutic approaches, such as antibody-toxin conjugates or CAR T cell therapies, offer potential by specifically targeting proteins on the glioblastoma cell surface. Combination strategies incorporating protein-targeted therapy and immune-based therapies demonstrate great promise for future clinical research. Moreover, gaining insights into the role of cell-of-origin in glioblastoma treatment response holds the potential to advance precision medicine approaches. Addressing these challenges is crucial to improving outcomes for glioblastoma patients and moving towards more effective precision therapies.
Collapse
Affiliation(s)
- Brittany Dewdney
- Cancer Centre, Telethon Kids Institute, Nedlands, WA, 6009, Australia.
- Centre For Child Health Research, University of Western Australia, Perth, WA, 6009, Australia.
| | - Misty R Jenkins
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
| | - Sarah A Best
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
| | - Saskia Freytag
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
| | - Krishneel Prasad
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
| | - Jeff Holst
- School of Biomedical Sciences, University of New South Wales, Sydney, 2052, Australia
| | - Raelene Endersby
- Cancer Centre, Telethon Kids Institute, Nedlands, WA, 6009, Australia
- Centre For Child Health Research, University of Western Australia, Perth, WA, 6009, Australia
| | - Terrance G Johns
- Cancer Centre, Telethon Kids Institute, Nedlands, WA, 6009, Australia
- Centre For Child Health Research, University of Western Australia, Perth, WA, 6009, Australia
| |
Collapse
|
|
4
|
Lin H, Zhou X, Sheng X, Liang X. Efficacy and Safety of Apatinib in Patients with Recurrent Glioblastoma. Drugs R D 2023; 23:239-244. [PMID: 37466833 PMCID: PMC10439071 DOI: 10.1007/s40268-023-00429-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 02/15/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND AND OBJECTIVE Glioblastoma is a cranial malignant tumor with a high recurrence rate after surgery and a poor response to chemoradiotherapy. Bevacizumab has demonstrated efficacy in the treatment of glioblastoma by inhibiting vascular endothelial growth factor, but the efficacy of vascular endothelial growth factor receptor tyrosine kinase inhibitors varies in treating glioblastoma. This single-arm prospective study aimed to explore the efficacy and safety of the vascular endothelial growth factor receptor tyrosine kinase inhibitor apatinib in treating recurrent glioblastoma after chemoradiotherapy. METHODS A total of 15 patients with recurrent glioblastoma (2016 World Health Organization grade IV) after chemoradiotherapy were enrolled in this study from September 2017 to September 2019 and treated with apatinib 500 mg once daily. Responses were evaluated according to the Response Assessment in Neuro-Oncology criteria, and adverse events were recorded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. RESULTS The overall response rate was 33.3%, and the disease control rate was 66.6%. The median progression-free survival was 2 months, and the median overall survival was 6.5 months. The apatinib dose was adjusted in seven patients because of adverse events (46.6%). The most common adverse events were thrombocytopenia (53.3%), asthenia (40%), and hand-foot syndrome (33.3%). CONCLUSIONS Apatinib might be effective in treating recurrent glioblastoma after chemoradiotherapy in terms of the overall response rate, but the efficacy is not durable and the clinical benefit is limited. The adverse effects of apatinib were acceptable. CLINICAL TRIAL REGISTRATION ChiCTR-ONC-17013098, date of registration: 24 October, 2017.
Collapse
Affiliation(s)
- Hao Lin
- Department of Oncology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xinli Zhou
- Department of Oncology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiaofang Sheng
- Radiation Therapy Center, Huashan Hospital, Fudan University, Shanghai, China.
| | - Xiaohua Liang
- Department of Oncology, Huashan Hospital, Fudan University, Shanghai, China.
| |
Collapse
|
|
5
|
Li G, Xu X, Cui J, Zhang F, Wang S. Efficacy of apatinib combined with temozolomide in the treatment of recurrent high‑grade glioma: A meta‑analysis. Exp Ther Med 2023; 26:452. [PMID: 37614429 PMCID: PMC10443066 DOI: 10.3892/etm.2023.12151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 07/07/2023] [Indexed: 08/25/2023] Open
Abstract
Recurrent high-grade glioma is a refractory disease, and its prognosis is poor. Although the treatment of apatinib combined with temozolomide provides improved efficacy and is able to prolong survival, this conclusion has been based on small samples. In order to clarify this treatment's efficacy, a meta-analysis was performed in the present study. Different databases were screened and finally, 10 studies were included, comprising 357 patients with recurrent high-grade gliomas. The efficacy and prognosis were analyzed using Stata software. The results indicated that the overall objective response rate (ORR) and disease control rate (DCR) of apatinib combined with temozolomide were 0.36 (95% CI, 0.26-0.46) and 0.86 (95% CI, 0.82-0.89), respectively. Subgroup analysis indicated that the overall ORR was 0.43 (95% CI, 0.29-0.57) and 0.26 (95% CI, 0.14-0.38), and the DCR was 0.89 (95% CI, 0.85-0.93) and 0.76 (95% CI, 0.69-0.84) in the treatment of apatinib with temozolomide dose-dense group and the conventional-dose group (5/28 regimen), respectively. Further prognostic analysis indicated that the median overall survival of patients with high-grade glioma treated with apatinib combined with temozolomide was 8.21 months (95% CI, 7.20-9.22 months) and the median progression-free survival was 5.45 months (95% CI, 4.53-6.37). Analysis of the publication bias of the effect size revealed that there was bias in the DCR, while no bias was found in the remaining effect size (ORR, median overall survival and median progression-free survival). After correction by the trim-and-fill method, bias was indicated to have no significant impact on the results. In conclusion, apatinib combined with temozolomide has the effect that, compared with traditional Bevacizumab treatment, it can improve the efficacy in the treatment of recurrent high-grade glioma and improve prognosis. When combining with dose-dense temozolomide, the effect may be better than that of the conventional 5/28 regimen.
Collapse
Affiliation(s)
- Guanglie Li
- Department of Head and Neck Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong 519000, P.R. China
| | - Xiwei Xu
- Department of Head and Neck Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong 519000, P.R. China
| | - Jianqi Cui
- Department of Head and Neck Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong 519000, P.R. China
| | - Fan Zhang
- Department of Head and Neck Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong 519000, P.R. China
| | - Siyang Wang
- Department of Head and Neck Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong 519000, P.R. China
| |
Collapse
|
|
6
|
Yashin KS, Yuzhakova DV, Sachkova DA, Kukhnina LS, Kharitonova TM, Zolotova AS, Medyanik IA, Shirmanova MV. Personalized Medicine in Brain Gliomas: Targeted Therapy, Patient-Derived Tumor Models (Review). Sovrem Tekhnologii Med 2023; 15:61-71. [PMID: 38435477 PMCID: PMC10904359 DOI: 10.17691/stm2023.15.3.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Indexed: 03/05/2024] Open
Abstract
Gliomas are the most common type of primary malignant brain tumors. The choice of treatments for these tumors was quite limited for many years, and therapy results generally remain still unsatisfactory. Recently, a significant breakthrough in the treatment of many forms of cancer occurred when personalized targeted therapies were introduced which inhibit tumor growth by affecting a specific molecular target. Another trend gaining popularity in oncology is the creation of patient-derived tumor models which can be used for drug screening to select the optimal therapy regimen. Molecular and genetic mechanisms of brain gliomas growth are considered, consisting of individual components which could potentially be exposed to targeted drugs. The results of the literature review show a higher efficacy of the personalized approach to the treatment of individual patients compared to the use of standard therapies. However, many unresolved issues remain in the area of predicting the effectiveness of a particular drug therapy regimen. The main hopes in solving this issue are set on the use of patient-derived tumor models, which can be used in one-stage testing of a wide range of antitumor drugs.
Collapse
Affiliation(s)
- K S Yashin
- Neurosurgeon, Department of Neurosurgery, University Clinic; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Assistant, Department of Traumatology and Neurosurgery named after M.V. Kolokoltsev; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Oncologist, Polyclinic Department; Nizhny Novgorod Regional Oncologic Dispensary, 11/1 Delovaya St., Nizhny Novgorod, 603126, Russia
| | - D V Yuzhakova
- Researcher, Laboratory of Genomics of Adaptive Antitumor Immunity, Research Institute of Experimental Oncology and Biomedical Technologies; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - D A Sachkova
- Master Student, Department of Biophysics; National Research Lobachevsky State University of Nizhni Novgorod, 23 Prospekt Gagarina, Nizhny Novgorod, 603950, Russia Laboratory Assistant, Laboratory of Fluorescent Bioimaging, Research Institute of Experimental Oncology and Biomedical Technologies; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - L S Kukhnina
- Student, Faculty of Medicine; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - T M Kharitonova
- Student, Faculty of Medicine; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - A S Zolotova
- Resident, Department of Neurosurgery, University Clinic; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - I A Medyanik
- Neurosurgeon, Department Neurosurgery, University Clinic; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Professor, Department of Traumatology and Neurosurgery named after M.V. Kolokoltsev; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Oncologist, Polyclinic Department; Nizhny Novgorod Regional Oncologic Dispensary, 11/1 Delovaya St., Nizhny Novgorod, 603126, Russia
| | - M V Shirmanova
- Deputy Director for Science, Research Institute of Experimental Oncology and Biomedical Technologies; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| |
Collapse
|
|
7
|
Szklener K, Mazurek M, Wieteska M, Wacławska M, Bilski M, Mańdziuk S. New Directions in the Therapy of Glioblastoma. Cancers (Basel) 2022; 14:5377. [PMID: 36358795 PMCID: PMC9655599 DOI: 10.3390/cancers14215377] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/20/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022] Open
Abstract
Glioblastoma is the most common histologic type of all gliomas and contributes to 57.3% of all cases. Despite the standard management based on surgical resection and radiotherapy, it is related to poor outcome, with a 5-year relative survival rate below 6.9%. In order to improve the overall outcome for patients, the new therapeutic strategies are needed. Herein, we describe the current state of knowledge on novel targeted therapies in glioblastoma. Based on recent studies, we compared treatment efficacy measured by overall survival and progression-free survival in patients treated with selected potential antitumor drugs. The results of the application of the analyzed inhibitors are highly variable despite the encouraging conclusions of previous preclinical studies. This paper focused on drugs that target major glioblastoma kinases. As far, the results of some BRAF inhibitors are favorable. Vemurafenib demonstrated a long-term efficacy in clinical trials while the combination of dabrafenib and trametinib improves PFS compared with both vemurafenib and dabrafenib alone. There is no evidence that any MEK inhibitor is effective in monotherapy. According to the current state of knowledge, BRAF and MEK inhibition are more advantageous than BRAF inhibitor monotherapy. Moreover, mTOR inhibitors (especially paxalisib) may be considered a particularly important group. Everolimus demonstrated a partial response in a significant proportion of patients when combined with bevacizumab, however its actual role in the treatment is unclear. Neither nintedanib nor pemigatinib were efficient in treatment of GBM. Among the anti-VEGF drugs, bevacizumab monotherapy was a well-tolerated option, significantly associated with anti-GBM activity in patients with recurrent GBM. The efficacy of aflibercept and pazopanib in monotherapy has not been demonstrated. Apatinib has been proven to be effective and tolerable by a single clinical trial, but more research is needed. Lenvatinib is under trial. Finally, promising results from a study with regorafenib may be confirmed by the ongoing randomized AGILE trial. The studies conducted so far have provided a relatively wide range of drugs, which are at least well tolerated and demonstrated some efficacy in the randomized clinical trials. The comprehensive understanding of the molecular biology of gliomas promises to further improve the treatment outcomes of patients.
Collapse
Affiliation(s)
- Katarzyna Szklener
- Department of Clinical Oncology and Chemotherapy, Medical University of Lublin, 8 Jaczewski Street, 20-090 Lublin, Poland
| | - Marek Mazurek
- Department of Neurosurgery, Medical University of Lublin, 20-090 Lublin, Poland
| | - Małgorzata Wieteska
- Department of Clinical Oncology and Chemotherapy, Medical University of Lublin, 8 Jaczewski Street, 20-090 Lublin, Poland
| | - Monika Wacławska
- Department of Clinical Oncology and Chemotherapy, Medical University of Lublin, 8 Jaczewski Street, 20-090 Lublin, Poland
| | - Mateusz Bilski
- Department of Radiotherapy, Medical University of Lublin, 20-090 Lublin, Poland
| | - Sławomir Mańdziuk
- Department of Clinical Oncology and Chemotherapy, Medical University of Lublin, 8 Jaczewski Street, 20-090 Lublin, Poland
| |
Collapse
|
|
8
|
Abstract
RATIONALE Outcomes remain poor in children with recurrent ependyomams (rEPNs), despite advances in surgery and radiotherapy. Systemic therapeutic options are limited, given the low response to chemotherapy and targeted drugs. There is an urgent need for efective pharmacotherapy. Apatinib is a multitarget tyrosine kinase inhibitor, which has been reported to exhibit broad antitumor profiles. However, its effects on rEPNs have not been reported thus far. PATIENT CONCERNS We present a 5-year-old recurrent ependyomam patient benefting from apatinib and temozolomide. The patient was diagnosed with ependyomam in January 2016 and treated with surgery and radiotherapy. After surgery, the patient walked with an mild unsteady gait. He was diagnosed with recurrence in November 2018 following which he was treated with reoperation, reirradiation and chemotherapy (etopside, cisplatin, and temozolomide [TMZ]). The patients increased gait instability in April 2019. DIAGNOSES Magnetic resonance imaging (MRI) showed progression of the disease. The lession at the left edge of the fourth ventricle and cerebellar peduncles was significantly increased. INTERVENTIONS The patient was administer TMZ (200 mg/m2/d, d1-5, 28 days as a cycle) + apatinib (250 mg, every other day). Twelve cycle of TMZ and apatinib were given. OUTCOMES The tumor significantly shrank during the patient received TMZ and apatinib. After 9 months of medication, MRI revealed a nearly complete response However, the tumor progressed on May 5, 2020. From the beginning of the application of TMZ and apatinib, the progression-free survival was 1 year and the survival time was 19 months. Grade 1 leukocytopenia was observed without other adverse effects. CONCLUSION Apatinib and temozolomide treatment with mild side effects may be a new option for children with recurrent ependyomams.
Collapse
Affiliation(s)
- Shuangshuang Zhao
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, P.R. China
| | - Zhipeng Shen
- Department of Neurosurgery, The Chilidren’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China
| | - Juan Li
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, P.R. China
| | - Lei Shi
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, P.R. China
| | - Ni Zhang
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, P.R. China
- *Correspondence: Ni Zhang, Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, 310002, PR China (e-mail: )
| |
Collapse
|
|
9
|
Guo K, Zhao J, Jin Q, Yan H, Shi Y, Zhao Z. CASP6 predicts poor prognosis in glioma and correlates with tumor immune microenvironment. Front Oncol 2022; 12:818283. [PMID: 36119521 PMCID: PMC9479196 DOI: 10.3389/fonc.2022.818283] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 08/15/2022] [Indexed: 12/24/2022] Open
Abstract
BackgroundGlioma is an aggressive tumor of the central nervous system. Caspase-6 (CASP6) plays a crucial role in cell pyroptosis and is a central protein involved in many cellular signaling pathways. However, the association between CASP6 and prognosis of glioma patients remains unclear.MethodsFour bioinformatic databases were analyzed to identify differentially expressed genes (DEGs) between glioma and healthy tissues. Eighty-one protein-coding pyroptosis-related genes (PRGs) were obtained from the GeneCards database. The pyroptosis-related DEGs (PRDEGs) were extracted from each dataset, and CASP6 was found to be aberrantly expressed in glioma. We then investigated the biological functions of CASP6 and the relationship between CASP6 expression and the tumor microenvironment and immunocyte infiltration. The half maximal inhibitory concentration of temozolomide and the response to immune checkpoint blockade in the high- and low-CASP6 expression groups were estimated using relevant bioinformatic algorithms. Quantitative real-time reverse transcription PCR and western blotting were carried out to confirm the different expression levels of CASP6 between human astrocytes and glioma cell lines (U251 and T98G). We determined the role of CASP6 in the tumorigenesis of glioma by knocking down CASP6 in U251 and T98G cell lines.ResultsWe found that CASP6 was overexpressed in glioma samples and in glioma cell lines. CASP6 expression in patients with glioma correlated negatively with overall survival. In addition, CASP6 expression correlated positively with the degree of glioma progression. Functional analysis indicated that CASP6 was primarily involved in the immune response and antigen processing and presentation. Patients with high CASP6 levels responded more favorably to temozolomide, while patients with low expression of CASP6 had a better response to immunotherapy. Finally, in vitro experiments showed that CASP6 knockdown inhibited glioma proliferation.ConclusionsThe pyroptosis-related gene CASP6 might represent a sensitive prognostic marker for patients with glioma and might predict their response of immunotherapy and temozolomide therapy. Our results might lead to more precise immunotherapeutic strategies for patients with glioma.
Collapse
Affiliation(s)
- Kai Guo
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Department of Neurosurgery, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, China
| | - Jiahui Zhao
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Qianxu Jin
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hongshan Yan
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yunpeng Shi
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zongmao Zhao
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- *Correspondence: Zongmao Zhao,
| |
Collapse
|
|
10
|
Guo K, Duan X, Zhao J, Sun B, Liu X, Zhao Z. A novel necroptosis-related gene signature for predict prognosis of glioma based on single-cell and bulk RNA sequencing. Front Mol Biosci 2022; 9:984712. [PMID: 36111134 PMCID: PMC9469195 DOI: 10.3389/fmolb.2022.984712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Glioma is the most fatal neoplasm among the primary intracranial cancers. Necroptosis, a form of programmed cell death, is correlated with tumor progression and immune response. But, the role of necroptosis-related genes (NRGs) in glioma has not been well-uncovered.Methods: Single-cell and bulk RNA sequencing data, obtained from publicly accessed databases, were used to establish a necroptosis-related gene signature for predicting the prognosis of glioma patients. Multiple bioinformatics algorithms were conducted to evaluate the efficacy of the signature. The relative mRNA level of each signature gene was validated by quantitative real-time reverse transcription PCR (qRT-PCR) in glioma cell lines compared to human astrocytes.Results: In this predicted prognosis model, patients with a high risk score showed a shorter overall survival, which was verified in the testing cohorts. The signature risk score was positively related with immune cell infiltration and some immune check points, such as CD276 (B7-H3), CD152 (CTLA-4), CD223 (LAG-3), and CD274 (PD-L1). Single-cell RNA sequencing analysis confirmed that the glioma microenvironment consists of various immune cells with different markers. The eight NRGs of the signature were detected to be expressed in several immune cells. QRT-PCR results verified that all the eight signature genes were differentially expressed between human astrocytes and glioma cells.Conclusion: The eight NRGs correlate with the immune microenvironment of glioma according to our bioinformatics analysis. This necroptosis-related gene signature may evaluate the precise methodology of predicting prognosis of glioma and provide a novel thought in glioma investigation.
Collapse
Affiliation(s)
- Kai Guo
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Department of Neurosurgery, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, China
| | - Xinxin Duan
- Department of Oncology, Hebei General Hospital, Shijiazhuang, China
- Graduate School, North China University of Science and Technology, Tangshan, China
| | - Jiahui Zhao
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Boyu Sun
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaoming Liu
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zongmao Zhao
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- *Correspondence: Zongmao Zhao,
| |
Collapse
|
|
11
|
Zhang HH, Du XJ, Deng ML, Zheng L, Yao DC, Wang ZQ, Yang QY, Wu SX. Apatinib for recurrent/progressive glioblastoma multiforme: A salvage option. Front Pharmacol 2022; 13:969565. [PMID: 36060005 PMCID: PMC9432461 DOI: 10.3389/fphar.2022.969565] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/25/2022] [Indexed: 12/01/2022] Open
Abstract
Purpose: The recurrent/progressive glioblastoma multiforme (GBM) carries a dismal prognosis and the definitive treatment strategy has not yet been established. This study aimed to assess the efficacy and safety of apatinib in recurrent/progressive GBM patients. Materials and methods: The clinical data of 19 recurrent/progressive GBM patients who received apatinib treatment from November 2015 to December 2019 at Sun Yat-sen University Cancer Center were collected retrospectively in this study. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (AEs) were reviewed and assessed. Results: The overall ORR was 52.6%, and the DCR was 73.7%. Median PFS and OS were 5.1 and 10.4 months, respectively. The 6-month PFS and OS rates were 38.9% and 68.4%, respectively. The 12-month PFS and OS rates were 16.7% and 36.8%, respectively. The treatment-related toxicities were generally well-tolerated. The most common grade 3/4 AEs were hand-foot syndrome (36.8%) and hypertension (21.1%). Conclusion: Our study showed that apatinib therapy provided a better salvaging option for recurrent/progressive GBM patients and the toxicity was manageable.
Collapse
Affiliation(s)
- Hong-Hong Zhang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Radiation Oncology, Xiang’an Hospital of Xiamen University, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Xiao-Jing Du
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Mei-Ling Deng
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Lie Zheng
- Department of Medical Imaging, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Dun-Chen Yao
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zhi-Qiang Wang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Qun-Ying Yang
- Department of Neurosurgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Shao-Xiong Wu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- *Correspondence: Shao-Xiong Wu,
| |
Collapse
|
|
12
|
Yao H, Liu J, Zhang C, Shao Y, Li X, Yu Z, Huang Y. Apatinib inhibits glioma cell malignancy in patient-derived orthotopic xenograft mouse model by targeting thrombospondin 1/myosin heavy chain 9 axis. Cell Death Dis 2021; 12:927. [PMID: 34635636 PMCID: PMC8505401 DOI: 10.1038/s41419-021-04225-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 09/09/2021] [Accepted: 09/23/2021] [Indexed: 12/13/2022]
Abstract
We determined the antitumor mechanism of apatinib in glioma using a patient-derived orthotopic xenograft (PDOX) glioma mouse model and glioblastoma (GBM) cell lines. The PDOX mouse model was established using tumor tissues from two glioma patients via single-cell injections. Sixteen mice were successfully modeled and randomly divided into two equal groups (n = 8/group): apatinib and normal control. Survival analysis and in vivo imaging was performed to determine the effect of apatinib on glioma proliferation in vivo. Candidate genes in GBM cells that may be affected by apatinib treatment were screened using RNA-sequencing coupled with quantitative mass spectrometry, data mining of The Cancer Genome Atlas, and Chinese Glioma Genome Atlas databases, and immunohistochemistry analysis of clinical high-grade glioma pathology samples. Quantitative reverse transcription-polymerase chain reaction (qPCR), western blotting, and co-immunoprecipitation (co-IP) were performed to assess gene expression and the apatinib-mediated effect on glioma cell malignancy. Apatinib inhibited the proliferation and malignancy of glioma cells in vivo and in vitro. Thrombospondin 1 (THBS1) was identified as a potential target of apatinib that lead to inhibited glioma cell proliferation. Apatinib-mediated THBS1 downregulation in glioma cells was confirmed by qPCR and western blotting. Co-IP and mass spectrometry analysis revealed that THBS1 could interact with myosin heavy chain 9 (MYH9) in glioma cells. Simultaneous THBS1 overexpression and MYH9 knockdown suppressed glioma cell invasion and migration. These data suggest that apatinib targets THBS1 in glioma cells, potentially via MYH9, to inhibit glioma cell malignancy and may provide novel targets for glioma therapy.
Collapse
Affiliation(s)
- Hui Yao
- Department of Neurosurgery, the First Affiliated Hospital of Soochow University, No188, Shizi Street, Suzhou, 215007, Jiangsu, China
| | - Jiangang Liu
- Department of Neurosurgery, the First Affiliated Hospital of Soochow University, No188, Shizi Street, Suzhou, 215007, Jiangsu, China
| | - Chi Zhang
- Department of Neurosurgery, the First Affiliated Hospital of Soochow University, No188, Shizi Street, Suzhou, 215007, Jiangsu, China
| | - Yunxiang Shao
- Department of Neurosurgery, the First Affiliated Hospital of Soochow University, No188, Shizi Street, Suzhou, 215007, Jiangsu, China
| | - Xuetao Li
- Department of Neurosurgery, Dushu Lake Hospital Affiliated of Soochow University, Suzhou, 215124, Jiangsu, China
| | - Zhengquan Yu
- Department of Neurosurgery, the First Affiliated Hospital of Soochow University, No188, Shizi Street, Suzhou, 215007, Jiangsu, China.
| | - Yulun Huang
- Department of Neurosurgery, the First Affiliated Hospital of Soochow University, No188, Shizi Street, Suzhou, 215007, Jiangsu, China.
- Department of Neurosurgery, Dushu Lake Hospital Affiliated of Soochow University, Suzhou, 215124, Jiangsu, China.
| |
Collapse
|
|
13
|
Schulte JD, Aghi MK, Taylor JW. Anti-angiogenic therapies in the management of glioblastoma. Chin Clin Oncol 2021; 10:37. [PMID: 32389001 PMCID: PMC10631456 DOI: 10.21037/cco.2020.03.06] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 03/13/2020] [Indexed: 11/06/2022]
Abstract
Angiogenesis is a central feature of glioblastoma (GBM), with contribution from several mechanisms and signaling pathways to produce an irregular, poorly constructed, and poorly connected tumor vasculature. Targeting angiogenesis has been efficacious for disease control in other cancers, and given the (I) highly vascularized environment in GBM and (II) correlation between glioma grade and prognosis, angiogenesis became a prime target of therapy in GBM as well. Here, we discuss the therapies developed to target these pathways including vascular endothelial growth factor (VEGF) signaling, mechanisms of tumor resistance to these drugs in the context of disease progression, and the evolving role of anti-angiogenic therapy in GBM.
Collapse
Affiliation(s)
- Jessica D. Schulte
- Department of Neurological Surgery, University of California, San Francisco, CA, USA
| | - Manish K. Aghi
- Department of Neurological Surgery, University of California, San Francisco, CA, USA
| | - Jennie W. Taylor
- Department of Neurological Surgery, University of California, San Francisco, CA, USA
- Department of Neurology, University of California, San Francisco, CA, USA
| |
Collapse
|
|
14
|
She L, Su L, Shen L, Liu C. Retrospective Study of the Safety and Efficacy of Anlotinib Combined With Dose-Dense Temozolomide in Patients With Recurrent Glioblastoma. Front Oncol 2021; 11:687564. [PMID: 34354945 PMCID: PMC8330423 DOI: 10.3389/fonc.2021.687564] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/30/2021] [Indexed: 01/20/2023] Open
Abstract
Purpose The purpose of this study was to retrospectively analyze the safety and clinical efficacy of anlotinib combined with dose-dense temozolomide (TMZ) as the first-line therapy in the treatment of recurrent glioblastoma (rGBM). Patients and Methods We collected the clinical data of 20 patients with rGBM. All patients received anlotinib (12 mg daily, orally for 2 weeks, discontinued for 1 week, repeated every 3 weeks) combined with dose-dense TMZ (100 mg/m2, 7 days on with 7 days off) until the disease progressed (PD) or adverse effects (AEs) above grade 4 appeared. Grade 3 AEs need to be restored to grade 2 before continuing treatment, and the daily dose of anlotinib is reduced to 10 mg. The patients were reexamined by head magnetic resonance imaging (MRI) every 1 to 3 months. The therapeutic effect was evaluated according to Response Assessment in Neuro-Oncology (RANO) criteria. The survival rate was analyzed by Kaplan-Meier survival curve analysis. The baseline of all survival index statistics was the start of anlotinib combined with dose-dense of TMZ. National Cancer Institute-Common Terminology Criteria Adverse Events version 4.0 (NCI-CTCAE 4.0) was used to evaluate AEs. Results Twenty cases of rGBM were evaluated according to the RANO criteria after treatment with anlotinib and dose-dense TMZ, including five cases of stable disease (SD), thirteen cases of partial response (PR), one case of complete response (CR), and one case of PD. The median follow-up time was 13.4 (95% CI, 10.5–16.3) months. The 1-year overall survival (OS) rate was 47.7%. The 6-month progression-free survival (PFS) rate was 55%. In the IDH wild type group, the median PFS and median OS were 6.1 and 11.9 months, respectively. We observed that AEs associated with treatment were tolerable. One patient stopped taking the drug because of cerebral infarction. There were no treatment-related deaths. Conclusion Anlotinib combined with dose-dense TMZ for the first-line therapy showed good efficacy in OS, PFS, ORR, and DCR in the treatment of rGBM, and the AEs were tolerant. Randomized controlled clinical trials investigating the treatment of rGBM with anlotinib are necessary.
Collapse
Affiliation(s)
- Lei She
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.,Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China
| | - Lin Su
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Liangfang Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Chao Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| |
Collapse
|
|
15
|
Chen Z, Wei X, Wang X, Zheng X, Chang B, Shen L, Zhu H, Yang M, Li S, Zheng X. NDUFA4L2 promotes glioblastoma progression, is associated with poor survival, and can be effectively targeted by apatinib. Cell Death Dis 2021; 12:377. [PMID: 33828084 PMCID: PMC8027655 DOI: 10.1038/s41419-021-03646-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 03/17/2021] [Accepted: 03/17/2021] [Indexed: 12/31/2022]
Abstract
NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2 (NDUFA4L2) is a subunit of Complex I of the mitochondrial respiratory chain, which is important in metabolic reprogramming and oxidative stress in multiple cancers. However, the biological role and molecular regulation of NDUFA4L2 in glioblastoma (GBM) are poorly understood. Here, we found that NDUFA4L2 was significantly upregulated in GBM; the elevated levels were correlated with reduced patient survival. Gene knockdown of NDUFA4L2 inhibited tumor cell proliferation and enhanced apoptosis, while tumor cells initiated protective mitophagy in vitro and in vivo. We used lentivirus to reduce expression levels of NDUFA4L2 protein in GBM cells exposed to mitophagy blockers, which led to a significant enhancement of tumor cell apoptosis in vitro and inhibited the development of xenografted tumors in vivo. In contrast to other tumor types, NDUFA4L2 expression in GBM may not be directly regulated by hypoxia-inducible factor (HIF)-1α, because HIF-1α inhibitors failed to inhibit NDUFA4L2 in GBM. Apatinib was able to effectively target NDUFA4L2 in GBM, presenting an alternative to the use of lentiviruses, which currently cannot be used in humans. Taken together, our data suggest the use of NDUFA4L2 as a potential therapeutic target in GBM and demonstrate a practical treatment approach.
Collapse
Affiliation(s)
- Zheng Chen
- Department of Neurosurgery, XinHua Hospital, Shanghai JiaoTong University School of Medicine, 1665 KongJiang Rd, 200092, Shanghai, China.,The Center for Diagnosis and Treatment of Cranial Nerve Diseases of Shanghai JiaoTong University, 200092, Shanghai, China
| | - Xiangyu Wei
- Department of Neurosurgery, XinHua Hospital, Shanghai JiaoTong University School of Medicine, 1665 KongJiang Rd, 200092, Shanghai, China.,The Center for Diagnosis and Treatment of Cranial Nerve Diseases of Shanghai JiaoTong University, 200092, Shanghai, China
| | - Xueyi Wang
- Department of Neurosurgery, XinHua Hospital, Shanghai JiaoTong University School of Medicine, 1665 KongJiang Rd, 200092, Shanghai, China.,The Center for Diagnosis and Treatment of Cranial Nerve Diseases of Shanghai JiaoTong University, 200092, Shanghai, China
| | - Xuan Zheng
- Department of Neurosurgery, XinHua Hospital, Shanghai JiaoTong University School of Medicine, 1665 KongJiang Rd, 200092, Shanghai, China.,The Center for Diagnosis and Treatment of Cranial Nerve Diseases of Shanghai JiaoTong University, 200092, Shanghai, China
| | - Bowen Chang
- Department of Neurosurgery, XinHua Hospital, Shanghai JiaoTong University School of Medicine, 1665 KongJiang Rd, 200092, Shanghai, China.,The Center for Diagnosis and Treatment of Cranial Nerve Diseases of Shanghai JiaoTong University, 200092, Shanghai, China
| | - Lin Shen
- Department of Neurosurgery, XinHua Hospital, Shanghai JiaoTong University School of Medicine, 1665 KongJiang Rd, 200092, Shanghai, China.,The Center for Diagnosis and Treatment of Cranial Nerve Diseases of Shanghai JiaoTong University, 200092, Shanghai, China
| | - Hanshuo Zhu
- Department of Neurosurgery, XinHua Hospital, Shanghai JiaoTong University School of Medicine, 1665 KongJiang Rd, 200092, Shanghai, China.,The Center for Diagnosis and Treatment of Cranial Nerve Diseases of Shanghai JiaoTong University, 200092, Shanghai, China
| | - Min Yang
- Department of Neurosurgery, XinHua Hospital, Shanghai JiaoTong University School of Medicine, 1665 KongJiang Rd, 200092, Shanghai, China.,The Center for Diagnosis and Treatment of Cranial Nerve Diseases of Shanghai JiaoTong University, 200092, Shanghai, China
| | - Shiting Li
- Department of Neurosurgery, XinHua Hospital, Shanghai JiaoTong University School of Medicine, 1665 KongJiang Rd, 200092, Shanghai, China. .,The Center for Diagnosis and Treatment of Cranial Nerve Diseases of Shanghai JiaoTong University, 200092, Shanghai, China.
| | - Xuesheng Zheng
- Department of Neurosurgery, XinHua Hospital, Shanghai JiaoTong University School of Medicine, 1665 KongJiang Rd, 200092, Shanghai, China. .,The Center for Diagnosis and Treatment of Cranial Nerve Diseases of Shanghai JiaoTong University, 200092, Shanghai, China.
| |
Collapse
|
|
16
|
Ge J, Li C, Xue F, Qi S, Gao Z, Yu C, Zhang J. Apatinib Plus Temozolomide: An Effective Salvage Treatment for Recurrent Glioblastoma. Front Oncol 2021; 10:601175. [PMID: 33634023 PMCID: PMC7901881 DOI: 10.3389/fonc.2020.601175] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 12/02/2020] [Indexed: 11/24/2022] Open
Abstract
Background Treatment for recurrent glioblastoma is poor, and there is a need for better therapies. Here we retrospectively assessed the efficacy and toxicity of temozolomide plus apatinib, an oral small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 in recurrent glioblastoma. Materials and Methods A retrospective analysis of patients with recurrent glioblastoma who underwent apatinib plus temozolomide treatment was performed. Apatinib was given at 500 mg once daily. Temozolomide was administered at 200 mg/m2/d on days 1–5 or 50 mg/m2/d continuous daily according to whether they had experienced temozolomide maintenance treatment before. The main clinical data collected included tumor characteristics, status of MGMT promoter, and IDH mutation, number of relapse, response, survival, adverse reactions, and salvage therapies. Results From April 2016 to August 2019, thirty-one patients were identified. The objective response rate was 26.3%, and the disease control rate was 84.2%. The progression-free survival (PFS) at 6 months and overall survival (OS) at 12 months were 44.6 and 30.2%. The median PFS and OS were 4.9 and 8.2 months, respectively. Two patients achieved long PFS of 30.9 and 38.7+ months. The median survival time after progression of the patients with or without salvage bevacizumab was 5.1 versus 1.2 months. The most common grade 3 or 4 toxicities were hypertension (5.8%), decreased appetite (5.8%), and thrombocytopenia (4.3%), most of which were resolved after symptomatic treatment or dose reduction. Conclusion Apatinib plus temozolomide is an effective salvage regimen with manageable toxicities for recurrent glioblastoma and could not reduce the sensitivity to bevacizumab.
Collapse
Affiliation(s)
- Jingjing Ge
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Cheng Li
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Fengjun Xue
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Shaopei Qi
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Zhimeng Gao
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Chunjiang Yu
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Junping Zhang
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
17
|
Liu HL, Wang YN, Feng SY. Brain tumors: Cancer stem-like cells interact with tumor microenvironment. World J Stem Cells 2020; 12:1439-1454. [PMID: 33505594 PMCID: PMC7789119 DOI: 10.4252/wjsc.v12.i12.1439] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 10/07/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer stem-like cells (CSCs) with potential of self-renewal drive tumorigenesis. Brain tumor microenvironment (TME) has been identified as a critical regulator of malignancy progression. Many researchers are searching new ways to characterize tumors with the goal of predicting how they respond to treatment. Here, we describe the striking parallels between normal stem cells and CSCs. We review the microenvironmental aspects of brain tumors, in particular composition and vital roles of immune cells infiltrating glioma and medulloblastoma. By highlighting that CSCs cooperate with TME via various cellular communication approaches, we discuss the recent advances in therapeutic strategies targeting the components of TME. Identification of the complex and interconnected factors can facilitate the development of promising treatments for these deadly malignancies.
Collapse
Affiliation(s)
- Hai-Long Liu
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Ya-Nan Wang
- Department of Pathology, Affiliated Hospital of Hebei University, Baoding 071000, Hebei Province, China
| | - Shi-Yu Feng
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing 100853, China
| |
Collapse
|