scholarly journals Upregulation of the APOBEC3 Family Is Associated with a Poor Prognosis and Influences Treatment Response to Raf Inhibitors in Low Grade Glioma

2021 ◽  
Vol 22 (19) ◽  
pp. 10390
Author(s):  
Cheng Luo ◽  
Songmao Wang ◽  
Weijie Liao ◽  
Shikuan Zhang ◽  
Naihan Xu ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Risk Groups ◽  
Mapk Signaling ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Cytosine Deamination ◽  
Treatment Benefits ◽  
Number Variation ◽  
Clinical Benefits ◽  
Apobec3 Family

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) has been identified as a group of enzymes that catalyze cytosine deamination in single-stranded (ss) DNA to form uracil, causing somatic mutations in some cancers. We analyzed the APOBEC3 family in 33 TCGA cancer types and the results indicated that APOBEC3s are upregulated in multiple cancers and strongly correlate with prognosis, particularly in low grade glioma (LGG). Then we constructed a prognostic model based on family expression in LGG where the APOBEC3 family signature is an accurate predictive model (AUC of 0.85). Gene mutation, copy number variation (CNV), and a differential gene expression (DEG) analysis were performed in different risk groups, and the weighted gene co-expression network analysis (WGCNA) was employed to clarify the role of various members in LGG; CIBERSORT algorithm was deployed to evaluate the landscape of LGG immune infiltration. We found that upregulation of the APOBEC3 family expression can strengthen Ras/MAPK signaling pathway, promote tumor progression, and ultimately reduce the treatment benefits of Raf inhibitors. Moreover, the APOBEC3 family was shown to enhance the immune response mediated by myeloid cells and interferon gamma, as well as PD-L1 and PD-L2 expression, implying that they have immunotherapy potential. Therefore, the APOBEC3 signature enables an efficient assessment of LGG patient survival outcomes and expansion of clinical benefits by selecting appropriate individualized treatment strategies.

scholarly journals PDCT-15. EFFICACY AND SAFETY OF BEVACIZUMAB IN TREATING RECURRENT PEDIATRIC LOW-GRADE GLIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF PATIENT OUTCOMES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi186-vi186
Author(s):  
Victor Lu ◽  
John Welby ◽  
David Daniels
Keyword(s):  
Adverse Events ◽  
Meta Analysis ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Serious Adverse Events ◽  
Radiographic Response ◽  
Treatment Benefits ◽  
Rate Of Progression ◽  
Grade 3

Abstract BACKGROUND Although rare, the propensity for pediatric low-grade glioma (pLGG) to recur despite upfront intervention presents a management conundrum for clinicians. One novel salvage option is anti-angiogenic bevacizumab, however, its safety and efficacy in this specific demographic is poorly defined. Correspondingly, our aim was to pool systematically-identified metadata in the literature to substantiate the clinical relevance of bevacizumab in treating recurrent pLGG. METHODS Searches of 7 electronic databases from inception to June 2019 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. The incidence of loss was then pooled by random-effects meta-analysis of proportions. RESULTS Six pertinent studies described the outcomes of 110 recurrent pLGG patients managed with bevacizumab. While on-treatment, the rate of clinical response was 58% (95% CI, 43–72%), and the rate of radiographic response was 80% (95% CI, 58–96%). Additionally, the rate of serious adverse events (Grade 3 and above) was 11% (95% CI, 5–18%), with proteinuria the most common of those events. By the time patients were off-treatment, the rate of progression was estimated to be 51% (95% CI, 28–74%). Certainty of these results ranged from very low to low. CONCLUSIONS The use of bevacizumab as therapy for recurrent pLGG appears to confer appreciable clinical and radiographic response with relatively low serious adverse events risk while on-treatment. However, the long-term off-treatment benefits of this therapy have yet to be consolidated. Traditional clinical heterogeneity concerns preclude the formalization of any recommendations until larger, more standardized investigations can be performed.

scholarly journals Efficacy and safety of bevacizumab in progressive pediatric low-grade glioma: a systematic review and meta-analysis of outcome rates

2020 ◽  
Vol 7 (4) ◽  
pp. 359-368
Author(s):  
Victor M Lu ◽  
John P Welby ◽  
Cody L Nesvick ◽  
David J Daniels
Keyword(s):  
Meta Analysis ◽  
Low Grade Glioma ◽  
Anatomical Location ◽  
Low Grade ◽  
Vegf Inhibitor ◽  
Molecular Features ◽  
Treatment Benefits ◽  
Radiographic Disease ◽  
Grade 3 ◽  
Meta Analyses

Abstract Background Successful management of pediatric low-grade glioma (pLGG) can be complicated by eloquent anatomical location, as well as specific pathologic and molecular features. Some authors have proposed using the VEGF inhibitor bevacizumab to improve disease control, but its safety and efficacy are poorly defined. Correspondingly, our aim was to pool systematically identified clinical data in the literature to assess the clinical utility of bevacizumab for pLGG at progression. Methods A systematic search of 7 electronic databases from inception to June 2019 was conducted following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Articles were screened against prespecified criteria. Outcomes were then pooled by random-effects meta-analyses of proportions. Results Seven pertinent studies described the outcomes of 110 progressive pLGG patients managed with bevacizumab in largely multiagent regimens. While on treatment, the rate of clinical response was 58% (95% CI, 43%-72%), and the rate of response on imaging was 80% (95% CI, 58%-96%). The rate of grade 3 or higher toxicity was 8% (95% CI, 2%-17%), with proteinuria the most commonly described. In the off-treatment period up to median 1 year, the rate of progression was estimated to be 51% (95% CI, 28%-74%). Conclusions Bevacizumab has the potential to control clinical and radiographic disease with relatively low grade 3 or higher toxicity risk in progressive pLGG patients. However, the long-term off-treatment benefits of this therapy are not yet well defined. Heterogeneity in the literature precludes any formal recommendations regarding its use until larger, more standardized investigations can be performed.

scholarly journals Temozolomide chemotherapy for progressive low-grade glioma: clinical benefits and radiological response

2003 ◽  
Vol 14 (12) ◽  
pp. 1722-1726 ◽  
Author(s):  
A. Pace ◽  
A. Vidiri ◽  
E. Galiè ◽  
M. Carosi ◽  
S. Telera ◽  
...  
Keyword(s):  
Low Grade Glioma ◽  
Low Grade ◽  
Clinical Benefits ◽  
Radiological Response ◽  
Temozolomide Chemotherapy

Phase II Study of Carboplatin in Children With Progressive Low-Grade Gliomas

2002 ◽  
Vol 20 (13) ◽  
pp. 2951-2958 ◽  
Author(s):  
Sridharan Gururangan ◽  
Christina M. Cavazos ◽  
David Ashley ◽  
James E. Herndon ◽  
Carol S. Bruggers ◽  
...  
Keyword(s):  
Tumor Response ◽  
Objective Response ◽  
Treatment Strategies ◽  
Neurofibromatosis Type ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Minor Response ◽  
Low Grade Gliomas ◽  
Disease Stabilization ◽  
Grade 3

PURPOSE: To assess the rate of tumor response and activity of carboplatin in stabilizing the growth of progressive low-grade gliomas. PATIENTS AND METHODS: Eligible patients received carboplatin 560 mg/m2 intravenously every 4 weeks for 1 year after maximum tumor response or until disease progression or unacceptable toxicity. RESULTS: Between October 1993 and October 2000, 81 children (median age, 79 months; range, 6 to 204) were enrolled onto this study. Patients received a median of 11 cycles of carboplatin (range, one to 29). Median follow-up from the time of enrollment was 55 months (range, 10 to 93). The overall objective response (complete response [CR] + partial response [PR] + minor response [MR]) and disease stabilization (CR + PR + stable disease + MR) rates to carboplatin treatment were 28% (95% confidence interval [CI], 18% to 38%) and 85% (95% CI, 74% to 93%), respectively. Eleven and 14 patients suffered progressive disease on study and after stopping therapy, respectively. Toxicity was predominantly myelosuppression and included grade 3/4 neutropenia in 56 patients and grade 3/4 thrombocytopenia in 40 patients. The 3-year failure-free survival (FFS) and overall survival (OS) for all patients were 64% (95% CI, 54% to 76%) and 84% (95% CI, 76% to 93%), respectively. Patients with diencephalic tumors had inferior FFS and OS compared with those with tumor at other sites (38% v 74% for FFS, P = .011; 54% v 91% for OS, P = .004). Neurofibromatosis type 1 patients with progressive low-grade glioma had a significantly better OS (95% v 80%; P = .052). CONCLUSION: Carboplatin, in the schedule used in this study, produced disease stabilization or improvement in a majority of children with progressive low-grade glioma, with manageable toxicity. Improved treatment strategies are particularly required for patients with diencephalic tumors.

scholarly journals Response to trametinib treatment in progressive pediatric low-grade glioma patients

2020 ◽  
Vol 149 (3) ◽  
pp. 499-510
Author(s):  
Florian Selt ◽  
Cornelis M. van Tilburg ◽  
Brigitte Bison ◽  
Philipp Sievers ◽  
Inga Harting ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Control ◽  
Treatment Time ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Low Grade Glioma ◽  
Mitogen Activated Protein Kinase ◽  
Individual Treatment ◽  
Low Grade ◽  
Current Standard

Abstract Introduction A hallmark of pediatric low-grade glioma (pLGG) is aberrant signaling of the mitogen activated protein kinase (MAPK) pathway. Hence, inhibition of MAPK signaling using small molecule inhibitors such as MEK inhibitors (MEKi) may be a promising strategy. Methods In this multi-center retrospective centrally reviewed study, we analyzed 18 patients treated with the MEKi trametinib for progressive pLGG as an individual treatment decision between 2015 and 2019. We have investigated radiological response as per central radiology review, molecular classification and investigator observed toxicity. Results We observed 6 partial responses (PR), 2 minor responses (MR), and 10 stable diseases (SD) as best overall responses. Disease control rate (DCR) was 100% under therapy. Responses were observed in KIAA1549:BRAF- as well as neurofibromatosis type 1 (NF1)-driven tumors. Median treatment time was 12.5 months (range: 2 to 27 months). Progressive disease was observed in three patients after cessation of trametinib treatment within a median time of 3 (2–4) months. Therapy related adverse events occurred in 16/18 patients (89%). Eight of 18 patients (44%) experienced severe adverse events (CTCAE III and/or IV; most commonly skin rash and paronychia) requiring dose reduction in 6/18 patients (33%), and discontinuation of treatment in 2/18 patients (11%). Conclusions Trametinib was an active and feasible treatment for progressive pLGG leading to disease control in all patients. However, treatment related toxicity interfered with treatment in individual patients, and disease control after MEKi withdrawal was not sustained in a fraction of patients. Our data support in-class efficacy of MEKi in pLGGs and necessity for upfront randomized testing of trametinib against current standard chemotherapy regimens.

Development of a novel assay suitable for pre-clinical testing of MAPK inhibitors in low-grade glioma

2017 ◽  
Author(s):  
D Usta ◽  
F Selt ◽  
J Hohloch ◽  
S Pusch ◽  
SM Pfister ◽  
...  
Keyword(s):  
Low Grade Glioma ◽  
Low Grade ◽  
Clinical Testing ◽  
Mapk Inhibitors
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