CSIG-14. PTEN AS A SIGNATURE OF VULNERABILITY OF GBM TO NEDDYLATION INHIBITION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi36-vi36
Author(s):  
Brett Taylor ◽  
Shayesteh Ferdosi ◽  
Matthew Lee ◽  
Nanyun Tang ◽  
Sen Peng ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Time Course ◽  
De Novo ◽  
Early Stage ◽  
Ubiquitin Proteasome System ◽  
Selective Vulnerability ◽  
Molecular Heterogeneity ◽  
Loss Of Function ◽  
Low Sensitivity ◽  
Orthotopic Xenografts

Abstract Neddylation is a specific pathway within the ubiquitin/proteasome system that is overactive in GBM, and whose upregulation has been associated with glioma progression and worse survival. Pevonedistat (MLN4924) is a first-in-class small-molecule neddylation inhibitor shown to inhibit growth of GBM cells by impacting protein degradation in culture and orthotopic xenografts. However, the determinants of vulnerability are not fully understood. Because the molecular heterogeneity within and across GBM patients obscures therapeutic targets and obfuscates signals of efficacy in clinical trials, we pursue the use of molecular “signatures of vulnerability” to targeted agents in subsets of preclinical models. Selective vulnerability to pevonedistat was shown in a subset of GBM; notably, models with mutations or copy number deletions of PTEN are associated with de novo resistance to pevonedistat. Time-course studies of sensitive and non-sensitive GBM cells using transcriptomics and proteomics/phosphoproteomics uncovered additional determinants of response to pevonedistat. Our results demonstrate that in GBM, resistance to pevonedistat is driven by reduced PTEN-chromatin binding (loss-of-function or lower expression) that is also independent of PTEN’s lipid phosphatase activity (i.e., PI3K/AKT signaling). Across 25 glioma cell lines, we found that PTEN signaling, DNA replication, and chromatin instability pathways are the most significant differentiators between pevonedistat sensitive vs. non-sensitive models. In GBM models with modest to low sensitivity to pevonedistat, TOP2A expression was elevated. Combination treatment with the TOP2A inhibitor, etoposide, proved synergistic with pevonedistat. We report that PTEN status both serves as a novel biomarker for GBM sensitivity to pevonedistat and reveals a synergistic vulnerability to TOP2A inhibitors in combination with pevonedistat. Paired use of GBM PDX models of varying sensitivity with drug development testing allows the advancement of a promising agent as well as a patient-enrollment “signature of vulnerability” likely to increase the likelihood of demonstrating therapeutic efficacy in early stage clinical trials.

Efficacy of ALL Therapy for WHO2016-Defined Mixed Phenotype Acute Leukemia: A Report from the Children's Oncology Group

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 883-883
Author(s):  
Etan Orgel ◽  
Thomas B. Alexander ◽  
Brent Wood ◽  
Samir Kahwash ◽  
Meenakshi Devidas ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Clinical Trials ◽  
Acute Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Molecular Heterogeneity ◽  
Oncology Group ◽  
Oncology Research ◽  
Mixed Phenotype Acute Leukemia ◽  
Mixed Phenotype

Abstract There remains uncertainty regarding the optimal treatment for mixed phenotype acute leukemia (MPAL), an uncommon leukemia that represents ~3% of de novo acuteleukemia. Because of the dearth of clinical trials, varying approaches are employed: acute lymphoblastic leukemia (ALL) regimens as well as more intensive acute myeloid leukemia (AML) and hybrid therapies. The evolution in the prevailing diagnostic criteria from the EGIL classification to the more narrowly defined WHO2008 and WHO2016 criteria has made the existing literature difficult to interpret. Increasing insight into the molecular heterogeneity of MPAL adds further complexity. Recently published studies (retrospective clinical case series), however, are beginning to suggest that ALL therapy may be the most appropriate form of initial therapy for MPAL. To further assess the efficacy of ALL therapy for pediatric MPAL, we reviewed the Children's Oncology Group (COG) experience. Possible MPAL cases were identified through the ALL biology studies (both AALL03B1 and AALL08B1 were open to MPAL) and from AAML0531, the phase 3 trial for de novo AML (patients enrolled on this trial subsequently found to have MPAL were taken off study). All identified cases were reviewed centrally. In cases where the original flow cytometry testing was inadequate to establish the diagnosis, flow cytometry was repeated with an expanded antibody panel using banked diagnostic specimens. Only cases meeting WHO2016 criteria were retained. Patients were treated per physician discretion and not on a therapeutic clinical trial. Supplemental data on treatment and outcomes were collected. From the study databases, 97 potential MPAL cases were identified; of these, 54 cases (56%) were confirmed to be MPAL via central review. Patients were diagnosed between 2003 and 2016. The majority of patients were <10 years of age and B/Myeloid MPAL (B/My) was the most common phenotype. Fewer than a third of patients presented with hyperleukocytosis, adverse recurrent cytogenetics, or central nervous system involvement (Table 1). In the cohort, 38 patients (70%) received ALL induction therapy, 12 (22%) AML induction, and 3 hybrid induction; 14 (28%) patients received hematopoietic stem cell transplantation (HSCT). The CR rate was 71.1% [27/38], 66.7% (8/12) and 100% (3/3) in patients receiving ALL, AML and hybrid induction, respectively (p=0.761). CR was achieved in 78.8% of B/My cases [26/33], 68.4% T/My cases [13/19], and no B/T cases (0/2, p=0.074). Treatment became more heterogeneous further into therapy due to varying incorporation of ALL, AML and hybrid elements and the varying use of HSCT. Three-year EFS was 65±17% in patients started on ALL therapy and 53±26% in patients started on AML therapy (p=0.169, Fig. 1A); 3-year OS was 79±15% and 60±27% respectively (p=0.510, Fig. 1B). SCT was not associated with a difference in EFS (p=0.935) or OS (p=0.726). In 20 patients receiving ALL therapy alone without SCT, 3-year EFS was 59±22% and OS 79±18%. This series represents a large cohort of centrally-reviewed pediatric MPAL cases diagnosed according to the most recent WHO2016 criteria and treated with COG-style chemotherapy. Our results add to the growing body of literature suggesting that ALL regimens may be effective for pediatric MPAL. It also suggests, however, that induction failure and relapse are still relatively common with ALL therapy and that alternative forms of treatment are necessary for some. The limited size of the sample and its heterogeneity preclude any conclusions regarding the relative efficacy of AML therapy and role for HSCT. Given the greater morbidity and mortality associated with these forms of therapy, consideration should be given to reserving their use for patients with a suboptimal response to ALL therapy. Continued variability in accurately diagnosing and treating MPAL as seen here also underscores the necessity of well-delineated clinical trials with integrated central review to advance MPAL therapy. Our results therefore further support the basis for the first-ever prospective evaluation of high risk ALL therapy for pediatric MPAL in a trial now being planned within the COG. In this trial, minimal residual disease testing with multiparameter flow cytometry will be employed to identify patients responding well to ALL therapy versus those who may benefit from more intensive AML therapy and transplantation. Disclosures Mullighan: Loxo Oncology: Research Funding; Amgen: Consultancy. Hunger: Erytech Pharmaceuticals: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Honoraria; Amgen: Consultancy, Equity Ownership. Berman: AGADA Therapeutics: Research Funding. Zweidler-McKay: ImmunoGen: Employment.

Evolution of Rituximab as “Standard” Therapy in Patients (pts) with Newly Diagnosed Follicular (FL), Mantle Cell (MCL), and Diffuse Large B Cell (DLCL) Non-Hodgkin’s Lymphoma (NHL) in 5 United States Comprehensive Cancer Centers: An Analysis from the National Comprehensive Cancer Network (NCCN) NHL Outcomes Project.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1391-1391 ◽  
Author(s):  
Jonathan W. Friedberg ◽  
Michelle E. Kho ◽  
Eva M. Lepisto ◽  
M. Alma Rodriguez ◽  
Anna TerVeer ◽  
...  
Keyword(s):  
Clinical Trials ◽  
De Novo ◽  
Early Stage ◽  
Clinical Trial Design ◽  
Multivariate Logistic Regression Model ◽  
Early Stage Disease ◽  
Treatment Regimens ◽  
Line Therapy ◽  
Confirmatory Clinical Trials ◽  
The Impact

Abstract Since 1997, rituximab (R) has had a dramatic impact on therapy of NHL. We analyzed R utilization in de novo FL, MCL and DLCL, and the motivation behind this use, using the NCCN NHL outcomes database. This project collects demographic, staging, treatment and outcome information on consecutive pts with NHL seen at 5 geographically diverse NCCN institutions (Dana-Farber, Roswell Park, City of Hope, Fox Chase and MD Anderson). Between 7/2000 and 5/2004, 1028 evaluable pts have been enrolled. R use (+/− chemo) must have occurred within 180 days of presentation, and rates were evaluated in 6-month periods. Pts previously treated or with relapse/transformation within 180 days were excluded. Pts with FL not treated within 180 days (“observation”) were included. Overall, 87% of DLCL pts (N=278) received R, including 116/135 (86%) pts with early stage disease, and 137/162 (85%) pts under age 60. The only significant predictor of R use was year of presentation (P<0.01), (adjusting for IPI, age, 1st line therapy, comorbidity, and center): after 7/01, 93% of pts received R compared with 69% prior to 7/01. Of 167 pts with FL, 52% received R, 11% received chemo only, 10% XRT only, 2% other, and 25% received no therapy. The final FL multivariate logistic regression model included time, stage, chemo, 1st line therapy, B-symptoms, comorbidity, and center. Unlike DLCL, center was a significant predictor of R use (P=0.001); rates of R use in FL varied from 7% to 84% within these 5 centers. Additionally, the overall approach to FL is clearly evolving: as of 7/01, significantly fewer pts were observed (21%) as compared to pre- 7/01 (36%). Of 65 MCL pts, 86% received R within 180 days of presentation. Similar to DLCL, the use of R increased over time: as of 7/01, 92% received R versus prior to 7/01, when only 62% received R. All 5 institutions had active clinical trials for these histologies that incorporated R during this time, however, only 28% of these pts were enrolled on clinical trials. Therefore, despite limited long-term follow-up of confirmatory clinical trials, R was rapidly incorporated into the upfront treatment regimens for the vast majority of pts seen in these NCCN institutions with FL, MCL and DLCL. Despite some variation between centers in FL, adaptation of “standard” R utilization in most institutions predated NCCN guideline inclusion, and occurred while national trials evaluating R benefit were still accruing. Widespread R utilization clearly impacted clinical trial design and accrual. Moreover, if this experience reflects national trends, a potential expenditure of at least $0.5 billion annually is associated with R for de novo NHL. Finally, the impact of widespread R use and changing approaches to FL on developing novel biological agents remains to be defined.

Who benefits from taxanes?

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e11503-e11503
Author(s):  
M. J. Piccart-Gebhart ◽  
P. L. Bedard
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Intracellular Signaling ◽  
Early Stage ◽  
Research Effort ◽  
Receptor Expression ◽  
Molecular Heterogeneity ◽  
Early Stage Disease ◽  
Her 2

e11503 Over the last fifteen years, 21 clinical trials randomized nearly 36,000 women with early-stage breast cancer to taxane-based versus non-taxane-based adjuvant chemotherapy regimens to establish the role of taxanes in early breast cancer therapy. Preliminary results from the Oxford Overview –pooling individual patient data from some of these studies –suggest that the inclusion of a taxane to an anthracycline-based regimen reduces 10-year breast cancer related mortality by an absolute value of 5% over anthracycline therapy alone. In spite of this enormous global research effort, there remains considerable uncertainty regarding which patients benefit from taxane therapy. Three recent meta-analyses indicate that taxanes are beneficial irrespective of age, lymph node involvement, and hormonal receptor expression. Unfortunately, differences in trial design, pathological evaluation, and outcome reporting limit the robustness of these findings. Individual studies have suggested that patients with HER-2 positive disease derive greater benefit from taxane therapy, although the methods used to assess HER-2 status have been heterogeneous and there is no clear biological rationale to account for differential benefit in this subset. A number of promising predictive molecular markers related to taxane metabolism, microtubule dynamics, and intracellular signaling warrant further evaluation using biospecimens collected from the first-generation taxane trials. Future clinical trials should account for the molecular heterogeneity of breast cancer, by excluding the chemotherapy insensitive luminal A subset and mandating upfront central pathological assessment to further optimize the role of taxane therapy in early-stage disease. No significant financial relationships to disclose.

Arabidopsis 4-COUMAROYL-COA LIGASE 8 contributes to the biosynthesis of the benzenoid ring of coenzyme Q in peroxisomes

2019 ◽  
Vol 476 (22) ◽  
pp. 3521-3532
Author(s):  
Eric Soubeyrand ◽  
Megan Kelly ◽  
Shea A. Keene ◽  
Ann C. Bernert ◽  
Scott Latimer ◽  
...  
Keyword(s):  
Oxidative Metabolism ◽  
Time Course ◽  
Reverse Genetics ◽  
De Novo ◽  
Coenzyme Q ◽  
Control Level ◽  
Wild Type ◽  
Fluorescent Reporters ◽  
Coa Ligase ◽  
Peroxisomal Targeting

Plants have evolved the ability to derive the benzenoid moiety of the respiratory cofactor and antioxidant, ubiquinone (coenzyme Q), either from the β-oxidative metabolism of p-coumarate or from the peroxidative cleavage of kaempferol. Here, isotopic feeding assays, gene co-expression analysis and reverse genetics identified Arabidopsis 4-COUMARATE-COA LIGASE 8 (4-CL8; At5g38120) as a contributor to the β-oxidation of p-coumarate for ubiquinone biosynthesis. The enzyme is part of the same clade (V) of acyl-activating enzymes than At4g19010, a p-coumarate CoA ligase known to play a central role in the conversion of p-coumarate into 4-hydroxybenzoate. A 4-cl8 T-DNA knockout displayed a 20% decrease in ubiquinone content compared with wild-type plants, while 4-CL8 overexpression boosted ubiquinone content up to 150% of the control level. Similarly, the isotopic enrichment of ubiquinone's ring was decreased by 28% in the 4-cl8 knockout as compared with wild-type controls when Phe-[Ring-13C6] was fed to the plants. This metabolic blockage could be bypassed via the exogenous supply of 4-hydroxybenzoate, the product of p-coumarate β-oxidation. Arabidopsis 4-CL8 displays a canonical peroxisomal targeting sequence type 1, and confocal microscopy experiments using fused fluorescent reporters demonstrated that this enzyme is imported into peroxisomes. Time course feeding assays using Phe-[Ring-13C6] in a series of Arabidopsis single and double knockouts blocked in the β-oxidative metabolism of p-coumarate (4-cl8; at4g19010; at4g19010 × 4-cl8), flavonol biosynthesis (flavanone-3-hydroxylase), or both (at4g19010 × flavanone-3-hydroxylase) indicated that continuous high light treatments (500 µE m−2 s−1; 24 h) markedly stimulated the de novo biosynthesis of ubiquinone independently of kaempferol catabolism.

Association of the Non-Motor Burden with Patterns of Striatal Dopamine Loss in de novo Parkinson’s Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 1541-1549
Author(s):  
Seok Jong Chung ◽  
Sangwon Lee ◽  
Han Soo Yoo ◽  
Yang Hyun Lee ◽  
Hye Sun Lee ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
De Novo ◽  
Early Stage ◽  
Striatal Dopamine ◽  
Motor Deficits ◽  
Dopamine Depletion ◽  
Severe Motor ◽  
Severe Group ◽  
Striatal Dopamine Depletion

Background: Striatal dopamine deficits play a key role in the pathogenesis of Parkinson’s disease (PD), and several non-motor symptoms (NMSs) have a dopaminergic component. Objective: To investigate the association between early NMS burden and the patterns of striatal dopamine depletion in patients with de novo PD. Methods: We consecutively recruited 255 patients with drug-naïve early-stage PD who underwent 18F-FP-CIT PET scans. The NMS burden of each patient was assessed using the NMS Questionnaire (NMSQuest), and patients were divided into the mild NMS burden (PDNMS-mild) (NMSQuest score <6; n = 91) and severe NMS burden groups (PDNMS-severe) (NMSQuest score >9; n = 90). We compared the striatal dopamine transporter (DAT) activity between the groups. Results: Patients in the PDNMS-severe group had more severe parkinsonian motor signs than those in the PDNMS-mild group, despite comparable DAT activity in the posterior putamen. DAT activity was more severely depleted in the PDNMS-severe group in the caudate and anterior putamen compared to that in the PDMNS-mild group. The inter-sub-regional ratio of the associative/limbic striatum to the sensorimotor striatum was lower in the PDNMS-severe group, although this value itself lacked fair accuracy for distinguishing between the patients with different NMS burdens. Conclusion: This study demonstrated that PD patients with severe NMS burden exhibited severe motor deficits and relatively diffuse dopamine depletion throughout the striatum. These findings suggest that the level of NMS burden could be associated with distinct patterns of striatal dopamine depletion, which could possibly indicate the overall pathological burden in PD.

BioMime – A Sirolimus-eluting Coronary Stent System for the Treatment of Patients with De Novo Coronary Lesions – meriT-1 Report

2011 ◽  
Vol 6 (1) ◽  
pp. 39
Author(s):  
Keyword(s):  
Stent Thrombosis ◽  
Time Course ◽  
De Novo ◽  
Drug Eluting Stent ◽  
Cobalt Chromium ◽  
Cardiac Events ◽  
End Points ◽  
Safety And Efficacy ◽  
Binary Restenosis

Background:Since the first reported use of percutaneous transluminal coronary angioplasty, advances in the interventional cardiology arena have been fast paced. Developers and clinicians are adapting from the learning curve awarded by the time-course of drug-eluting stent (DES) evolution. BioMime™ sirolimus-eluting stent (SES) is a step towards biomimicry. The stent is built on a strut of ultra-low thickness (65μm), a cobalt–chromium platform using an intelligent hybrid of closed and open cells allowing for morphology-mediated expansion. It employs a well-known antiproliferative – sirolimus – that elutes from a known biodegradable copolymer formulation within 30 days. The resultant stent demonstrates almost 100% endothelialisation at 30 days in preclinical models.Methods:The meriT-1 was a prospective, single-arm, single-centre trial to evaluate the safety and efficacy of BioMime SES in 30 patients with a single de novo lesion in native coronary arteries. The primary safety and efficacy end-points were major adverse cardiac events (MACE) at 30 days and in-stent late lumen loss at eight months, as measured using quantitative coronary angiographic (QCA) method. Secondary safety and efficacy end-points included MACE at one and two years and angiographic binary restenosis at eight-month angiographic follow-up. Other end-points included the occurrence of stent thrombosis at acute, subacute, late and very late periods and the percentage of diameter stenosis by QCA.Results:No MACE were observed and the median in-stent late luminal loss in 20 (67%) subjects studied by QCA was 0.15mm, with 0% binary restenosis at eight-month follow-up. No stent thrombosis was observed up to one-year follow-up.Conclusions:In comparison to currently available DES, BioMime SES appears to have a considerable scientific basis for prevention of neointimal proliferation, restenosis and associated clinical events.

scholarly journals ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization

2021 ◽  
Vol 22 (5) ◽  
pp. 2689
Author(s):  
Jianmin Si ◽  
Chris Van den Haute ◽  
Evy Lobbestael ◽  
Shaun Martin ◽  
Sarah van Veen ◽  
...  
Keyword(s):  
Membrane Integrity ◽  
Ubiquitin Proteasome System ◽  
Regulatory Function ◽  
Membrane Association ◽  
Loss Of Function ◽  
Atypical Form ◽  
Polyamine Transport ◽  
Independent Functions ◽  
Ubiquitin Proteasome ◽  
The Impact

ATP13A2, a late endo-/lysosomal polyamine transporter, is implicated in a variety of neurodegenerative diseases, including Parkinson’s disease and Kufor–Rakeb syndrome, an early-onset atypical form of parkinsonism. Loss-of-function mutations in ATP13A2 result in lysosomal deficiency as a consequence of impaired lysosomal export of the polyamines spermine/spermidine. Furthermore, accumulating evidence suggests the involvement of ATP13A2 in regulating the fate of α-synuclein, such as cytoplasmic accumulation and external release. However, no consensus has yet been reached on the mechanisms underlying these effects. Here, we aimed to gain more insight into how ATP13A2 is linked to α-synuclein biology in cell models with modified ATP13A2 activity. We found that loss of ATP13A2 impairs lysosomal membrane integrity and induces α-synuclein multimerization at the membrane, which is enhanced in conditions of oxidative stress or exposure to spermine. In contrast, overexpression of ATP13A2 wildtype (WT) had a protective effect on α-synuclein multimerization, which corresponded with reduced αsyn membrane association and stimulation of the ubiquitin-proteasome system. We also found that ATP13A2 promoted the secretion of α-synuclein through nanovesicles. Interestingly, the catalytically inactive ATP13A2 D508N mutant also affected polyubiquitination and externalization of α-synuclein multimers, suggesting a regulatory function independent of the ATPase and transport activity. In conclusion, our study demonstrates the impact of ATP13A2 on α-synuclein multimerization via polyamine transport dependent and independent functions.

scholarly journals Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Nathan L Absalom ◽  
Vivian W Y Liao ◽  
Kavitha Kothur ◽  
Dinesh C Indurthi ◽  
Bruce Bennetts ◽  
...  
Keyword(s):  
De Novo ◽  
Drug Effects ◽  
Receptor Expression ◽  
Aminobutyric Acid ◽  
Loss Of Function ◽  
Molecular Phenotype ◽  
Gain Of Function ◽  
Gene Encoding ◽  
Epileptic Encephalopathies ◽  
Receptor Phenotype

Abstract Variants in the GABRB3 gene encoding the β3-subunit of the γ-aminobutyric acid type A ( receptor are associated with various developmental and epileptic encephalopathies. Typically, these variants cause a loss-of-function molecular phenotype whereby γ-aminobutyric acid has reduced inhibitory effectiveness leading to seizures. Drugs that potentiate inhibitory GABAergic activity, such as nitrazepam, phenobarbital or vigabatrin, are expected to compensate for this and thereby reduce seizure frequency. However, vigabatrin, a drug that inhibits γ-aminobutyric acid transaminase to increase tonic γ-aminobutyric acid currents, has mixed success in treating seizures in patients with GABRB3 variants: some patients experience seizure cessation, but there is hypersensitivity in some patients associated with hypotonia, sedation and respiratory suppression. A GABRB3 variant that responds well to vigabatrin involves a truncation variant (p.Arg194*) resulting in a clear loss-of-function. We hypothesized that patients with a hypersensitive response to vigabatrin may exhibit a different γ-aminobutyric acid A receptor phenotype. To test this hypothesis, we evaluated the phenotype of de novo variants in GABRB3 (p.Glu77Lys and p.Thr287Ile) associated with patients who are clinically hypersensitive to vigabatrin. We introduced the GABRB3 p.Glu77Lys and p.Thr287Ile variants into a concatenated synaptic and extrasynaptic γ-aminobutyric acid A receptor construct, to resemble the γ-aminobutyric acid A receptor expression by a patient heterozygous for the GABRB3 variant. The mRNA of these constructs was injected into Xenopus oocytes and activation properties of each receptor measured by two-electrode voltage clamp electrophysiology. Results showed an atypical gain-of-function molecular phenotype in the GABRB3 p.Glu77Lys and p.Thr287Ile variants characterized by increased potency of γ-aminobutyric acid A without change to the estimated maximum open channel probability, deactivation kinetics or absolute currents. Modelling of the activation properties of the receptors indicated that either variant caused increased chloride flux in response to low concentrations of γ-aminobutyric acid that mediate tonic currents. We therefore propose that the hypersensitivity reaction to vigabatrin is a result of GABRB3 variants that exacerbate GABAergic tonic currents and caution is required when prescribing vigabatrin. In contrast, drug strategies increasing tonic currents in loss-of-function variants are likely to be a safe and effective therapy. This study demonstrates that functional genomics can explain beneficial and adverse anti-epileptic drug effects, and propose that vigabatrin should be considered in patients with clear loss-of-function GABRB3 variants.

scholarly journals Sequential fate-switches in stem-like cells drive the tumorigenic trajectory from human neural stem cells to malignant glioma

Cell Research ◽  
2021 ◽  
Author(s):  
Xiaofei Wang ◽  
Ran Zhou ◽  
Yanzhen Xiong ◽  
Lingling Zhou ◽  
Xiang Yan ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Single Cell ◽  
De Novo ◽  
Early Stage ◽  
Lineage Tracing ◽  
Human Neural Stem Cells ◽  
Transcriptional Reprogramming ◽  
Neural Stem Progenitor Cells ◽  
Human Gbm ◽  
End Stage

AbstractGlioblastoma (GBM) is an incurable and highly heterogeneous brain tumor, originating from human neural stem/progenitor cells (hNSCs/hNPCs) years ahead of diagnosis. Despite extensive efforts to characterize hNSCs and end-stage GBM at bulk and single-cell levels, the de novo gliomagenic path from hNSCs is largely unknown due to technical difficulties in early-stage sampling and preclinical modeling. Here, we established two highly penetrant hNSC-derived malignant glioma models, which resemble the histopathology and transcriptional heterogeneity of human GBM. Integrating time-series analyses of whole-exome sequencing, bulk and single-cell RNA-seq, we reconstructed gliomagenic trajectories, and identified a persistent NSC-like population at all stages of tumorigenesis. Through trajectory analyses and lineage tracing, we showed that tumor progression is primarily driven by multi-step transcriptional reprogramming and fate-switches in the NSC-like cells, which sequentially generate malignant heterogeneity and induce tumor phenotype transitions. We further uncovered stage-specific oncogenic cascades, and among the candidate genes we functionally validated C1QL1 as a new glioma-promoting factor. Importantly, the neurogenic-to-gliogenic switch in NSC-like cells marks an early stage characterized by a burst of oncogenic alterations, during which transient AP-1 inhibition is sufficient to inhibit gliomagenesis. Together, our results reveal previously undercharacterized molecular dynamics and fate choices driving de novo gliomagenesis from hNSCs, and provide a blueprint for potential early-stage treatment/diagnosis for GBM.

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