Combining selinexor with alisertib to target the p53 pathway in neuroblastoma

Nguyen, Rosa; Wang, Hong; Sun, Ming; Lee, Dong Geun; Peng, Junmin; Thiele, Carol J.

doi:10.1016/j.neo.2022.100776

Cited by 12 publications

(12 citation statements)

References 48 publications

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“…In general, this study demonstrated the ferroptosis-related gene signatures in NB associated with the prognosis and proposed the possibility of the AURKA gene as a prognostic marker in NB, which is consistent with many preclinical studies ( Berwanger et al, 2002 ; Otto et al, 2009 ; Ramani et al, 2015 ; Xie et al, 2017 ; Boi et al, 2021 ; Roeschert et al, 2021 ; Nguyen et al, 2022 ). We call for more attention to AURKA , expecting to open up a new way to treat NB.…”

Section: Discussionsupporting

confidence: 90%

“…Previous microarray analyses showed that MYCN-amplified NBs had higher levels of AURKA mRNA than nonamplified NBs ( Berwanger et al, 2002 ) and this was confirmed in another study ( Otto et al, 2009 ), which showed that AURKA was not only required for the growth of MYCN-amplified NB cells but also for cells lacking amplified MYCN, which is consistent with the study of Roeschert et al (2021 ). In addition, it has been reported that changing the conformation of the AURKA activation loop with small molecules can effectively disrupt the AURKA /N-myc interaction in NB cancer cells ( Boi et al, 2021 ), and using selinexor and the AURKA inhibitor alisertib to synergistically increase the cytotoxicity of p53-mediated high-risk NB has potential therapeutic benefits ( Nguyen et al, 2022 ). As a result, we believe that AURKA may open up new avenues for biomarkers used in the prognosis of NB.…”

Section: Discussionmentioning

confidence: 99%

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Ferroptosis-related gene signatures in neuroblastoma associated with prognosis

Chen

Cao

et al. 2022

Front. Cell Dev. Biol.

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Background: Ferroptosis, a form of regulatory cell death, has been linked to the development of various tumors. Peripheral neuroblastoma (NB) is one of the most common extracranial solid tumors in children, and it has been proposed that regulating tumor cell ferroptosis may be a future treatment for NB. However, it is unclear how ferroptosis contributes to NB development.Methods: Expression data were collected from two independent cohorts (GEO and Arrayexpress databases). Univariate Cox analysis, multivariate Cox analysis, and the least absolute shrinkage and selection operator (Lasso) algorithm were applied to create a prognostic signature, whose performance was quantified using the area under the receiver operating characteristic curve (AUC) and Kaplan–Meier curves. A prognostic meta-analysis was used to test the suitability and stability of the FRG signature. Drug sensitivity analyses were performed using the data collected from Cell Miner™.Results:PROM2, AURKA, STEAP3, CD44, ULK2, MAP1LC3A, ATP6V1G2, and STAT3 are among the eight genes in the FRG prognostic signature, all of which were highly expressed in stage 1 NB, except AURKA. Furthermore, the high-risk group, which was stratified by signature, had a lower overall survival rate than the low-risk group. GSEA revealed that high-risk groups have more biological processes related to ferroptosis.Conclusion: Ferroptosis-related genes are expressed differently between stages 1 and 4 NB. The FRG signature successfully stratified NB patients into two risk groups and can accurately predict the overall survival in NB. In addition, we found that the gene AURKA might have the potential to be a prognostic marker in NB.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Ferroptosis-related gene signatures in neuroblastoma associated with prognosis

Chen

Cao

et al. 2022

Front. Cell Dev. Biol.

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“…This PDX line has molecular features of high-risk NB ( MYCN amplification), and most tumor-bearing mice treated with conventional chemotherapy and/or immunotherapy cannot be cured. 32 33 Three weeks after tumor implantation, mice were randomized to receive either UT mock T cells or 2.5×10 6 CAR + T cells. Four weeks post CAR T cell infusion (Day 50 post tumor implantation), CT3.28H.BBζ induced the most significant tumor regression comparing all three CAR constructs ( figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

Preclinical optimization of a GPC2-targeting CAR T-cell therapy for neuroblastoma

Sun¹,

Cao

Okada³

et al. 2023

J Immunother Cancer

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BackgroundAlthough most patients with newly diagnosed high-risk neuroblastoma (NB) achieve remission after initial therapy, more than 50% experience late relapses caused by minimal residual disease (MRD) and succumb to their cancer. Therapeutic strategies to target MRD may benefit these children. We developed a new chimeric antigen receptor (CAR) targeting glypican-2 (GPC2) and conducted iterative preclinical engineering of the CAR structure to maximize its anti-tumor efficacy before clinical translation.MethodsWe evaluated different GPC2-CAR constructs by measuring the CAR activity in vitro. NOD-SCID mice engrafted orthotopically with human NB cell lines or patient-derived xenografts and treated with human CAR T cells served as in vivo models. Mechanistic studies were performed using single-cell RNA-sequencing.ResultsApplying stringent in vitro assays and orthotopic in vivo NB models, we demonstrated that our single-chain variable fragment, CT3, integrated into a CAR vector with a CD28 hinge, CD28 transmembrane, and 4-1BB co-stimulatory domain (CT3.28H.BBζ) elicits the best preclinical anti-NB activity compared with other tested CAR constructs. This enhanced activity was associated with an enrichment of CD8+effector T cells in the tumor-microenvironment and upregulation of several effector molecules such asGNLY,GZMB,ZNF683, andHMGN2. Finally, we also showed that the CT3.28H.BBζ CAR we developed was more potent than a recently clinically tested GD2-targeted CAR to control NB growth in vivo.ConclusionGiven the robust preclinical activity of CT3.28H.BBζ, these results form a promising basis for further clinical testing in children with NB.

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“…These data therefore reinforce the beneficial effect that activators of the p53 pathway may have in combination with AURKAi. More recently, a study from Nguyen et al [ 132 ] found that selinexor, an inhibitor of the nuclear export protein XPO1, induced p53 phosphorylation at serine 315, an initiating step for p53 degradation undertaken by AURKA, as previously referred. By using alisertib, p53-mediated cell death was enhanced in NB xenograft mouse models.…”

Section: The P53 Family Proteins: P53 and Tap73mentioning

confidence: 76%

Deciphering the Role of p53 and TAp73 in Neuroblastoma: From Pathogenesis to Treatment

Almeida

Mota

Škoda

et al. 2022

Cancers

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Neuroblastoma (NB) is an embryonic cancer that develops from neural crest stem cells, being one of the most common malignancies in children. The clinical manifestation of this disease is highly variable, ranging from spontaneous regression to increased aggressiveness, which makes it a major therapeutic challenge in pediatric oncology. The p53 family proteins p53 and TAp73 play a key role in protecting cells against genomic instability and malignant transformation. However, in NB, their activities are commonly inhibited by interacting proteins such as murine double minute (MDM)2 and MDMX, mutant p53, ΔNp73, Itch, and Aurora kinase A. The interplay between the p53/TAp73 pathway and N-MYC, a known biomarker of poor prognosis and drug resistance in NB, also proves to be decisive in the pathogenesis of this tumor. More recently, a strong crosstalk between microRNAs (miRNAs) and p53/TAp73 has been established, which has been the focused of great attention because of its potential for developing new therapeutic strategies. Collectively, this review provides an updated overview about the critical role of the p53/TAp73 pathway in the pathogenesis of NB, highlighting encouraging clues for the advance of alternative NB targeted therapies.

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Combining selinexor with alisertib to target the p53 pathway in neuroblastoma

Cited by 12 publications

References 48 publications

Ferroptosis-related gene signatures in neuroblastoma associated with prognosis

Ferroptosis-related gene signatures in neuroblastoma associated with prognosis

Preclinical optimization of a GPC2-targeting CAR T-cell therapy for neuroblastoma

Deciphering the Role of p53 and TAp73 in Neuroblastoma: From Pathogenesis to Treatment

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