Establishment of multiple novel patient-derived models of desmoplastic small round cell tumor enabling functional characterization of ERBB pathway signaling and pre-clinical evaluation of a novel targeted therapy approach

Smith, Roger S.; Odintsov, Igor; Liu, Zebing; Lui, Allan Jo-Weng; Hayashi, Takuo; Vojnic, Morana; Suehara, Yoshiyuki; Delasos, Lukas; Mattar, Marissa S.; Hmeljak, Julija; Ramirez, Hillary A.; Shaw, Melissa; Bui, Gabrielle; Hartono, Alifiani B.; Gladstone, Eric; Kunte, Siddharth; Magnan, Heather; Khodos, Inna; Stanchina, Elisa de; Quaglia, Michael P. La; Yao, Jinjuan; Laé, Marick; Lee, Sean Bong; Spraggon, Lee; Pratilas, Christine A.; Ladanyi, Marc; Somwar, Romel

doi:10.1101/2020.09.22.308940

Cited by 3 publications

(1 citation statement)

References 36 publications

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“…Figure 4 provides a list of PDX repositories entailing pediatric sarcoma. The Memorial Sloan Kettering Cancer Center’s Department of Pediatrics will also soon be releasing their collection of pediatric PDX models including several sarcoma entities such as desmoplastic small round cell tumor (DSRCT) [ 51 ].…”

Section: Established In Vivo Models Of Pediatric Sarcomamentioning

confidence: 99%

Preclinical In Vivo Modeling of Pediatric Sarcoma—Promises and Limitations

Imle

Kommoss

Banito

2021

JCM

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Pediatric sarcomas are an extremely heterogeneous group of genetically distinct diseases. Despite the increasing knowledge on their molecular makeup in recent years, true therapeutic advancements are largely lacking and prognosis often remains dim, particularly for relapsed and metastasized patients. Since this is largely due to the lack of suitable model systems as a prerequisite to develop and assess novel therapeutics, we here review the available approaches to model sarcoma in vivo. We focused on genetically engineered and patient-derived mouse models, compared strengths and weaknesses, and finally explored possibilities and limitations to utilize these models to advance both biological understanding as well as clinical diagnosis and therapy.

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Section: Established In Vivo Models Of Pediatric Sarcomamentioning

confidence: 99%

Preclinical In Vivo Modeling of Pediatric Sarcoma—Promises and Limitations

Imle

Kommoss

Banito

2021

JCM

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Multi-site desmoplastic small round cell tumors are genetically related and immune-cold

Beird

Lamhamedi-Cherradi

et al. 2022

npj Precis. Onc.

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Desmoplastic small round cell tumor (DSRCT) is a highly aggressive soft tissue sarcoma that is characterized by the EWSR1-WT1 fusion protein. Patients present with hundreds of tumor implants in their abdominal cavity at various sites. To determine the genetic relatedness among these sites, exome and RNA sequencing were performed on 22 DSRCT specimens from 14 patients, four of whom had specimens from various tissue sites. Multi-site tumors from individual DSRCT patients had a shared origin and were highly related. Other than the EWSR1-WT1 fusion, very few secondary cancer gene mutations were shared among the sites. Among these, ARID1A, was recurrently mutated, which corroborates findings by others in DSRCT patients. Knocking out ARID1A in JN-DSRCT cells using CRISPR/CAS9 resulted in significantly lower cell proliferation and increased drug sensitivity. The transcriptome data were integrated using network analysis and drug target database information to identify potential therapeutic opportunities in EWSR1-WT1-associated pathways, such as PI3K and mTOR pathways. Treatment of JN-DSRCT cells with the PI3K inhibitor alpelisib and mTOR inhibitor temsirolimus reduced cell proliferation. In addition, the low mutation burden was associated with an immune-cold state in DSRCT. Together, these data reveal multiple genomic and immune features of DSRCT and suggest therapeutic opportunities in patients.

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Therapeutic Potential of NTRK3 Inhibition in Desmoplastic Small Round Cell Tumor

Somwar

Hmeljak

Magnan

et al. 2021

Clinical Cancer Research

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Purpose: Desmoplastic small round cell tumor (DSRCT) is a highly lethal intra-abdominal sarcoma of adolescents and young adults. DSRCT harbors a t(11;22)(p13:q12) that generates the EWSR1-WT1 chimeric transcription factor, the key oncogenic driver of DSRCT. EWSR1-WT1 rewires global gene expression networks and activates aberrant expression of targets that together mediate oncogenesis. EWSR1-WT1 also activates a neural gene expression program. Experimental Design: Among these neural markers, we found prominent expression of neurotrophic tyrosine kinase receptor 3 (NTRK3), a druggable receptor tyrosine kinase. We investigated the regulation of NTRK3 by EWSR1-WT1 and its potential as a therapeutic target in vitro and in vivo, the latter using novel patient-derived models of DSRCT. Results: We found that EWSR1-WT1 binds upstream of NTRK3 and activates its transcription. NTRK3 mRNA is highly expressed in DSRCT compared with other major chimeric transcription factor–driven sarcomas and most DSRCTs are strongly immunoreactive for NTRK3 protein. Remarkably, expression of NTRK3 kinase domain mRNA in DSRCT is also higher than in cancers with NTRK3 fusions. Abrogation of NTRK3 expression by RNAi silencing reduces growth of DSRCT cells and pharmacologic targeting of NTRK3 with entrectinib is effective in both in vitro and in vivo models of DSRCT. Conclusions: Our results indicate that EWSR1-WT1 directly activates NTRK3 expression in DSRCT cells, which are dependent on its expression and activity for growth. Pharmacologic inhibition of NTRK3 by entrectinib significantly reduces growth of DSRCT cells both in vitro and in vivo, providing a rationale for clinical evaluation of NTRK3 as a therapeutic target in DSRCT.

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Establishment of multiple novel patient-derived models of desmoplastic small round cell tumor enabling functional characterization of ERBB pathway signaling and pre-clinical evaluation of a novel targeted therapy approach

Cited by 3 publications

References 36 publications

Preclinical In Vivo Modeling of Pediatric Sarcoma—Promises and Limitations

Preclinical In Vivo Modeling of Pediatric Sarcoma—Promises and Limitations

Multi-site desmoplastic small round cell tumors are genetically related and immune-cold

Therapeutic Potential of NTRK3 Inhibition in Desmoplastic Small Round Cell Tumor

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