Desmoplastic Small Round Cell Tumor / Ewing Sarcoma

Desmoplastic Small Round Cell Tumor (DSRCT) is primarily characterized by the EWSR1-WT1 fusion gene resulting from a chromosomal translocation between the EWSR1 gene on chromosome 22 and the WT1 gene on chromosome 11. This fusion gene is considered the hallmark genetic alteration in DSRCT. A specific translocation, t(11;22)(p13;q12), is seen in almost all cases, juxtaposing the EWS gene to the WT1 tumor suppressor gene.

EWSR1 is involved in RNA processing, transcription regulation, and protein-protein interactions. Alterations caused by the fusion with WT1 might affect EWSR1's interactions with other transcription factors, RNA-binding proteins, and signaling pathways.

WT1 is a transcription factor involved in kidney and gonad development. Its fusion with EWSR1 could lead to altered target gene regulation, potentially impacting pathways related to cell growth, differentiation, and survival.

Desmoplastic small round cell tumors most frequently harbor alterations in EWSR1, WT1, KMT2C, HRAS, and ARID1A (tumor suppressor)

gene

hras

The following oncogenes and tumor suppressor genes could be involved in DSRCT:

Oncogenes

MYC Amplification and overexpression of the MYC oncogene.

HRAS, KRAS

BRAF

CTNNB1 (Beta-catenin)

EGFR

MET 

SURVIVIN

 Tumor Suppressor Genes

TP53

RB1 

PTEN {ref}

CDKN2A (p16)

CDKN1A (p21)

APC

SMAD4

VHL

Recurrent secondary somatic alterations in FGFR4, ARID1A, TP53, MSH3, and MLL3 were detected in 82% of DSRCT {ref}

PI3K/AKT/mTOR Pathway {ref}  

Wnt/β-catenin Pathway {ref}

role for SIK1 in the regulation of Wnt/β-catenin signaling

SIK1 (Salt-inducible Kinase)

depletion of SIK1 causes inhibition of tumor cell growth, similar to the growth inhibition observed when EWSR1-WT1 is depleted. {ref}

Identification of SIK1 as a potential therapeutic target for desmoplastic small round cell tumor {ref}

SIK1 Couples LKB1 to p53-Dependent Anoikis and Suppresses Metastasis {ref}

The effect of SIK1 on tumor development occurs at least partially through the regulation of β-catenin, as evidenced by the fact that SIK1 overexpression leads to repression of β-catenin transcriptional activity, while SIK1 depletion has the opposite effect {ref} 

HDAC3

GLUT1

Aspirin {ref}

PD-1

The expression of PD1, PDL-1, and CD8 was analyzed in a cohort of 11 patients with DSRCT and it was observed a high rate of PD1 (81%), CD8 (64%) and low PDL-1 (18%) expression 

Elevated Expression Level of Survivin Protein in Soft-Tissue Sarcomas Is a Strong Independent Predictor of Survival {ref}

GD2, GD3 {ref}

Desmoplastic Small Round Cell Tumor: A Review of Main Molecular Abnormalities and Emerging Therapy {ref} 

One important molecular aberration that distinguishes DSRCT from ES is the increased Androgen Receptor (AR) expression. 

Comprehensive Molecular Profiling of Desmoplastic Small Round Cell Tumor {ref}

VAIA regimen (ifosfamide, vincristine, doxorubicin, actinomycin D) presented longer event- free survival (29.4 months) compared to other protocols, including the P6 protocol.

The interval-compressed regimen of vincristine, irinotecan, temozolamide (VIT) was evaluated in 6 pediatric patients and showed a tolerable profile with an objective response rate of 50% to the first 2 cycles of VIT .

As a hypervascular tumor, DSRCT is characterized by an overexpression of proteins that promote and maintain the angiogenic process necessary for continued tumor growth and proliferation. EWS-WT1 is able to induce PDGFA expression [21] and activation of the IGF1R gene [14] (Figure 2). Other tyrosine kinase receptors (TKR) expression have been found to be disrupted in DSRCT and are related to proliferation and angiogensis. VEGFR-2 and VEGFA expression was found to be markedly increased in the DSRCT tumor sample and in the human DSRCT cell line, JN-DSRCT.

Therapeutic Potential of NTRK3 Inhibition in Desmoplastic Small Round Cell Tumor {ref}

A review of NTRK fusions in cancer {ref}

Gene fusions in soft tissue tumors: Recurrent and overlapping pathogenetic themes {ref}

Identification of SIK1 as a potential therapeutic target for desmoplastic small round cell tumor {ref}

We showed that EWS-WT1 directly binds to a 2kb proximal promoter region of SIK1. Following SIK1 depletion, JN-DSRCT-1 cell proliferation sharply decreased, similar to the growth inhibition observed when EWS-WT1 is depleted. We further showed that cells do not transit to S phase when SIK1 is depleted, suggesting a critical role of SIK1 in cell cycle regulation in DSRCT. Taken together, we have established that EWS-WT1 directly activates SIK1 expression and promotes cell proliferation through SIK1. Therefore, our work identified SIK1 as a new potential therapeutic target in DSRCT.

Desmoplastic Small Round Cell Tumors (DSRCT) {ref} 

Small round cell sarcomas {ref}

Desmoplastic small round cell tumor: from state of the art to future clinical prospects {ref}

Desmoplastic Small Round Cell Tumor: A Review of Main Molecular Abnormalities and Emerging Therapy {ref}

Mini-Review on Targeted Treatment of Desmoplastic Small Round Cell Tumor {ref}

Desmoplastic Small Round Cell Tumor: A Review of Main Molecular Abnormalities and Emerging Therapy {ref}

Desmoplastic Small Round Cell Tumors {ref}

The genomics of desmoplastic small round cell tumor reveals the deregulation of genes related to DNA damage response, epithelial–mesenchymal transition, and immune response {ref}

Desmoplastic small round cell tumor: A nationwide study of a rare sarcoma {ref}

Molecular mechanisms underpinning sarcomas and implications for current and future therapy {ref}

Desmoplastic small round cell tumor cancer stem cell-like cells resist chemotherapy but remain dependent on the EWSR1-WT1 oncoprotein {ref}

The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma {ref}

CXCR4-Directed Imaging and Endoradiotherapy in Desmoplastic Small Round Cell Tumors {ref}

Immunotherapy and Radioimmunotherapy for Desmoplastic Small Round Cell Tumor {ref}

Desmoplastic Small Round Cell Tumour Successfully Treated with Caffeine-assisted Chemotherapy: A Case Report and Review of the Literature {ref}

Chemotherapy combined with apatinib for the treatment of desmoplastic small round cell tumors: A case report {ref}

Clinical Activity of Pazopanib in Patients with Advanced Desmoplastic Small Round Cell Tumor {ref}

Olaparib and temozolomide in desmoplastic small round cell tumors: a promising combination in vitro and in vivo.{ref}

Desmoplastic Small Round Blue Cell Tumor: A Review of Treatment and Potential Therapeutic Genomic Alterations {ref}

Desmoplastic small round cell tumor 20 years after its discovery {ref}

Desmoplastic Small Round Cell Tumors: A review with focus on clinical management and therapeutic options {ref}

Desmoplastic Small Round Cell Tumor: A Case Report {ref}

Desmoplastic Small Round Cell Tumor: Pathology, Genetics, and Potential Therapeutic Strategies {ref}

Desmoplastic small round cell tumor (DSRCT) xenografts and tissue culture lines: Establishment and initial characterization {ref}

Desmoplastic small round cell tumor: A clinicopathologic, immunohistochemical and molecular study of 32 tumors {ref}

Desmoplastic Small Round Cell Tumour (DSRCT) - A Case Report and Review of Literature {ref}

Desmoplastic Small Round Cell Tumor: Impact of 18F-FDG PET Induced Treatment Strategy in a Patient with Long-Term Outcome {ref}

Expression profiles of exosomal miRNAs isolated from plasma of patients with desmoplastic small round cell tumor {ref}

Desmoplastic Small Round Cell Tumors: Cytologic, Histologic, and Immunohistochemical Features {ref}

Long-term survivors with desmoplastic small round cell tumor (DSRCT): Results from a retrospective single-institution case series analysis {ref} Complete surgery seems to play a crucial role while the addition of WAP-RT +/− MC to R0/R1 resection deserves further investigation. Incorporating irinotecan in the primary disease treatment also deserves further evaluation.

Natural products remodel cancer-associated fibroblasts in desmoplastic tumors {ref}

Shikonin Inhibits Cancer Through P21 Upregulation and Apoptosis Induction {ref}

In silico and in vitro drug screening identifies new therapeutic approaches for Ewing sarcoma {ref} 

A Combination of  Triterpene Acids and Mistletoe Lectins Induces Highly Effective Apoptosis in Ewing's Sarcoma {ref} 

The Effect of Fucoidan, a Potential New, Natural, Anti-Neoplastic Agent on Uterine Sarcomas and Carcinosarcoma Cell Lines {ref} 

Caffeine-potentiated chemotherapy for patients with high-grade soft tissue sarcoma: Long-term clinical outcome {ref} 

In vivo growth inhibition of sarcoma 180 by piperlonguminine, an alkaloid amide from the Piper species {ref} 

Inhibition of HDACs reduces Ewing sarcoma tumor growth through EWS-FLI1 protein destabilization (retracted but reasons for retraction don't seem relevant to the content) {ref} 

Systemic Treatment of Ewing Sarcoma: Current Options and Future Perspectives {ref} 

METTL3-modified lncRNA-MALAT1 regulates the molecular axis of miR-124-3p/CDK4 involved in Ewing's sarcoma {ref} "METTL3 promotes tumorigenesis of ES through the MALAT1/miR-124-3p/CDK4 axis."

6-shogaol induces apoptosis and enhances radiosensitivity in head and neck squamous cell carcinoma cell lines {ref} 

Role of Combination Therapy in Relapsed Ewing's Sarcoma {ref} 

Curcumin-altered p53-Response Genes Regulate Radiosensitivity in p53-Mutant Ewing's Sarcoma Cells {ref} 

Cell cycle inhibition and apoptosis induced by Curcumin in Ewing sarcoma cell line SK-NEP-1 {ref} 

Melatonin Cytotoxicity Is Associated to Warburg Effect Inhibition in Ewing Sarcoma Cells {ref} 

Mechanisms Involved in the Pro-Apoptotic Effect of Melatonin in Cancer Cells {ref} 

Celecoxib inhibits Ewing sarcoma cell migration via actin modulation {ref} 

Celecoxib inhibits invasion and metastasis via a cyclooxygenase 2-independent mechanism in an in vitro model of Ewing sarcoma {ref} 

In vivo growth-inhibition of Sarcoma 180 by piplartine and piperine, two alkaloid amides from Piper {ref} 

Ewing sarcoma: investigational mono- and combination therapies in clinical trials {ref} 

Magnolol induces human Ewing sarcoma SK-ES-1 cell apoptosis via the mitochondrial and death receptor pathways {ref} 

Inhibition of HDACs reduces Ewing sarcoma tumor growth through EWS-FLI1 protein destabilization {ref}

Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma {ref} 

Sulforaphane induces apoptosis in rhabdomyosarcoma and restores TRAIL-sensitivity in the aggressive alveolar subtype leading to tumor elimination in mice {ref} 

Effects of baicalein on proliferation, apoptosis, migration and invasion of Ewing's sarcoma cells {ref} 

β3-Adrenoreceptor Activity Limits Apigenin Efficacy in Ewing Sarcoma Cells: A Dual Approach to Prevent Cell Survival {ref} 

Epigallocatechin gallate (EGCG) causes antiproliferation and induction of apoptosis of Ewing sarcoma tumor cells through the inhibition of IGF-1R {ref} 

Anti-cancer effect of (-)-epigallocatechin-3-gallate (EGCG) in head and neck cancer through repression of transactivation and enhanced degradation of β-catenin {ref}

Anticancer Effects of Combination of Indole-3-Carbinol and Hydroxychloroquine on Ehrlich Ascites Carcinoma via Targeting Autophagy and Apoptosis {ref} 

ETV6 Protein Could Be an Important Target for Ewing Sarcoma Treatment {ref}

Honokiol degrades cytosolic β-catenin and reduces nuclear accumulation of β-catenin

Honokiol enhanced phosphorylation of β-catenin, important for the degradation or 

inactivation of β-catenin. {ref|ref}

Ursolic acid inhibits the expression of β-catenin and its dependent genes {ref}

Celecoxib and 2,5-dimethylcelecoxib inhibit intestinal cancer growth by suppressing the Wnt/β-catenin signaling pathway {ref}

Indole-3-carbinol inhibits prostate cancer cell migration via degradation of beta-catenin {ref}

Indole-3-carbinol-induced death in cancer cells involves EGFR downregulation and is exacerbated in a 3D environment {ref}

Curcumin inhibits NF-kB and Wnt/β-catenin pathways in cervical cancer cells{ref}

Quercetin, a potent inhibitor against beta-catenin/Tcf signaling in SW480 colon cancer cells {ref}

Vitamin D Is a Multilevel Repressor of Wnt/β-Catenin Signaling in Cancer Cells {ref}

Docosahexaenoic acid induces proteasome-dependent degradation of beta-catenin, down-regulation of survivin and apoptosis in human colorectal cancer cells not expressing COX-2 {ref}

Dietary Feeding of Grape Seed Extract Prevents Intestinal Tumorigenesis in APCmin/+ Mice 1

"reduced cell proliferation and increased apoptosis together with down-regulation in COX-2, iNOS, beta-catenin, cyclin D1, and c-Myc expression, and increased Cip1/p21" {ref}

Pterostilbene inhibits the metastasis of TNBC via suppression of β-catenin-mediated epithelial to mesenchymal transition and stemness {ref}

Serum lactate dehydrogenase (LDH) as a tumor marker in Ewing's sarcoma {ref|ref}

Glycogen synthase kinase 3β biology in bone and soft tissue sarcomas {ref}

Ivermectin inhibited cell migration and reduced the expression of phosphorylated GSK-3β {ref}

Dihydroartemisinin inhibits cell proliferation via AKT/GSK3β/cyclinD1 pathway {ref}

Mechanisms of Chemopreventive and Therapeutic Proprieties of Ginger Extracts in Cancer {ref}

Survivin Inhibition by Piperine Sensitizes Glioblastoma Cancer Stem Cells and Leads to Better Drug Response {ref}

Honokiol Enhances TRAIL-Mediated Apoptosis through STAMBPL1-Induced Survivin and c-FLIP Degradation {ref}

Honokiol reduces drug resistance by down-regulation of survivin expression in multidrug resistant squamous cell carcinoma of the head and neck {ref}

Downregulation of survivin and activation of caspase-3 through the PI3K/Akt pathway in ursolic acid-induced HepG2 cell apoptosis {ref}

Downregulation of survivin expression and concomitant induction of apoptosis by celecoxib and its non-cyclooxygenase-2-inhibitory analog, dimethyl-celecoxib (DMC), in tumor cells in vitro and in vivo {ref}

Silibinin Sensitizes Human Glioma Cells to TRAIL-Mediated Apoptosis via DR5 Up-regulation and Down-regulation of c-FLIP and Survivin {ref}

Inhibition of IL-6 expression in LNCaP prostate cancer cells by a combination of atorvastatin and celecoxib "treatment of the mice with a combination of celecoxib and atorvastatin resulted in a much stronger inhibition in the increase in IL-6 and survivin expression" {ref}

Curcumin Inhibits Constitutive STAT3 Phosphorylation in Human Pancreatic Cancer Cell lines and Downregulation of Survivin/BIRC5 Gene Expression {ref}

Berberine and Curcumin Target Survivin and STAT3 in Gastric Cancer Cells and Synergize Actions of Standard Chemotherapeutic 5-Fluorouracil {ref}

Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/beta-catenin signaling pathway {ref}

Down-regulation and nuclear localization of survivin by sodium butyrate induces caspase-dependent apoptosis in human oral mucoepidermoid carcinoma {ref}

Shikonin Inhibits Non-Small-Cell Lung Cancer H1299 Cell Growth through Survivin Signaling Pathway {ref}

Grape seed extract inhibit proliferation of breast cancer cell MCF-7 and decrease the gene expression of Survivin {ref}

Indole-3-carbinol inhibition of androgen receptor expression and downregulation of androgen responsiveness in human prostate cancer cells {ref}

Honokiol Inhibits Androgen Receptor Activity in Prostate Cancer Cells {ref}

Downregulation of androgen receptor expression by luteolin causes inhibition of cell proliferation and induction of apoptosis in human prostate cancer cells and xenografts {ref}

Curcumin downregulates prostate specific antigen expression through the inhibition of androgen receptor expression in human prostatic carcinoma cells {ref}

Berberine Suppresses Androgen Receptor Signaling in Prostate Cancer {ref}

D,L-Sulforaphane causes transcriptional repression of androgen receptor in human prostate cancer cells {ref}

Magnolol down-regulates HER2 gene expression, leading to inhibition of HER2-mediated metastatic potential in ovarian cancer cells {ref}

Effects of Annona muricata Extract on Triple-Negative Breast Cancer Cells Mediated Through EGFR Signaling {ref}

Honokiol Inhibits Epidermal Growth Factor Receptor Signaling and Enhances the Antitumor Effects of Epidermal Growth Factor Receptor Inhibitors {ref}

Luteolin exerts anti-tumor activity through the suppression of epidermal growth factor receptor-mediated pathway in MDA-MB-231 ER-negative breast cancer cells {ref}

Magnolol Induces Apoptosis Via Inhibiting the EGFR/PI3K/Akt Signaling Pathway in Human Prostate Cancer Cells {ref}

Curcumin Induces EGFR Degradation in Lung Adenocarcinoma and Modulates p38 Activation in Intestine: The Versatile Adjuvant for Gefitinib Therapy {ref}

Berberine Inhibits Proliferation and Down-Regulates Epidermal Growth Factor Receptor through Activation of Cbl in Colon Tumor Cells {ref}

EGCG down-regulates EGFR expression {ref}

Honokiol Suppresses Survival Signals Mediated by Ras-Dependent Phospholipase D Activity in Human Cancer Cells {ref}

Apigenin suppresses proliferation, invasion, and epithelial–mesenchymal transition of cervical carcinoma cells by regulation of miR ‐152/ BRD4 axis (target MYC via BRD4?) {ref}

Sanguinarine targets BRD4 to suppress cell proliferation and migration in clear cell renal cell carcinoma {ref}

Inhibiting High Glucose-Induced Vascular Smooth Muscle Cell Proliferation via Pin1/BRD4 Pathway {ref| juglone (black walnut)}

Protein phosphatase 2A (PP2A) activation as a therapeutic strategy for managing MYC-driven cancers {ref}

Carnosic acid modulates Akt/IKK/NF-κB signaling by PP2A and induces intrinsic and extrinsic pathway mediated apoptosis in human prostate carcinoma PC-3 cells {ref}

PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect {ref}

Increased chemopreventive effect by combining arctigenin, green tea polyphenol and curcumin in prostate and breast cancer cells {ref} "The strongest effects on cell cycle arrest and apoptosis were achieved by combining all three compounds in both cell lines. The combination treatment significantly increased the ratio of Bax to Bcl-2 proteins, decreased the activation of NFκB, PI3K/Akt and Stat3 pathways and cell migration compared to individual treatment."

Combined treatment with artesunate and bromocriptine has synergistic anticancer effects in pituitary adenoma cell lines {ref} "We suggest that ART and BRC used in combination exert synergistic apoptotic and antitumor effects by suppressing miR-200c and stimulating Pten expression."

Melittin Restores PTEN Expression by Down-Regulating HDAC2 in Human Hepatocelluar Carcinoma HepG2 Cells {ref}

Last updated: September 18, 2023