scholarly journals Hippo pathway effectors YAP1/TAZ induce an EWS–FLI1 ‐opposing gene signature and associate with disease progression in Ewing sarcoma

2020 ◽  
Vol 250 (4) ◽  
pp. 374-386 ◽  
Author(s):  
Pablo Rodríguez‐Núñez ◽  
Laura Romero‐Pérez ◽  
Ana T Amaral ◽  
Pilar Puerto‐Camacho ◽  
Carmen Jordán ◽  
...  
Keyword(s):  
Disease Progression ◽  
Ewing Sarcoma ◽  
Hippo Pathway ◽  
Gene Signature

scholarly journals Hippo pathway effectors YAP1/TAZ induce a EWS-FLI1-opposing gene signature and associate with disease progression in Ewing Sarcoma

2019 ◽  
Author(s):  
Pablo Rodríguez-Núñez ◽  
Laura Romero-Pérez ◽  
Ana T. Amaral ◽  
Pilar Puerto-Camacho ◽  
Carmen Jordán ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Fusion Protein ◽  
Cell Lines ◽  
Ewing Sarcoma ◽  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Hippo Pathway ◽  
Protein A ◽  
Gene Signature ◽  
Cell Of Origin

AbstractYAP1 and TAZ (WWTR1) oncoproteins are the final transducers of Hippo tumor suppressor pathway. Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon. Ewing Sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized by a canonical fusion involvingEWSR1gene, andFLI1as the most common partner. The fusion protein is a potent driver of oncogenesis but secondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse or progression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 primary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the disease and predicted poorer outcome.We did not observe recurrent SNV or copy number gains/losses in Hippo pathway-related loci. However, differential CpG methylation ofRASSF1locus -a regulator of Hippo pathway- was observed in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethylation ofRASSF1correlated with the transcriptional silencing of the tumor suppressor isoformRASFF1A, and transcriptional activation of the protumorigenic isoformRASSF1Cpromoting YAP1/TAZ activation. Knockdown of YAP1/TAZ decreased proliferation and invasion abilities of EwS cells, and revealed that YAP1/TAZ transcription activity is inversely correlated with the EWS-FLI1 transcriptional signature. This transcriptional antagonism could be partly explained by EWS-FLI1-mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the transcriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamic fluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS.

scholarly journals Three-gene signature predicts disease progression of non-muscle invasive bladder cancer

2011 ◽  
Vol 2 (4) ◽  
pp. 679-684 ◽  
Author(s):  
PILDU JEONG ◽  
YUN-SOK HA ◽  
IN-CHANG CHO ◽  
SEOK-JOONG YUN ◽  
EUN SANG YOO ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Disease Progression ◽  
Gene Signature ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

scholarly journals A Four-Gene Signature Predicts Disease Progression in Muscle Invasive Bladder Cancer

2011 ◽  
Vol 17 (5-6) ◽  
pp. 478-485 ◽  
Author(s):  
Wun-Jae Kim ◽  
Seon-Kyu Kim ◽  
Pildu Jeong ◽  
Seok-Joong Yun ◽  
In-Chang Cho ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Disease Progression ◽  
Gene Signature ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

Evaluation of local control in patients with non-metastatic Ewing sarcoma of the bone: A report from the Children's Oncology Group

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10013-10013
Author(s):  
S. G. DuBois ◽  
M. D. Krailo ◽  
E. F. Cook ◽  
N. J. Tarbell ◽  
C. J. Fryer ◽  
...  
Keyword(s):  
Disease Progression ◽  
Local Control ◽  
Ewing Sarcoma ◽  
Tumor Size ◽  
Cumulative Incidence ◽  
Hazard Ratio ◽  
Local Failure ◽  
Control Mode ◽  
Distant Failure ◽  
Risk Of Disease

10013 Background: Options for local control in patients (pts) with Ewing sarcoma (EWS) include surgery (S), radiation (R), or surgery plus radiation (S+R). The choice of local control depends on factors that also impact outcome in EWS, including tumor site, tumor size, and age. Our objective was to determine if risk of disease progression differs between local control methods, after controlling for potential confounders. Methods: We analyzed the cohort of pts with non-metastatic EWS of the bone treated on Intergroup Study-0091 (Grier et al, NEJM, 2003). Local control decisions were made on an individual basis. We excluded pts with tumors of the skull/face, progression prior to end of local control, or incomplete local control data. Disease progression was recorded from end of local control. Cumulative incidence of disease progression was determined using a competing risks approach. We constructed a Cox proportional hazards model of progression free survival incorporating local control mode and potential confounders into the model. Secondary analyses evaluated overall survival, local failure, and distant failure. Results: 329 pts met eligibility criteria for analysis. 122 pts received S, 142 received R, and 65 received S+R. The cumulative incidence of disease progression at 5 years was 22.1% (95% CI 15.1–29.9%) for S, 36.9% (29.0–44.9%) for R, and 48.1% (35.5- 59.7%) for S+R. Using R as the reference group and controlling for age, tumor size, tumor location, and chemotherapy regimen, the hazard ratio for progression was 0.66 (95% CI 0.38–1.13) for S and 1.55 (0.96–2.49) for S+R. The hazard ratio for death was 0.77 (95% CI 0.44–1.34) for S and 1.46 (0.88–2.42) for S+R. The hazard ratio for local failure was 0.38 (95% CI 0.15–0.98; p=0.04) for S and 0.77 (0.34–1.75) for S+R. The hazard ratio for distant failure was 0.78 (0.42–1.46) for S and 1.60 (0.91–2.82) for S+R. Conclusions: Observed differences in outcome between local control groups are largely due to confounding factors that affect outcome and local control choice. Risk of disease progression, distant failure, or death does not differ between pts who receive S or R. Pts who receive S have a decreased risk of local failure compared to pts who receive R. No significant financial relationships to disclose.

Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10011-10011
Author(s):  
P. Leavey ◽  
L. Mascarenhas ◽  
N. Marina ◽  
Z. Chen ◽  
M. Krailo ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Disease Progression ◽  
Metastatic Disease ◽  
Ewing Sarcoma ◽  
Significant Risk ◽  
Female Gender ◽  
Initial Diagnosis ◽  
Phase Iii ◽  
Rank Test ◽  
First Recurrence

10011 Background: The prognosis for patients with recurrent Ewing sarcoma (EWS) is very poor with 5-year survival of 13%. Since 30–40% of patients with newly diagnosed, non-metastatic EWS develop recurrence, the Children's Oncology Group (COG) sought to evaluate prognostic factors for these patients. Data was derived from the phase III, multi-institutional study INT 0091. Methods: Between 1988 and 1994, five hundred and seventy-eight eligible patients with previously untreated EWS or PNET of bone were enrolled on INT 0091. Patients who experienced recurrence or disease progression as their first analytic event were considered. Survival was calculated from date of disease progression to death or last patient contact. Comparisons of the risk for death across groups were accomplished using the log-rank test. Survivor functions were estimated by the method of Kaplan and Meier. Results: Two hundred and sixty-two patients experienced disease progression or recurrence. The median time to first recurrence was 1.3 years (range 0–7.4 years) for all patients, 1.4 years (range 0 to 7.4 years) for patients with initially localized disease and 1 year (range 0 to 6 years) for patients with initially metastatic disease. Time to first recurrence from date of initial diagnosis was a predictor of post-recurrence survival (p<0.0001). Twenty-one percent of patients whose disease recurred or progressed experienced first recurrence 2 or more years from initial diagnosis and had an estimated 5 year post-recurrence survival of 30%. This compares with 7% for those whose first recurrence or progression was earlier. No statistical difference was detected when patients whose disease recurred < 12 months were compared with those whose recurrence was 12–24 months from initial diagnosis. Significant risk factors for death after recurrence included metastatic disease at initial diagnosis, elevated LDH at initial diagnosis and female gender. In patients non-metastatic at initial diagnosis pelvic primary site was also a risk factor for death after recurrence. Conclusions: Patients with longer time to first recurrence represent the subset of patients most likely to survive following recurrence. All patients with recurrent Ewing sarcoma would benefit from collaborative trials to investigate new therapeutic options. No significant financial relationships to disclose.

A phase I/II clinical trial of the reversible LSD1 inhibitor, seclidemstat, in patients with relapsed/refractory Ewing sarcoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS11567-TPS11567
Author(s):  
Damon R. Reed ◽  
Leo Mascarenhas ◽  
Paul A. Meyers ◽  
Sant P. Chawla ◽  
Douglas James Harrison ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trial ◽  
Disease Progression ◽  
Dose Escalation ◽  
Ewing Sarcoma ◽  
The United States ◽  
Vehicle Group ◽  
Tumor Growth Inhibition ◽  
Aberrant Gene Expression ◽  
Aberrant Gene

TPS11567 Background: Ewing sarcoma (ES) is a rare, aggressive bone and soft tissue cancer that predominantly afflicts adolescents and young adults. Novel therapeutic agents are needed as there are no approved targeted treatments for this disease. ES is characterized by a chromosomal translocation resulting in an EWS/ETS fusion oncoprotein, a transcription factor that results in aberrant gene expression leading to ES progression. Lysine specific demethylase 1 (LSD1) associates with EWS/ETS oncoproteins to alter gene expression and contribute to disease progression. Directly inhibiting EWS/ETS is challenging and little progress has been made, though targeting LSD1 presents a viable therapeutic strategy for ES. Seclidemstat (SP-2577, Salarius Pharmaceuticals) is a first-in-class, orally bioavailable, small molecule with reversible and noncompetitive selective inhibition of LSD1 at low nanomolar concentrations (IC50: 25-50 nM). Seclidemstat inhibits LSD1’s scaffolding functions and enzymatic activity to help reverse aberrant gene expression. In vitro data show that treatment with seclidemstat, or seclidemstat analog, modulates EWS/ETS transcriptional activity, down-regulating oncogene expression and up-regulating tumor-suppressor gene expression. In in vivo xenograft studies (e.g., SK-N-MC, A673), mice treated with seclidemstat show significant tumor growth inhibition/regression vs the control vehicle group. Methods: This phase 1/2 clinical study of seclidemstat is being conducted in relapsed or refractory ES (NCT03600649). The trial is an open-label, non-randomized dose-escalation/dose-expansion study designed to determine the maximum tolerated dose through single-patient dose escalation followed by traditional 3+3 design. The primary objective is to assess seclidemstat’s safety and tolerability while secondary objectives include pharmacokinetics, efficacy and exploratory pharmacodynamic markers. Patients must be ≥12 years old, have received at least 1 prior line of therapy including a prior camptothecin-based regimen, with a life expectancy > 4 months. All patients receive seclidemstat twice-daily (BID) as oral tablets until unacceptable toxicity or disease progression. Patients are followed for survival until the end of study. The trial is currently recruiting across 8 locations in the United States. Upon identification of the recommended phase 2 dose, that cohort will be expanded to enroll a total of 20 patients. Clinical trial information: NCT03600649 .

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