Current and Future Treatment Strategies for Rhabdomyosarcoma

Chen, Celine; García, Heathcliff Dorado; Scheer, Monika; Henssen, Anton

doi:10.3389/fonc.2019.01458

Cited by 122 publications

(137 citation statements)

References 187 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…3 Currently, the standard of care is multimodal and intensive, consisting of multiagent chemotherapy, radiation, and surgery. 4,5 Given the substantial morbidity and mortality of FP-RMS, there is a need for novel, translatable treatment options.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic regulator BMI1 promotes fusion-positive rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

Shields

Potlapalli

Cuya-Smith

et al. 2020

Preprint

View full text Add to dashboard Cite

Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma that continues to present significant challenges to pediatric oncology. There are two major subtypes of pediatric rhabdomyosarcoma, alveolar and embryonal. Alveolar rhabdomyosarcomas are characterized by the presence of a PAX-FOXO1 fusion protein and termed fusion-positive (FP-RMS); embryonal rhabdomyosarcomas (ERMS) lack these fusions and are termed fusion-negative (FN-RMS). Fusion-positive rhabdomyosarcoma (FP-RMS) harbors PAX-FOXO1 fusion proteinsand has a worse overall outcome compared to FN-RMS, underscoring the critical need to identify novel targets for this disease. While fusion proteins remain challenging therapeutic targets, recent studies have begun to reveal the key intersection of PAX-FOXO1 fusion proteins with the malignant epigenome, suggesting that epigenetic proteins may serve as novel targets in FP-RMS. Here, we investigate the contribution of the epigenetic regulator BMI1 to FP-RMS.We examined RNA-seq tumor datasets and determined that BMI1 is robustly expressed in FP-RMS tumors, patient derived xenografts (PDXs), and cell lines. We depleted BMI1 using RNA interference and find that this leads to a marked decrease in cell growth.Next, we used two BMI1 inhibitors, PTC-209 and PTC-028, and showed that BMI1 inhibition decreases cell cycle progression and increases apoptosis in FP-RMS cell lines. In the in vivo setting, targeting BMI1 leads to decreased tumor growth.Mechanistically, we observe that BMI1 inhibition activates the tumor suppressive Hippo pathway. Collectively, these results identify BMI1 as a novel therapeutic vulnerability in

show abstract

Section: Introductionmentioning

confidence: 99%

Epigenetic regulator BMI1 promotes fusion-positive rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

Shields

Potlapalli

Cuya-Smith

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Rhabdomyosarcoma (RMS) is a malignant tumor that can develop in any part of the body, with a primitive mesenchymal cell origin and a propensity for striated muscle differentiation [1][2][3]. It accounts for over 50% of childhood soft tissue sarcoma [4,5].…”

Section: Introductionmentioning

confidence: 99%

“…It accounts for over 50% of childhood soft tissue sarcoma [4,5]. The estimated incidence is about 4.5 cases per 1 million children and young adults aged under 20 years [2,3]. Over the last 3 decades great survival improvement has been achieved in RMS patients with 5-year overall survival (OS) exceeding 70% [2,5].…”

Section: Introductionmentioning

confidence: 99%

“…The estimated incidence is about 4.5 cases per 1 million children and young adults aged under 20 years [2,3]. Over the last 3 decades great survival improvement has been achieved in RMS patients with 5-year overall survival (OS) exceeding 70% [2,5]. And this is mainly attributed to risk strati cation-based treatment plan and multimodal treatment strategy [5].…”

Section: Introductionmentioning

confidence: 99%

“…And this is mainly attributed to risk strati cation-based treatment plan and multimodal treatment strategy [5]. But the survival of patients with relapsed and advanced disease remains poor with 5-year OS about 30% [2,5,6].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Risk Factors for Disease Progression and Prognosis Analysis in Pediatric Head and Neck Rhabdomyosarcoma Patients: a Historical Cohort Study From a Single Center

Wen¹,

Zhang²,

Zhang³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: The purposes of this study are to explore risk factors for disease progression during primary treatment, and to analyze disease prognosis of different event groups in a historical cohort of 56 pediatric patients with head and neck rhabdomyosarcoma.Methods: From June 1st, 2016 to June 30th, 2019, a historical cohort of 56 pediatric patients diagnosed as head and neck rhabdomyosarcoma was chosen. Clinical data were collected including general information about diagnosis, treatment, prognostic factors, and follow up results. Patients were divided into non-event group, disease-progression group and disease-relapse group according different types of events. Comparison among the three groups was made to reveal different clinical features and prognosis. Patients were further divided into disease-progression group and non-progression group to explore risk factors for disease progression, with univariate and multivariate analysis.Results: The median follow-up time of all 56 patients was 31.8 months (range 3.5-74.6 months). There were 30 non-event patients, 12 disease relapse patients, and 14 disease-progression patients. The estimated 5-year overall survival rates were 100.0%, 82.5%, and 11.9% for non-event, disease-relapse and disease-progression patients respectively (p<0.001). Compared with non-event patients, disease-progression patients had higher rates of tumor size>5cm (p=0.008) and non-initial radiation therapy (p=0.001). Compared with disease-relapse patients, disease-progression patients had a higher rate of tumor size>5cm (p=0.002), and higher ranks of surgical-pathologic group (p=0.009) and risk group (p<0.001). Compare with non-progression patients, univariate analysis demonstrated that tumor size>5cm, alveolar histology, non-initial radiation therapy, and higher ranks of surgical-pathologic group as well as risk group were statistically significant risk factors for disease progression. The multivariate analysis result showed tumor size>5cm (OR=6.75, 95%CIs 1.02-44.78), alveolar histology (OR=7.10, 95%CIs 1.08-46.57), and non-initial radiation therapy (OR=15.26, 95%CIs 2.38-97.70) to be independent risk factors for disease progression.Conclusions: Pediatric head and neck rhabdomyosarcoma patients with disease progression have significantly worse overall survival, and the prognosis is obviously different from patients with disease relapse and patients without events. Tumor size>5cm, alveolar histology and non-initial radiation therapy are independent risk factors for disease progression. Patients with disease progression tend to have higher ranks of surgical-pathologic group and risk group.

show abstract

Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

et al. 2021

View full text Add to dashboard Cite

Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma. There are two main subtypes of RMS, alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma. ARMS typically encompasses fusion-positive rhabdomyosarcoma, which expresses either PAX3-FOXO1 or PAX7-FOXO1 fusion proteins. There are no targeted therapies for ARMS; however, recent studies have begun to illustrate the cooperation between epigenetic proteins and the PAX3-FOXO1 fusion, indicating that epigenetic proteins may serve as targets in ARMS. Here, we investigate the contribution of BMI1, given the established role of this epigenetic regulator in sustaining aggression in cancer. We determined that BMI1 is expressed across ARMS tumors, patient-derived xenografts, and cell lines. We depleted BMI1 using RNAi and inhibitors (PTC-209 and PTC-028) and found that this leads to a decrease in cell growth/increase in apoptosis in vitro, and delays tumor growth in vivo. Our data suggest that BMI1 inhibition activates the Hippo pathway via phosphorylation of LATS1/2 and subsequent reduction in YAP levels and YAP/TAZ target genes. These results identify BMI1 as a potential therapeutic vulnerability in ARMS and warrant further investigation of BMI1 in ARMS and other sarcomas.

show abstract

Current and Future Treatment Strategies for Rhabdomyosarcoma

Cited by 122 publications

References 187 publications

Epigenetic regulator BMI1 promotes fusion-positive rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

Epigenetic regulator BMI1 promotes fusion-positive rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

Risk Factors for Disease Progression and Prognosis Analysis in Pediatric Head and Neck Rhabdomyosarcoma Patients: a Historical Cohort Study From a Single Center

Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

Contact Info

Product

Resources

About