Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Prioritization of Novel Agents for Patients with Rhabdomyosarcoma: A Report from the Children's Oncology Group (COG) New Agents for Rhabdomyosarcoma Task Force.

ABSTRACT: Rhabdomyosarcoma is the most common soft tissue sarcoma diagnosed in children and adolescents. Patients that are diagnosed with advanced or relapsed disease have exceptionally poor outcomes. The Children's Oncology Group (COG) convened a rhabdomyosarcoma new agent task force in 2020 to systematically evaluate novel agents for inclusion in phase 2 or phase 3 clinical trials for patients diagnosed with rhabdomyosarcoma, following a similar effort for Ewing sarcoma. The task force was comprised of clinicians and basic scientists who collectively identified new agents for evaluation and prioritization in clinical trial testing. Here, we report the work of the task force including the framework upon which the decisions were rendered and review the top classes of agents that were discussed. Representative agents include poly-ADP-ribose polymerase (PARP) inhibitors in combination with cytotoxic agents, mitogen-activated protein kinase (MEK) inhibitors in combination with type 1 insulin-like growth factor receptor (IGFR1) inhibitors, histone deacetylase (HDAC) inhibitors, and novel cytotoxic agents.

SUBMITTER: Pacenta HL

PROVIDER: S-EPMC8037615 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Emerging novel agents for patients with advanced Ewing sarcoma: a report from the Children's Oncology Group (COG) New Agents for Ewing Sarcoma Task Force.

Project description:Ewing sarcoma is a small round blue cell malignancy arising from bone or soft tissue and most commonly affects adolescents and young adults. Metastatic and relapsed Ewing sarcoma have poor outcomes and recurrences remain common. Owing to the poor outcomes associated with advanced disease and the need for a clear research strategy, the Children's Oncology Group Bone Tumor Committee formed the New Agents for Ewing Sarcoma Task Force to bring together experts in the field to evaluate and prioritize new agents for incorporation into clinical trials. This group's mission was to evaluate scientific and clinical challenges in moving new agents forward and to recommend agents and trial designs to the Bone Tumor Committee. The task force generated a framework for vetting prospective agents that included critical evaluation of each drug by using both clinical and non-clinical parameters. Representative appraisal of agents of highest priority, including eribulin, dinutuximab, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, anti-angiogenic tyrosine kinase inhibitors, and poly-ADP-ribose polymerase (PARP) inhibitors, is described. The task force continues to analyze new compounds by using the paradigm established.

| S-EPMC6468706 | biostudies-literature

Charting a path for prioritization of novel agents for clinical trials in osteosarcoma: A report from the Children's Oncology Group New Agents for Osteosarcoma Task Force.

Project description:Osteosarcoma is the most common bone tumor in children and young adults. Metastatic and relapsed disease confer poor prognosis, and there have been no improvements in outcomes for several decades. The disease's biological complexity, lack of drugs developed specifically for osteosarcoma, imperfect preclinical models, and limits of existing clinical trial designs have contributed to lack of progress. The Children's Oncology Group Bone Tumor Committee established the New Agents for Osteosarcoma Task Force to identify and prioritize agents for inclusion in clinical trials. The group identified multitargeted tyrosine kinase inhibitors, immunotherapies targeting B7-H3, CD47-SIRPα inhibitors, telaglenastat, and epigenetic modifiers as the top agents of interest. Only multitargeted tyrosine kinase inhibitors met all criteria for frontline evaluation and have already been incorporated into an upcoming phase III study concept. The task force will continue to reassess identified agents of interest as new data become available and evaluate novel agents using this method.

| S-EPMC8316376 | biostudies-literature

Imaging in childhood cancer: a Society for Pediatric Radiology and Children's Oncology Group Joint Task Force report.

Project description:Contemporary medical imaging is a cornerstone of care for children with cancer. As 5-year survival rates for children with cancer exceed 80%, imaging technologies have evolved in parallel to include a wide array of modalities. Here, we overview the risks and benefits associated with commonly used imaging modalities and survey the current landscape of medical imaging for children with cancer. We find evidence-based imaging guidelines to assist in protocol development and to guide decision-making for optimal patient care are often lacking. The substantial variation in protocol-based recommendations for imaging both during and following therapy may hinder optimal clinical research and clinical care for children with cancer.

| S-EPMC4636336 | biostudies-literature

Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group.

Project description:BackgroundSeveral cancer-susceptibility syndromes are reported to underlie pediatric rhabdomyosarcoma (RMS); however, to our knowledge there have been no systematic efforts to characterize the heterogeneous genetic etiologies of this often-fatal malignancy.MethodsWe performed exome-sequencing on germline DNA from 615 patients with newly diagnosed RMS consented through the Children's Oncology Group. We compared the prevalence of cancer predisposition variants in 63 autosomal-dominant cancer predisposition genes in these patients with population controls (n = 9963). All statistical tests were 2-sided.ResultsWe identified germline cancer predisposition variants in 45 RMS patients (7.3%; all FOXO1 fusion negative) across 15 autosomal dominant genes, which was statistically significantly enriched compared with controls (1.4%, P = 1.3 × 10-22). Specifically, 73.3% of the predisposition variants were found in predisposition syndrome genes previously associated with pediatric RMS risk, such as Li-Fraumeni syndrome (TP53) and neurofibromatosis type I (NF1). Notably, 5 patients had well-described oncogenic missense variants in HRAS (p.G12V and p.G12S) associated with Costello syndrome. Also, genetic etiology differed with histology, as germline variants were more frequent in embryonal vs alveolar RMS patients (10.0% vs 3.0%, P = .02). Although patients with a cancer predisposition variant tended to be younger at diagnosis (P = 9.9 × 10-4), 40.0% of germline variants were identified in those older than 3 years of age, which is in contrast to current genetic testing recommendations based on early age at diagnosis.ConclusionsThese findings demonstrate that genetic risk of RMS results from germline predisposition variants associated with a wide spectrum of cancer susceptibility syndromes. Germline genetic testing for children with RMS should be informed by RMS subtypes and not be limited to only young patients.

| S-EPMC8246828 | biostudies-literature

Germline genetic variants and pediatric rhabdomyosarcoma outcomes: a report from the Children's Oncology Group.

Project description:BackgroundRelative to other pediatric cancers, survival for rhabdomyosarcoma (RMS) has not improved in recent decades, suggesting the need to enhance risk stratification. Therefore, we conducted a genome-wide association study for event-free survival (EFS) and overall survival (OS) to identify genetic variants associated with outcomes in individuals with RMS.MethodsThe study included 920 individuals with newly diagnosed RMS who were enrolled in Children's Oncology Group protocols. To assess the association of each single nucleotide polymorphism (SNP) with EFS and OS, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards models, adjusted for clinical covariates. All statistical tests were two sided. We also performed stratified analyses by histological subtype (alveolar and embryonal RMS) and carried out sensitivity analyses of statistically significant SNPs by PAX3/7-FOXO1 fusion status and genetic ancestry group.ResultsWe identified that rs17321084 was associated with worse EFS (HR = 2.01, 95% CI = 1.59 to 2.53, P = 5.39 × 10-9) and rs10094840 was associated with worse OS (HR = 1.84, 95% CI = 1.48 to 2.27, P = 2.13 × 10-8). Using publicly available data, we found that rs17321084 lies in a binding region for transcription factors GATA2 and GATA3, and rs10094840 is associated with SPAG1 and RNF19A expression. We also identified that CTNNA3 rs2135732 (HR = 3.75, 95% CI = 2.34 to 5.99, P = 3.54 × 10-8) and MED31 rs74504320 (HR = 3.21, 95% CI = 2.12 to 4.86, P = 3.60 × 10-8) were associated with worse OS among individuals with alveolar RMS.ConclusionsWe demonstrated that common germline variants are associated with EFS and OS among individuals with RMS. Additional replication and investigation of these SNP effects may further support their consideration in risk stratification protocols.

| S-EPMC10248851 | biostudies-literature

Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: A report from the Children's Oncology Group.

Project description:Distinguishing alveolar rhabdomyosarcoma (ARMS) from embryonal rhabdomyosarcoma (ERMS) has historically been of prognostic and therapeutic importance. However, classification has been complicated by shifting histologic criteria required for an ARMS diagnosis. Children's Oncology Group (COG) studies after IRS-IV, which included the height of this diagnostic shift, showed both an increased number of ARMS and an increase in the proportion of fusion-negative ARMS. Following diagnostic standardization and histologic re-review of ARMS cases enrolled during this era, analysis of low-risk (D9602) and intermediate-risk (D9803) rhabdomyosarcoma (RMS) studies showed that fusion status rather than histology best predicts prognosis for patients with RMS. This analysis remains to be completed for patients with high-risk RMS.We re-reviewed cases on high-risk COG studies D9802 and ARST0431 with an enrollment diagnosis of ARMS. We compared the event-free survival (EFS) and overall survival by histology, PAX-FOXO1 fusion, and clinical risk factors (Oberlin score) for patients with metastatic RMS using the log-rank test.Histology re-review resulted in reclassification as ERMS for 12% of D9802 cases and 5% of ARST0431 cases. Fusion-negative RMS had a superior EFS to fusion-positive RMS; however, poorer outcome for metastatic RMS was most related to clinical risk factors including age, primary site, and number of metastatic sites.In contrast to low- or intermediate-risk RMS, in metastatic RMS, clinical risk factors have the most impact on patient outcome. PAX-FOXO1 fusion is more common in patients with a high Oberlin score, but fusion status is not an independent biomarker of prognosis.

| S-EPMC5647228 | biostudies-literature

The impact of chemotherapy shortages on COG and local clinical trials: a report from the Children's Oncology Group.

Project description:Oncology drug shortage is associated with increased patient adverse events and decreased enrollment on clinical trials for adult patients; however, the impact of oncology drug shortages has not been well studied in children with cancer.The Children's Oncology Group (COG) distributed a 5-item survey to 226 COG site-specific principal investigators (PI's) and 14-item survey to 161 COG pharmacists to gather data the impact of chemotherapeutic shortages on clinical trials and patient care.The response rate was 66.4% (150/226) for PI's and 29.8% (48/161) for pharmacists. COG PI's reported daunorubicin (73%), methotrexate (56%), asparaginase/PEG-asparaginase (42%), doxorubicin (26%), thiotepa (21%), and cytarabine (20%) were most commonly in shortage, while COG pharmacists reported daunorubicin (80%), methotrexate (66%), vincristine (21%), thiotepa (41%), asparaginase/PEG-asparaginase (34%), and cytarabine (34%) were most commonly in shortage over the past two years. Pharmacists were twice as likely to report a shortage compared with PI's (OR 2.1, 95% CI: 1.6-2.7, P?<?0.0001). Fifty percent (74/147) of COG PI's reported at least one patient enrolled on a clinical trial was impacted by drug shortage, and 66% (98/148) of COG PI's reported at least one patient had clinical care impacted by drug shortage.Chemotherapy shortages remain widespread across institutions, hinder clinical trials, and may contribute to adverse events in children with cancer. The increased frequency of chemotherapy shortages reported by pharmacists suggests that pharmacist efforts may mitigate negative impact chemotherapy shortages. Over half of pediatric institutions are implementing recommendations to address shortages, such as cross-institutional collaboration and center-level guidelines.

| S-EPMC4670038 | biostudies-literature

Genomic and clinical analysis of fusion gene amplification in rhabdomyosarcoma: a report from the Children's Oncology Group.

Project description:Alveolar rhabdomyosarcoma (RMS) is an aggressive pediatric cancer of the myogenic lineage with frequent chromosomal translocations involving the PAX3 or PAX7 and FOXO1 genes. Based on previous studies indicating that the fusion genes are amplified in a subset of these cancers, we conducted a comprehensive molecular and clinical investigation of these amplification events. Using oligonucleotide arrays to localize amplicons, we found that the minimal 1p36 amplicon measured 0.13 Mb and only contained PAX7 whereas the minimal 13q14 amplicon measured 0.53 Mb and contained FOXO1 and the poorly characterized LOC646982 gene. Application of a fluorescence in situ hybridization assay to over 100 fusion-positive cases revealed that the fusion gene is amplified in 93% of PAX7-FOXO1-positive and 9% of PAX3-FOXO1-positive cases. While most cells in amplified PAX7-FOXO1-positive cases contained the amplicon, only a fraction of cells in the amplified PAX3-FOXO1-positive cases contained the amplicon. Expression studies demonstrated that the fusion transcripts were generally expressed at higher levels in amplified cases, and that the PAX7-FOXO1 fusion transcript was expressed at higher levels than the PAX3-FOXO1 fusion transcript. Finally, fusion gene amplification and PAX7-FOXO1 fusion status were each associated with significantly improved outcome; a multivariate analysis demonstrated that this predictive value was independent of other standard prognostic parameters. These findings therefore provide further evidence for a novel good prognosis subset of fusion-positive RMS.

| S-EPMC3348443 | biostudies-literature

Hedgehog pathway activity in pediatric embryonal rhabdomyosarcoma and undifferentiated sarcoma: a report from the Children's Oncology Group.

Project description:BackgroundAberrant activation of the hedgehog (Hh) signaling pathway is implicated widely in both pediatric and adult malignancies. Inactivation of the Hh regulator PTCH is responsible for the Gorlin cancer predisposition syndrome. The spectrum of tumors found in Gorlin Syndrome includes basal cell carcinoma, medulloblastoma, and rarely, rhabdomyosarcoma (RMS). A previous report utilizing in situ hybridization has provided initial evidence for the expression of Hh targets GLI1 and PTCH in RMS tumors.ProcedureTo investigate the role of Hh pathway signaling in pediatric RMS and undifferentiated sarcoma (US) tumors, the expression of Hh pathway targets GLI1 and PTCH was measured. RNA was extracted from archival human tumor specimens collected from pediatric patients enrolled on Intergroup Rhabdomyosarcoma Study III and IV, and subjected to quantitative reverse transcriptase-polymerase chain reaction.ResultsExpression of GLI1 with or without PTCH was detected in substantial subsets of embryonal RMS (ERMS) and US tumors but only rarely in alveolar RMS tumors. Neither PTCH mutations nor activating SMO mutations were detected in ERMS tumors with high GLI1 expression. Microarray analysis demonstrated relative overexpression of downstream Hh targets in ERMS tumors with high or intermediate GLI1 expression. Unlike a recent report, Hh pathway activity in ERMS tumors did not correlate with a unique clinical phenotype.ConclusionsOur findings support a role for Hh pathway activation in the genesis of a subset of ERMS and US tumors. Hh signaling may represent a novel therapeutic target in affected tumors.

| S-EPMC3164386 | biostudies-literature

Molecular classification of rhabdomyosarcoma--genotypic and phenotypic determinants of diagnosis: a report from the Children's Oncology Group.

Project description:Rhabdomyosarcoma (RMS) in children occurs as two major histological subtypes, embryonal (ERMS) and alveolar (ARMS). ERMS is associated with an 11p15.5 loss of heterozygosity (LOH) and may be confused with nonmyogenic, non-RMS soft tissue sarcomas. ARMS expresses the product of a genomic translocation that fuses FOXO1 (FKHR) with either PAX3 or PAX7 (P-F); however, at least 25% of cases lack these translocations. Here, we describe a genomic-based classification scheme that is derived from the combined gene expression profiling and LOH analysis of 160 cases of RMS and non-RMS soft tissue sarcomas that is at variance with conventional histopathological schemes. We found that gene expression profiles and patterns of LOH of ARMS cases lacking P-F translocations are indistinguishable from conventional ERMS cases. A subset of tumors that has been histologically classified as RMS lack myogenic gene expression. However, classification based on gene expression is possible using as few as five genes with an estimated error rate of less than 5%. Using immunohistochemistry, we characterized two markers, HMGA2 and TFAP2ss, which facilitate the differential diagnoses of ERMS and P-F RMS, respectively, using clinical material. These objectively derived molecular classes are based solely on genomic analysis at the time of diagnosis and are highly reproducible. Adoption of these molecular criteria may offer a more clinically relevant diagnostic scheme, thus potentially improving patient management and therapeutic RMS outcomes.

| S-EPMC2630563 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data