BRAF V600E-mutated metastatic pediatric Wilms tumor with complete response to targeted RAF/MEK inhibition

Obasaju, Patience; Shahab, Shubin; Dunn, Emily; Rhee, Daniel S.; Jiang, Liqun; Dome, Jeffrey S.; Friedman, Alan D.; Argani, Pedram; Pratilas, Christine A.

doi:10.1101/mcs.a004820

Cited by 5 publications

(4 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a phase 2 trial (ClinicalTrials.gov identifier: NCT02684058), dabrafenib plus trametinib improved the ORR and prolonged PFS compared to standard chemotherapy in 110 pediatric patients (aged 1-17 years) with BRAFV600-mutant LGG 31 . There are also case reports of the pediatric population benefiting with dabrafenib plus trametinib in the treatment of BRAF mutation-positive glioblastoma and gliomas [32][33][34] , pancreatic acinar cell carcinoma 35 and Wilms tumor 36 .…”

Section: Discussionmentioning

confidence: 99%

Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial

Subbiah

Kreitman

Wainberg

et al. 2023

Nat Med

View full text Add to dashboard Cite

BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110.

show abstract

Section: Discussionmentioning

confidence: 99%

Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial

Subbiah

Kreitman

Wainberg

et al. 2023

Nat Med

View full text Add to dashboard Cite

show abstract

“…The mTOR pathway is a signal regulatory system that performs a variety of important biological functions [17,18]. Recently, the mTOR pathway has been shown to be associated with various cancer processes [19,20], and genes in this pathway, such as PTEN and BRAF1, also function in the process of Wilms' tumor [21,22]. We demonstrated by MeRIP-qPCR that ve m6A-modi ed genes in the mTOR pathway (STK11, CAB39L, AKT1S1, EIF4E2, and PTEN) were hypomethylated in the WT group compared with the NC group, and the mRNA levels of AKT1S1 and EIF4E2 were upregulated in the WT group.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide screening of m6A-modified transcript in the Wilms’ tumor

Liu

et al. 2021

Preprint

View full text Add to dashboard Cite

Background Wilms’ tumor, also called nephroblastoma, is the most common pediatric renal malignancy. The pathogenesis of Wilms’ tumor has been attributed to several genetic and epigenetic factors. However, the most pervasive internal mRNA modification that affects almost every process of RNA metabolism, RNA N6-Methyladenosine (m6A) methylation, has not been characterized in Wilms’ tumor. Methods Wilms’ tumor (WT) and adjacent non-cancerous (NC) tissue samples were obtained from 23 children with nephroblastoma, and the global m6A levels were measured by mass spectrometry. Analyses by m6A-mRNA epitranscriptomic microarray and mRNA microarray were performed, and m6A-related mRNAs were validated by quantitative real-time PCR for input and m6A-immunoprecipitated RNA samples from WT and NC tissues. Gene ontology analysis and KEGG pathway analysis were performed for differentially expressed genes, and expression of RNA methylation-related factors was measured by quantitative real-time PCR. Results The total m6A methylation levels in total RNA of WT samples and NC samples were (0.21 ± 0.01)% and (0.22 ± 0.01)%, respectively, with no statistically significant difference. Fifty-nine transcripts were differentially m6A-methylated between the WT and NC groups, which showed distinct m6A modification patterns. Gene ontology analysis indicated that m6A-modified genes were enriched in cancer-associated pathways, including the mTOR pathway, and conjoint analysis of the unique methylation and gene expression patterns in WT samples suggested an association with metabolic pathways.The mRNA levels of the m6A-related “reader” genes, YTHDF1, YTHDF2 and IGF2BP3, were statistically higher in WT samples than in NC samples. Conclusion This is the first study to determine the m6A modification profiles in Wilms’ tumor. Our data provide novel information regarding patterns of m6A modification that correlate with carcinogenesis in Wilms’ tumor.

show abstract

“…Along these lines, in a recent study, our group found that a subset of Wilms tumors with areas morphologically resembling metanephric adenoma harbored BRAF V600E mutations that are typical of metanephric adenoma15 and not previously found in Wilms tumor 16. One pediatric patient with metastatic disease had a complete response to combined targeted RAF/MEK inhibitors dabrafenib and trametinib 16,17. While these cases were identified based on morphologic features, 2 of the 4 cases occurred in adults, raising the possibility that BRAF V600E mutations may be more frequent in adult Wilms tumors.…”

mentioning

confidence: 90%

“…16 One pediatric patient with metastatic disease had a complete response to combined targeted RAF/MEK inhibitors dabrafenib and trametinib. 16,17 While these cases were identified based on morphologic features, 2 of the 4 cases occurred in adults, raising the possibility that BRAF V600E mutations may be more frequent in adult Wilms tumors. In the current study, we perform a more comprehensive genetic analysis of 14 adult Wilms tumors, including expanded targeted sequencing of 11 of these cases.…”

mentioning

confidence: 99%

Adult Wilms Tumor

Argani¹,

Tickoo

Matoso

et al. 2022

American Journal of Surgical Pathology

Self Cite

View full text Add to dashboard Cite

The genetics of nephroblastoma (Wilms tumor) occurring in adults is largely unknown, as studies have largely been limited to isolated case reports. We, therefore, studied 14 adult Wilms tumors for genetic alterations, using expanded targeted sequencing on 11 cases. The patients ranged from 17 to 46 years of age (mean and median, 31 y), and there were 8 males and 6 females. Five Wilms tumors harbored BRAF V600E mutations. All of these had better-differentiated areas identical to metanephric adenoma, as has previously been described. In 3 such cases, microdissection studies revealed that the BRAF V600E mutation was present in both the metanephric adenoma and Wilms tumor areas; however, additional genetic alterations (including TERT promoter mutations in 2 cases, ASLX1/ATR mutations in 1 other case) were limited to the Wilms tumor component. These findings suggest that the Wilms tumor developed from the metanephric adenoma. Other adult Wilms tumors harbored genetic alterations previously reported in the more common pediatric Wilms tumors, including WT1 mutations (2 cases), ASLX1 mutations (3 additional cases), NSD2 mutation (1 additional case), and 11p loss (3 cases). In summary, a significant subset of adult Wilms tumors (specifically those of epithelial type with differentiated areas) harbor targetable BRAF V600E mutations and appear to arise from metanephric adenomas as a consequence of additional acquired genetic alterations. Other adult Wilms tumors often harbor genetic alterations found in their more common pediatric counterparts, suggesting at least some similarities in their pathogenesis.

show abstract

BRAF V600E-mutated metastatic pediatric Wilms tumor with complete response to targeted RAF/MEK inhibition

Cited by 5 publications

References 50 publications

Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial

Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial

Genome-wide screening of m6A-modified transcript in the Wilms’ tumor

Adult Wilms Tumor

Contact Info

Product

Resources

About