Abstract 1481: DAY101, a potent pan-RAF inhibitor with activity in preclinical models harboring MAPK pathway alterations beyond BRAF V600E mutation

2021 ◽  
Author(s):  
Eleni Venetsanakos ◽  
Mike Preigh ◽  
Jeannie Hou ◽  
Michael C. Cox ◽  
Jeremy Bender ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Preclinical Models

Treatment of a BRAF V600E Positive Ameloblastoma in a Pediatric Patient with MEK Inhibitor Monotherapy

FACE ◽  
2021 ◽  
pp. 273250162110051
Author(s):  
Steven Daws ◽  
Kongkrit Chaiyasate ◽  
Arshi Lehal
Keyword(s):  
Mapk Pathway ◽  
Case Reports ◽  
Radical Resection ◽  
Mek Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Targeted Chemotherapy ◽  
Odontogenic Epithelium ◽  
Genetic Landscape ◽  
Frequent Presence

Ameloblastomas are uncommon tumors of the odontogenic epithelium standardly treated with radical resection. Recent studies of the genetic landscape of ameloblastoma have revealed the frequent presence of the BRAF V600E mutation, suggesting a possible role for targeted chemotherapy. We present the case of a primary mandibular ameloblastoma found in a 13-year-old female with confirmed BRAF V600E mutation. Prior to invasive surgical intervention she was treated for 8 weeks with the MEK inhibitor trametinib, but her tumor demonstrated little radiographic, clinical, or histologic response. Previous case reports have shown ameloblastoma in adult patients to be responsive to other agents targeting the MAPK pathway. Our observations in the presented case demonstrate the need for further research into the utility of targeted chemotherapy in ameloblastoma treatment.

Polymorphous Low-Grade Neuroepithelial Tumor of the Young (PLNTY): Molecular Profiling Confirms Frequent MAPK Pathway Activation

2021 ◽  
Author(s):  
Cristiane M Ida ◽  
Derek R Johnson ◽  
Asha A Nair ◽  
Jaime Davila ◽  
Thomas M Kollmeyer ◽  
...  
Keyword(s):  
Copy Number ◽  
Mapk Pathway ◽  
Braf V600e Mutation ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Low Grade ◽  
Pathway Activation ◽  
Mitogen Activated Protein ◽  
Copy Number Changes ◽  
Cd34 Expression

Abstract Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and frequent mitogen-activated protein kinase (MAPK) pathway activation. We molecularly profiled 13 cases with diagnostic histopathological features of PLNTY (10 female; median age, 16 years; range, 5–52). Patients frequently presented with seizures (9 of 12 with available history) and temporal lobe tumors (9 of 13). MAPK pathway activating alterations were identified in all 13 cases. Fusions were present in the 7 youngest patients: FGFR2-CTNNA3 (n = 2), FGFR2-KIAA1598 (FGFR2-SHTN1) (n = 1), FGFR2-INA (n = 1), FGFR2-MPRIP (n = 1), QKI-NTRK2 (n = 1), and KIAA1549-BRAF (n = 1). BRAF V600E mutation was present in 6 patients (17 years or older). Two fusion-positive cases additionally harbored TP53/RB1 abnormalities suggesting biallelic inactivation. Copy number changes predominantly involving whole chromosomes were observed in all 10 evaluated cases, with losses of chromosome 10q occurring with FGFR2-KIAA1598 (SHTN1)/CTNNA3 fusions. The KIAA1549-BRAF and QKI-NTRK2 fusions were associated respectively with a 7q34 deletion and 9q21 duplication. This study shows that despite its name, PLNTY also occurs in older adults, who frequently show BRAF V600E mutation. It also expands the spectrum of the MAPK pathway activating alterations associated with PLNTY and demonstrates recurrent chromosomal copy number changes consistent with chromosomal instability.

scholarly journals RARE-32. POLYMORPHOUS LOW-GRADE NEUROEPITHELIAL TUMOR OF THE YOUNG (PLNTY): GENETIC ANALYSIS CONFIRMS FREQUENT MAPK PATHWAY ACTIVATION

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi228-vi228
Author(s):  
Cristiane Ida ◽  
Derek Johnson ◽  
Thomas Kollmeyer ◽  
DongKun Kim ◽  
Timothy Kaufmann ◽  
...  
Keyword(s):  
Pilocytic Astrocytoma ◽  
Mapk Pathway ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Chromosome 17 ◽  
Chromosomal Microarray ◽  
Low Grade ◽  
Fusion Event ◽  
Dna And Rna ◽  
Pathway Activation

Abstract Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and genetic MAPK pathway activation through alterations such as BRAF V600E mutation, and FGFR2-KIAA1598/CTNNA3 and FGFR3-TACC3 fusions. We report the molecular profiling of PLNTY in 9 patients, 7 female: 2 male, median age at diagnosis of 16 years (range, 5–34). All tumors were supratentorial with diagnostic morphological features of PLNTY including oligodendroglioma-like areas and strong diffuse CD34 immunostaining. Four (of 9; 44%) tumors were positive for BRAF V600E immunostain, indicating the presence of a BRAF V600E mutation. The 6 cases evaluated for IDH status were negative by IDH1-R132H immunostain (n=5; 3 BRAF V600E-negative and 2 BRAF V600E-positive) or by NGS (n=1; BRAF V600E-negative). Oncoscan chromosomal microarray performed in 5 BRAF V600E-negative tumors showed recurrent copy number changes including gain of whole chromosomes 5, 7, 8, 9, 12, 18, 19, 20, 21 and X, and loss of chromosomes 1, 2, 10q, 13, 22 and Xq. The 10q losses (n=2) were highly suggestive of an FGFR2-KIAA1598 and of a potentially novel FGFR2 underlying fusion event in one case each. Custom targeted neuro-oncology DNA and RNA NGS panel performed in 2 cases revealed a fusion similar to fusions previously reported in pilocytic astrocytoma: one with a KIAA1549-BRAF (exon 15-exon 9) fusion associated with a 7q34 ~785 kilobase deletion rather than the characteristic ~2 megabase duplication seen in pilocytic astrocytoma, and another with a QKI-NTRK2 (exon 6-exon 15) fusion associated with a 9q21 ~191 kilobase duplication disrupting NTRK2. The KIAA1549-BRAF fusion-positive case also had a TP53 mutation with loss of whole chromosome 17, suggesting TP53 complete inactivation. This study confirms that PLNTY is a low-grade neuroepithelial tumor with frequent MAPK pathway activation and expands the spectrum of MAPK activating alterations observed in PLNTY.

scholarly journals BRAF Rearrangements and BRAF V600E Mutations Are Seen in a Subset of Pancreatic Carcinomas With Acinar Differentiation

2021 ◽  
Author(s):  
Toshi Ghosh ◽  
Patricia T. Greipp ◽  
Darlene Knutson; ◽  
Sara Kloft-Nelson; ◽  
Sarah Jenkins ◽  
...  
Keyword(s):  
Overall Survival ◽  
In Situ Hybridization ◽  
Mapk Pathway ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Genomic Profiling ◽  
Clinicopathologic Features ◽  
Comprehensive Genomic Profiling

Context.— Comprehensive genomic profiling has demonstrated that approximately 20% of pancreatic carcinomas with acinar differentiation harbor potentially targetable BRAF fusions that activate the MAPK pathway. Objectives.— To validate the above finding by BRAF break-apart fluorescence in situ hybridization (FISH) in a large series of pure acinar cell carcinomas (ACCs), evaluate tumors for the presence of BRAF V600E mutations, and compare clinicopathologic features of tumors with BRAF rearrangements with those without. Design.— Thirty cases of pure ACC and 6 cases of mixed acinar-neuroendocrine carcinoma (ACC-NEC) were retrieved. A break-apart FISH probe was used to detect BRAF rearrangements. Immunohistochemistry for BRAF V600E was performed. Results.— BRAF rearrangements by FISH were found in 6 of 36 cases (17%), 5 of which were pure ACC and 1 was a mixed ACC-NEC. Follow-up was available in 29 of 36 (81%). The median survival was 22 months for BRAF-rearranged cases and 16 months for BRAF-intact cases; the 2-year overall survival was 50% for BRAF-rearranged cases and 35% for BRAF-intact cases. No significant clinicopathologic differences were identified in cases with BRAF rearrangement compared with those without BRAF rearrangement. BRAF V600E mutation was identified in 2 of 34 cases (6%), both of which were pure ACC and were BRAF-intact by FISH. Conclusions.— This study supports the finding that BRAF rearrangements are present in approximately 20% of cases and identified BRAF V600E mutations in approximately 5% of cases. These cases may benefit from targeted therapy.

scholarly journals Mutation in BRAF and Other Members of the MAPK Pathway in Papillary Thyroid Carcinoma in the Pediatric Population

2016 ◽  
Vol 140 (2) ◽  
pp. 134-139 ◽  
Author(s):  
Ryan J. Gertz ◽  
Yuri Nikiforov ◽  
William Rehrauer ◽  
Lee McDaniel ◽  
Ricardo V. Lloyd
Keyword(s):  
Polymerase Chain Reaction ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Mapk Pathway ◽  
Pediatric Population ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Papillary Thyroid ◽  
Chain Reaction ◽  
Polymerase Chain

Context Papillary thyroid carcinoma (PTC) is an uncommon tumor in the pediatric population. A limited number of studies have examined genetic mutations affecting the mitogen-activated protein kinase (MAPK) pathway in the pediatric population. Objective To examine mutations affecting this pathway in PTC in our pediatric population and compare the BRAF V600E mutation rates in pediatric and adult tumors. Design Eighty-four patients, including 14 pediatric and 70 adult, with PTC were tested for the BRAF V600E mutation by using real-time polymerase chain reaction and sequencing. Additionally, we examined the rate of RAS point mutations with real-time polymerase chain reaction and rearrangements of RET/PTC1 and RET/PTC3 in the pediatric group with fluorescence in situ hybridization. Clinical and histologic data were compared as well. Results Of 77 tumors that had an interpretable result, the BRAF V600E mutant was identified in 4 of 13 pediatric patients (31%) and 43 of 64 adult patients (67%), which was a significant difference (using Fisher exact test, P = .03). One pediatric and 6 adult cases did not reveal an interpretable result with melting curve analysis. One of these cases harbored a rare 3–base pair deletion mutation (c.1799_1801delTGA). Mutations in RAS genes were not seen in any pediatric tumors. One tumor with a RET/PTC1 rearrangement and another with RET/PTC3 were identified in the pediatric population (15%). Conclusions The rate of the BRAF V600E mutation in the pediatric population is significantly lower than that seen in the adult population. Mutations in RAS do not contribute significantly to pediatric PTC. This experience from our institution adds to the growing body of knowledge regarding tumor genetics in pediatric PTC.

scholarly journals BRAF Mutations in Low-Grade Serous Ovarian Cancer and Response to BRAF Inhibition

2018 ◽  
pp. 1-14 ◽  
Author(s):  
Tania Moujaber ◽  
Dariush Etemadmoghadam ◽  
Catherine J. Kennedy ◽  
Yoke-Eng Chiew ◽  
Rosemary L. Balleine ◽  
...  
Keyword(s):  
Braf Mutation ◽  
Mapk Pathway ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Targeted Treatment ◽  
Ca 125 ◽  
Low Grade ◽  
Tumor Type ◽  
Braf Inhibitors ◽  
Braf Mutations

Purpose Low-grade serous ovarian carcinoma (LGSC) responds poorly to chemotherapy and is characterized by activating mutations in the Ras sarcoma–mitogen-activated protein kinase (RAS-MAPK) pathway, including oncogenic BRAF. However, response to BRAF inhibitors is tumor-type specific. Significant improvement in survival is seen in patients with BRAF-mutant melanoma, but other cancer types, such as colorectal cancers, are generally less sensitive. We examined the frequency and characteristics of BRAF-mutated LGSC and described the response to treatment with BRAF inhibitors. Patients and Methods Mutations were assessed in LGSC (N = 65) by using targeted, exome, and whole-genome sequencing. Patient characteristics, treatment, and clinical outcome were assessed, and the median follow-up time was more than 5 years. BRAF inhibitors were trialed in two patients with a somatic BRAF V600E mutation: one patient received dabrafenib monotherapy and was monitored clinically, biochemically (cancer antigen [CA]-125 levels), and with positron emission tomography (PET) imaging. Expression of the BRAF V600E protein in this patient was assessed by immunohistochemistry. Results Among patients with LGSC, nine (13.8%) of 65 had a somatic BRAF mutation. Of the nine patients with BRAF mutation–positive LGSC, four experienced progressive disease that did not respond to conventional chemotherapy. Two of the patients experienced progression quickly and died as a result of disease progression, and two received targeted treatment. Two patients with BRAF V600E mutation received BRAF inhibitors at relapse and both achieved durable responses. Conclusion BRAF mutations are not uncommon in patients with LGSC and should be routinely tested, because BRAF inhibitors can be an effective treatment for these patients. The results highlight the need for targeted treatment in this rare tumor type, and a prospective study is needed to formally assess the response rate and clinical benefit.

scholarly journals CS-03 BRAF V600E mutation mediates FDG-methionine uptake mismatch in polymorphous low-grade neuroepithelial tumor of the young

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii20-ii20
Author(s):  
Takahiro Hayashi ◽  
Kensuke Tateishi ◽  
Naoki Ikegaya ◽  
Naoko Udaka ◽  
Jo Sasame ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Positron Emission Tomography Imaging ◽  
Mapk Signaling ◽  
Braf V600e Mutation ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Low Grade ◽  
Protein Levels ◽  
Positron Emission ◽  
Methionine Uptake

Abstract We present a case of a 14-year old boy with tumor-associated refractory epilepsy. Positron emission tomography imaging demonstrated a region with heterogeneous high 11 C-methionine uptake and a region with homogenous low 18 F- fluorodeoxyglucose uptake within the tumor. Histopathological and genomic analyses confirmed the tumor as BRAF V600E-mutated PLNTY (polymorphous low-grade neuroepithelial tumor of the young). Within the high-methionine-uptake region, we observed increased protein levels of L-type amino acid transporter 1 (LAT1) and constituents of the mitogen-activated protein kinase (MAPK) pathway. We also found that LAT1 expression was linked to BRAF V600E mutation and subsequent activation of MAPK signaling. Pharmacological inhibition of the MAPK pathway suppressed LAT1 expression and cell viability in PLNTY cells. Collectively, our results indicate that BRAF V600E mutation-activated MAPK signaling induces specific metabolic alterations in PLNTY, and may represent an attractive target in the treatment of the disease.

Therapie des BRAF-mutierten NSCLC

2018 ◽  
Vol 09 (05) ◽  
pp. 239-239
Author(s):  
Dr. Susanne Krome
Keyword(s):  
Phase Ii ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Alk Rearrangement

BRAF-mutierte nicht kleinzellige Bronchialkarzinome (NSCLC) sind besonders aggressiv. Gezielte Antikörpertherapien verbesserten die Behandlungsergebnisse. Bei einem ALK-Rearrangement ging eine lange progressionsfreie Zeit nicht zu Lasten der Post-Progressionsphase. Die Sekundäranalyse einer nicht randomisierten Phase-II-Studie zeigt dies nun auch für Patienten mit einer BRAF-V600E-Mutation.

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