Feasibility of CSF (Cerebrospinal Fluid) and Plasma ctDNA (Circulating Tumor Deoxyribonucleic) in BRAF (V-raf Murine Sarcoma Viral Oncogene Homolog B1)-Altered Glioma During Treatment With Plixorafenib

Evaluating the sensitivity and feasibility of using ctDNA assays optimized for detecting very low ctDNA counts from cerebrospinal fluid (CSF) and plasma. The investigators will evaluate the sensitivity of ctDNA from plasma and CSF at baseline (defined as Cycle1 Day1 (C1D1) pre-treatment) and over time in response to treatment with plixorafenib co-administered with cobicistat in BRAF-V600E mutant glioma refractory to prior therapies.

Start Date10 Jan 2025

Sponsor / Collaborator

The Sidney Kimmel Comprehensive Cancer Center

[+2]

NCT06159478

/ RecruitingPhase 2IIT

Phase II Investigator-initiated Trial of Binimetinib in Patients With BRAF Fusion-positive Low-grade Glioma or Pancreatic Cancer (Perfume)

This study is an open-label, parallel, 2-cohort, multicenter, investigator-initiated Phase 2 trial to evaluate the efficacy and safety of binimetinib in patients with advanced or recurrent low-grade glioma or pancreatic cancer harboring BRAF fusion/rearrangement.

Start Date29 Mar 2023

Sponsor / Collaborator

National Cancer Center

[+1]

NCT04985604

/ Active, not recruitingPhase 1/2

A Phase 1b/2, Open Label Study of DAY101 Monotherapy or Combination With Other Therapies for Patients With Recurrent, Progressive, or Refractory Solid Tumors Harboring MAPK Pathway Aberrations

This is a Phase 1b/2, multi-center, open label umbrella study of patients ≥12 years of age with recurrent, progressive, or refractory melanoma or other solid tumors with alterations in the key proteins of the RAS/RAF/MEK/ERK pathway, referred to as the MAPK pathway.

Start Date15 Jul 2021

Sponsor / Collaborator

Day One Biopharmaceuticals, Inc.

100 Clinical Results associated with BRAF Fusion Glioma

100 Translational Medicine associated with BRAF Fusion Glioma

0 Patents (Medical) associated with BRAF Fusion Glioma

Literatures (Medical) associated with BRAF Fusion Glioma

01 Oct 2024·Journal of Clinical Investigation

Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF fusion pilocytic astrocytoma

Article

Author: Sooreshjani, Moloud ; Rao, Ganesh ; Lukas, Rimas V ; Du, Ruochen ; DeCuypere, Michael ; Nicolaides, Theodore P ; Sonabend, Adam M ; Wadhwani, Nitin R ; Lam, Sandi K ; Najem, Hinda ; Horbinski, Craig M ; Dussold, Corey ; Lopez, Giselle ; Castro, Maria G ; Brown, Valerie ; Stupp, Roger ; Xiu, Joanne ; Chandler, James P ; Tripathi, Shashwat ; Hurley, Lisa ; James, Charles David ; Pacheco, Sebastian ; Heimberger, Amy B

Despite being the leading cause of cancer-related childhood mortality, pediatric gliomas have been relatively understudied, and the repurposing of immunotherapies has not been successful. Whole-transcriptome sequencing, single-cell sequencing, and sequential multiplex immunofluorescence were used to identify an immunotherapeutic strategy that could be applied to multiple preclinical glioma models. MAPK-driven pediatric gliomas have a higher IFN signature relative to other molecular subgroups. Single-cell sequencing identified an activated and cytotoxic microglia (MG) population designated MG-Act in BRAF-fused, MAPK-activated pilocytic astrocytoma (PA), but not in high-grade gliomas or normal brain. T cell immunoglobulin and mucin domain 3 (TIM3) was expressed on MG-Act and on the myeloid cells lining the tumor vasculature but not normal brain vasculature. TIM3 expression became upregulated on immune cells in the PA microenvironment, and anti-TIM3 reprogrammed ex vivo immune cells from human PAs to a proinflammatory cytotoxic phenotype. In a genetically engineered murine model of MAPK-driven, low-grade gliomas, anti-TIM3 treatment increased median survival over IgG- and anti-PD-1-treated mice. Single-cell RNA-Seq data during the therapeutic window of anti-TIM3 revealed enrichment of the MG-Act population. The therapeutic activity of anti-TIM3 was abrogated in mice on the CX3CR1 MG-KO background. These data support the use of anti-TIM3 in clinical trials of pediatric low-grade, MAPK-driven gliomas.

01 Jan 2022·The Lancet Oncology

Targeting BRAF-mutant glioma: reflections on the ROAR trial

Article

Author: Peters, Katherine B

A review.In The Lancet Oncol., Patrick Y Wen and colleagues present interim results from the Rare Oncol. Agnostic Research (ROAR) study, an ongoing phase 2, open-label, single-arm, multicenter basket trial of targeted therapies in BRAF-mutant cancers, showing pos. results for dabrafenib plus trametinib in patients with high-grade glioma and low-grade glioma.In this study, Wen and colleagues used a combinatorial approach to target the MAPK pathway in adult gliomas with BRAF V600E mutations.Patients were given dabrafenib (an oral BRAF inhibitor) and trametinib (an oral MEK inhibitor), and the primary endpoint was the objective response rate by Response Assessment in Neuro-Oncol. criteria.Median overall survival in the high-grade glioma patients was 17. 6 mo (95% CI 9·5-45·2), with a median overall survival of 13. 7 mo (8·4-25·6) when one considers only the 31 patients with glioblastoma.Monotherapy studies involving inhibition of the MAPK pathway, similarly designed as basket studies, have shown activity in patients with BRAF mutations.Results from the glioma cohort of the ROAR trial support the updated WHO recommendations for the classification of CNS tumors.The study by Wen and colleagues represents a paradigm shift in thoughtfully integrating targeted therapies into care of patients with glioma.Evidence and experience on combination MEK plus ERK inhibition for adults and pediatric patients with BRAF-mutant gliomas and other rather brain tumors is much needed.

01 Jun 2021·Endocrine-Related CancerQ2 · MEDICINE

Co-inhibition of SMAD and MAPK signaling enhances 124I uptake in BRAF-mutant thyroid cancers

Q2 · MEDICINE

Article

Author: Leach, Steven D ; Fagin, James A ; Nagarajah, James ; Luckett, Kathleen A ; Knauf, Jeffrey A ; Saqcena, Mahesh ; Ho, Alan L ; Cracchiolo, Jennifer R ; Lowe, Scott W ; Krishnamoorthy, Gnana P ; Leandro-Garcia, Luis Javier ; Im, Soo Y ; de Stanchina, Elisa ; Zhao, Zhen ; Lester, Rona ; Sherman, Eric J

Constitutive MAPK activation silences genes required for iodide uptake and thyroid hormone biosynthesis in thyroid follicular cells. Accordingly, most BRAFV600E papillary thyroid cancers (PTC) are refractory to radioiodide (RAI) therapy. MAPK pathway inhibitors rescue thyroid-differentiated properties and RAI responsiveness in mice and patient subsets with BRAFV600E-mutant PTC. TGFB1 also impairs thyroid differentiation and has been proposed to mediate the effects of mutant BRAF. We generated a mouse model of BRAFV600E-PTC with thyroid-specific knockout of the Tgfbr1 gene to investigate the role of TGFB1 on thyroid-differentiated gene expression and RAI uptake in vivo. Despite appropriate loss of Tgfbr1, pSMAD levels remained high, indicating that ligands other than TGFB1 were engaging in this pathway. The activin ligand subunits Inhba and Inhbb were found to be overexpressed in BRAFV600E-mutant thyroid cancers. Treatment with follistatin, a potent inhibitor of activin, or vactosertib, which inhibits both TGFBR1 and the activin type I receptor ALK4, induced a profound inhibition of pSMAD in BRAFV600E-PTCs. Blocking SMAD signaling alone was insufficient to enhance iodide uptake in the setting of constitutive MAPK activation. However, combination treatment with either follistatin or vactosertib and the MEK inhibitor CKI increased 124I uptake compared to CKI alone. In summary, activin family ligands converge to induce pSMAD in Braf-mutant PTCs. Dedifferentiation of BRAFV600E-PTCs cannot be ascribed primarily to activation of SMAD. However, targeting TGFβ/activin-induced pSMAD augmented MAPK inhibitor effects on iodine incorporation into BRAF tumor cells, indicating that these two pathways exert interdependent effects on the differentiation state of thyroid cancer cells.

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