News - PDGFR wild-type

1year

Comprehensive Genomic Assessment of Advanced-Stage GI Stromal Tumors Using the Japanese National Center for Cancer Genomics and Advanced Therapeutics Database. (PubMed, JCO Precis Oncol)

This study highlights the genomic landscape of advanced GISTs and the important role of CGP in identifying rational molecular-targeted therapeutic options.

1 year ago

Retrospective data • Journal • Tumor mutational burden • PD(L)-1 Biomarker • Stroma • Metastases

HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • STK11 (Serine/threonine kinase 11) • HRD (Homologous Recombination Deficiency) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • ETV6 (ETS Variant Transcription Factor 6) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) • NTRK (Neurotrophic receptor tyrosine kinase) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)

TMB-H • NTRK3 fusion • HRD • ETV6-NTRK3 fusion • PDGFRA mutation • PDGFR wild-type

Keytruda (pembrolizumab)

1year

Oncogenetic Panel and Integrated Clinical Data Registry Study for Wild Type Gastrointestinal Stromal Tumor Patients (clinicaltrials.gov)

P=N/A; Trial primary completion date: Dec 2025 --> Dec 2024

1 year ago

Trial primary completion date • Stroma

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

PDGFRA mutation • KIT wild-type • PDGFR wild-type

OncoPanel™ Assay

over1year

Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors. (PubMed, Cancers (Basel))

Compared to KIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.

over 1 year ago

Journal • Next-generation sequencing • Stroma

BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • PTEN (Phosphatase and tensin homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • FGFR1 (Fibroblast growth factor receptor 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • ETV6 (ETS Variant Transcription Factor 6) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) • AURKA (Aurora kinase A) • SDHC (Succinate Dehydrogenase Complex Subunit C) • SDHD (Succinate Dehydrogenase Complex Subunit D) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)

TP53 mutation • BRAF V600E • BRAF V600 • NTRK3 fusion • PTEN deletion • PTEN mutation • NF1 mutation • ETV6-NTRK3 fusion • CHEK2 mutation • PDGFRA mutation • FANCA mutation • FGFR1 fusion • FANCA deletion • PDGFR wild-type

imatinib

over1year

TIMP-3 Alleviates White Matter Injury After Subarachnoid Hemorrhage in Mice by Promoting Oligodendrocyte Precursor Cell Maturation. (PubMed, Cell Mol Neurobiol)

The data indicates TIMP-3 could promote the differentiation and maturation of OPCs and subsequently improve neurological outcomes after SAH. Therefore, TIMP-3 could be beneficial for repair after white matter injury and could be a potential therapeutic target in SAH.

over 1 year ago

Preclinical • Journal

PDGFRB (Platelet Derived Growth Factor Receptor Beta) • TIMP3 (TIMP Metallopeptidase Inhibitor 3)

PDGFR wild-type

over1year

Pediatric-type high-grade gliomas with PDGFRA amplification in adult patients with Li-Fraumeni syndrome: clinical and molecular characterization of three cases. (PubMed, Acta Neuropathol Commun)

These data suggest that high-grade gliomas developed in adult patients with LFS may be involved in pHGG H3-/IDH-wt. PDGFRA and homozygous alterations in TP53 may play pivotal roles in the development of this type of glioma in adult patients with LFS.

over 1 year ago

Journal

EGFR (Epidermal growth factor receptor) • TP53 (Tumor protein P53) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • TERT (Telomerase Reverse Transcriptase)

TP53 mutation • EGFR mutation • EGFR amplification • TERT mutation • IDH wild-type • TERT promoter mutation • PDGFR wild-type

almost2years

Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA. (PubMed, Nat Commun)

Against this background, we solve the crystal structures of avapritinib in complex with wild-type and mutant PDGFRA and stem cell factor receptor (KIT), which provide evidence and understanding of inhibitor binding and lead to the identification of a sub-pocket (Gα-pocket). We utilize this information to design, synthesize and characterize avapritinib derivatives for the determination of key pharmacophoric features to overcome drug resistance and limit potential blood-brain barrier penetration.

almost 2 years ago

Journal

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

PDGFRA D842V • PDGFRA mutation • PDGFR wild-type

Ayvakit (avapritinib)

almost2years

Molecular and clinicopathological features of KIT/PDGFRA wild-type gastrointestinal stromal tumors. (PubMed, Cancer Sci)

NF1-GISTs involved multifocal spindle cell tumors in the small intestine. SDH-GISTs occurred in young patients and were multifocal in the stomach and clinically indolent.

almost 2 years ago

Journal • Stroma

BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • CHEK2 (Checkpoint kinase 2) • CREBBP (CREB binding protein) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)

TP53 mutation • BRAF V600E • BRAF V600 • NF1 mutation • CHEK2 mutation • PDGFRA mutation • SDHB mutation • PDGFR wild-type

2years

A Phase 1, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Patients With Advanced Gastrointestinal Stromal Tumor. (PubMed, Clin Cancer Res)

Targeting GPR20 with DS-6157a was tolerated in patients with advanced GIST with tumor shrinkage demonstrated in KIT/PDGFRA wild type GIST. However, the study did not proceed further due to lower efficacy outcomes than anticipated.

2 years ago

P1 data • Journal • Stroma • Metastases

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • GPR20 (G Protein-Coupled Receptor 20)

PDGFR wild-type

DS-6157

over2years

EFFICACY OF RIPRETINIB IN A MULTICENTER EXPANDED ACCESS PROGRAM IN PATIENTS WITH ADVANCED GASTROINTESTINAL STROMAL TUMORS HARBOURING NON-KIT EXON 11 MUTATIONS. (CTOS 2023)

Objective: There remains an unmet need for effective and well tolerated systemic therapy for metastatic gastrointestinal stromal tumors (GISTs) after disease progression on imatinib is challenging. In the real world setting, ripretinib has durable benefit in metastatic GISTs harbouring non KIT exon 11 primary mutations. Ripretinib at a dose of 150 mg BD can be safely administered. Ripretinib is generally well tolerated with toxicity profile consistent with previous reports.

over 2 years ago

Clinical • Stroma • Metastases

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

KIT exon 11 mutation • PDGFRA D842V • PDGFRA mutation • PDGFR wild-type

imatinib • Qinlock (ripretinib)

over2years

CLINICO-GENOMIC ANALYSIS OF KIT/PDGFRA/SDH WILD-TYPE GASTROINTESTINAL STROMAL TUMORS IDENTIFIES POTENTIAL DRIVER MUTATIONS (CTOS 2023)

The patient with ETV6-NTRK3 fusion was treated with larotrectinib for 28.7 months prior to progression, likely due to acquired NTRK3 gatekeeper mutation (F617L) rendering resistance to larotrectinib, then was on a second generation NTRK inhibitor, selitrectinib, for 16.5 months prior to progression. Triple negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA mutant GIST, limited benefit was observed with imatinib in triple negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.

over 2 years ago

Genomic analysis • Stroma • Omic analysis

PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • FGFR1 (Fibroblast growth factor receptor 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • ETV6 (ETS Variant Transcription Factor 6) • CHEK2 (Checkpoint kinase 2) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) • AURKA (Aurora kinase A) • NTRK (Neurotrophic receptor tyrosine kinase) • SDHC (Succinate Dehydrogenase Complex Subunit C) • SDHD (Succinate Dehydrogenase Complex Subunit D) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)

BRAF V600E • PIK3CA mutation • BRAF V600 • NTRK3 fusion • PTEN deletion • PTEN mutation • NF1 mutation • ETV6-NTRK3 fusion • CHEK2 mutation • PDGFRA mutation • FGFR1 fusion • PIK3CA I391M • PDGFR wild-type

Vitrakvi (larotrectinib) • imatinib • selitrectinib (BAY 2731954)