Different staining was also noted in nontumor kidney tissue, whereas an NTRK1-rearranged tumor used as positive control was strongly stained with both A7H6R and EPR17341 clones.
Abnormally expressed Trk receptors or chimeric Trk fusion proteins are also well-characterized oncogenic drivers in a variety of neurogenic and non-neurogenic human neoplasms and are currently the focus of intensive clinical research.
Chromosomal rearrangements involving the NTRK1, NTRK2, and NTRK3 genes (NTRK genes), which encode the high-affinity nerve growth factor receptor (TRKA), brain-derived neurotrophic factor/neurotrophin-3 (BDNF/NT-3) growth factor receptor (TRKB), and neurotrophin-3 (NT-3) growth factor receptor (TRKC) tyrosine kinases (TRK proteins), act as oncogenic drivers in a broad range of pediatric and adult tumor types.
Tumors expressing NTRK1-pY674/pY675 and low or undetectable levels of PTPN6 and TP53 were significantly associated with 5-year RFS (P = .014) when the dataset was stratified by MYCN amplification, segmental chromosomal abnormalities and histology.
We provide recommendations for screening pediatric tumors for the presence of TRK fusions, including the use of immunohistochemistry or fluorescence in situ hybridization for patients with tumors likely to harbor TRK fusions.
Entrectinib (Rozlytrek<sup>®</sup>) is an oral selective inhibitor of the tyrosine kinases tropomyosin receptor kinases (Trk)A/B/C [encoded by the genes neurotrophic tyrosine receptor kinase (NTRK) 1, 2 and 3, respectively], c-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK) with central nervous system (CNS) activity developed by Roche for the treatment of various solid tumours harbouring NTRK1/2/3 or ROS1 gene fusions.
Together, these data suggest that Ntrk1 activates Jak/Stat signaling to regulate expression of immunosuppressive molecules including PD-L1, promoting exhaustion within the tumor microenvironment.
After targeted RNA-sequencing, dual FISH fusion and array-CGH analysis, 7 of 13 tumors exhibited NTRK rearrangements (6 TPM3-NTRK1 and 1 EML4-NTRK3) and 3 a COL1A1-PDGFB fusion; in the other 3 neoplasms, all of which were positive with S100 (2 diffuse, 1 focal), we identified no rearrangement.
The present study aimed to investigate the antitumor activity and hepatoprotective effect of the MTC, when combined with CHAM oil nanoemulsion (NE), (CHAM-MTC) on the tumor growth.
Dr. George also discussed updated data for sorafenib in the treatment of desmoid tumors, as well as the importance of larotrectinib in TRK fusion-positive tumors.
MTC-100038 produced significant efficacy (tumor growth index ∼102%; p = <0.0001), in several murine xenograft models of HCC, and was superior to both free DM1 and the current standard of care, sorafenib.
Increasing lines of evidence indicate that Anaplastic lymphoma kinase (ALK), a druggable tyrosine kinase receptor over-expressed in GBM, represents a potential therapeutic target in this tumor.
The patient then began treatment with crizotinib at an oral dose of 450 mg per day, based on the detection of a LMNA-NTRK1 fusion gene in the tumor by next-generation sequencing.
Genes encoding TRK are oncogenic drivers in multiple tumour types including infantile fibrosarcoma, papillary thyroid cancer and high-grade gliomas (HGG).
The TRK inhibitor larotrectinib was well tolerated in paediatric patients and showed encouraging antitumour activity in all patients with TRK fusion-positive tumours.
A recent "basket" study of larotrectinib, a TRK inhibitor, has demonstrated significant efficacy in TRK fusion-positive tumors of all types from infants to the elderly.
Here, we report that merestinib inhibits neurotrophic receptor tyrosine kinases NTRK1/2/3 which are oncogenic drivers in tumors bearing NTRK fusion resulting from chromosomal rearrangements.