1,724,317 research outputs found
Neurotrophin receptors (Trk A, Trk B, and Trk C) in the developing and adult human retina
No full textIn this study, the ontogeny and distribution patterns of three neurotrophin receptors (Trk A, Trk B, and Trk C) were examined in the human retinas. Immunohistochemistry was performed on sections of retina and optic nerve from fetuses (11-24 weeks of gestation, wg), one infant (4-month-old) and two adult (35- and 65-years-old) subjects. At 11 wg, Trk A was expressed in the nerve fiber and inner plexiform layers, while Trk B and Trk C were expressed in many neuroblastic cells. By 16-17 wg, the photoreceptors showed immunoreactivity for all three receptors. The ganglion cell layer and amacrine cells were conspicuously immunoreactive for Trk A and Trk C, but labeled diffusely for Trk B. The horizontal cells were labeled for Trk A and Trk B. The pattern was same in the retinas at midgestation (20-21 wg). Shortly after this period, there was an apparent decrease in receptor immunoreactivity in the fetal retinas. In the infant retina, Trk A immunoreactivity was absent from horizontal cells. The photoreceptors were immunopositive for Trk B and Trk C, in infant and adult retinas. In the adults, few cells of the ganglion cell layer and inner nuclear layer were clearly labeled for Trk A and Trk C, and diffusely for Trk B. The glial cells of the retina and optic nerve immunoreacted for Trk A only, right from fetal 16 wg. The early expression of Trk B and Trk C on neuroblastic cells suggests that both play a role in cell proliferation. The developmental distribution pattern of Trk A, on the other hand, provides evidence for its involvement in differentiation of the inner plexiform layer, horizontal cells and neuroglia. The results strongly suggest that photoreceptor development is mediated by Trk receptors. The novel localization of Trk B and Trk C on adult photoreceptors points to a possible therapeutic potential for BDNF and NT-3, respectively, in photoreceptor diseases
Rationale and design of ON-TRK: a novel prospective non-interventional study in patients with TRK fusion cancer treated with larotrectinib
No full textBackground: Tropomyosin receptor kinase (TRK) fusion proteins resulting from neurotrophic tyrosine receptor kinase (NTRK) gene fusions are rare primary oncogenic drivers in a wide array of tumors. Larotrectinib is a first-in-class, highly selective, central nervous system-active TRK inhibitor approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and over 40 countries for the treatment of TRK fusion solid tumors in adult and pediatric patients. Due to the rarity of TRK fusion cancer, larotrectinib was granted accelerated approval based on a relatively small number of patients enrolled in three early phase trials. ON-TRK aims to evaluate the safety profile of larotrectinib in a broader population and over extended time periods.
Methods: ON-TRK is a prospective, non-interventional, open-label, multicenter, multi-cohort, post-approval study in adult and pediatric patients with locally advanced or metastatic TRK fusion cancer treated with larotrectinib that will describe the safety and effectiveness of larotrectinib in real-world practice conditions. Adult patients will be grouped by tumor type and followed for at least 2 years. Patients < 18 years old will be enrolled under a 'pediatric' cohort regardless of tumor type and will be followed for 5 years to evaluate the risk of potential long-term adverse effects of larotrectinib on their growth and development. The effectiveness of larotrectinib in the overall study population as well as in patient subgroups will also be evaluated. Procedures avoided in patients with infantile fibrosarcoma (e.g., amputation) and the number of patients who were able to undergo surgery with a curative intent (excluding amputation) because of the use of larotrectinib will be described. Larotrectinib treatment patterns in real-world practice, including dosing and duration of treatment, will be described.
Discussion: The FDA Accelerated Approval Program allows for earlier approval of and patient access to drugs that treat serious conditions and fill an unmet medical need. This study is designed to fulfill post-approval requirements set by the FDA as well as post-marketing requirements set forth by local regulatory bodies and is part of the risk management plan for the EMA.Depto. de Medicina Legal, Psiquiatría y PatologíaFac. de MedicinaTRUEpu
TRK Inhibitors: Tissue-Agnostic Anti-Cancer Drugs
No full textRecently, two tropomycin receptor kinase (Trk) inhibitors, larotrectinib and entrectinib, have been approved for Trk fusion-positive cancer patients. Clinical trials for larotrectinib and entrectinib were performed with patients selected based on the presence of Trk fusion, regardless of cancer type. This unique approach, called tissue-agnostic development, expedited the process of Trk inhibitor development. In the present review, the development processes of larotrectinib and entrectinib have been described, along with discussion on other Trk inhibitors currently in clinical trials. The on-target effects of Trk inhibitors in Trk signaling exhibit adverse effects on the central nervous system, such as withdrawal pain, weight gain, and dizziness. A next generation sequencing-based method has been approved for companion diagnostics of larotrectinib, which can detect various types of Trk fusions in tumor samples. With the adoption of the tissue-agnostic approach, the development of Trk inhibitors has been accelerated
STAT3 activation by TRK oncogenes.
No full text<p>(<b>A</b>) Western blot analysis of PC12 cells transfected with empty pRC/CMV vector, TRKA, TRK-T3, and TRK cDNAs. NGF treatment (50ng/ml, 10′) is indicated. Cell lysates and immunocomplexes were separated by SDS PAGE as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009446#s4" target="_blank">Material and Methods</a> and immunoblotted with indicated antibodies. In the bottom panel two distinct exposures of the same blot were used for documenting TRKA or TRK oncoproteins phosphorylation. (<b>B</b>) HeLa cells were co-transfected with pM67 and pRL-TK in combination with the indicated TRK oncogene cDNAs in the absence (left graph) or presence (right graph) of STAT3 cDNA and assayed for STAT3-dependent luciferase activity 48 hours later. Activity is expressed as the ratio of luciferase/renilla activity, and reported as fold-inductions over empty vector (left panel) or STAT3 (right panel) (RLA: Relative Luciferase Activity). The data represent the mean values ± SD of triplicate samples. Similar results were obtained in three independent experiments. (<b>C</b>) MAPK involvement in TRK-induced Stat3 phosphorylation. Western blot analysis of PC12 cells transfected with empty pRC/CMV vector, TRK-T3 or TRK cDNAs. NGF (10′, 50ng/ml) and UO126 (16 hr, 10 µM) treatments are indicated. Immunoblotting was performed with the indicated antibodies.</p
A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion–Positive Solid Tumors
No full textAbstract
Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion–positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion–positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.
Significance: LOXO-195 abrogated resistance in TRK fusion–positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963–72. ©2017 AACR.
See related commentary by Parikh and Corcoran, p. 934.
This article is highlighted in the In This Issue feature, p. 920</jats:p
Five Trk Receptors in the Zebrafish
No full textAbstractUsing a homology-based cloning strategy we have identified five members of the Trk family in the zebrafish Danio rerio. They are homologous to the three mammalian Trk receptors in their conserved intracellular kinase regions and the organization of their extracellular regions. The five trk genes are differentially expressed in the developing brain, spinal cord, cranial ganglia, and retina. Full-length forms of three of the trk genes are expressed when neurons pioneer the major axon tracts, whereas the two other trk genes have a later onset of expression. Truncated transcripts and forms containing an extracellular juxtamembrane region insert were found. The degree of sequence variation and expression differences within the family suggest that each of the five zebrafish Trk receptors have a functionally distinct role. These findings demonstrate that the vertebrate Trk family is larger than previously appreciated
Expression of the neurotrophin receptors Trk A and Trk B in adult human astrocytoma and glioblastoma
No full textNeurotrophins and their receptors of the Trk family play a critical role in proliferation, differentiation and survival of the developing neurons. There are reports on their expression in neoplasms too, namely, the primitive neuroectodermal tumours of childhood, and in adult astrocytic gliomas. The involvement of Trk receptors in tumour pathogenesis, if any, is not known. With this end in view, the present study has examined 10 tumour biopsy samples (identified as astrocytoma, pilocytic astrocytoma and glioblastoma) and peritumoral brain tissue of adult patients, for the presence of Trk A and Trk B receptors, by immunohistochemistry. The nature of the tumour samples was also confirmed by their immunoreactivity (IR) to glial fibrillary acidic protein. In the peritumoral brain tissue, only neurons showed IR for Trk A and Trk B. On the contrary, in the tumour sections, the IR to both receptors was localized in the vast majority of glia and capillary endothelium. There was an obvious pattern of IR in these gliomas: high levels of IR were present in the low-grade (type I and II) astrocytoma; whereas in the advanced malignant forms (WHO grade IV giant cell glioblastoma and glio-blastoma multiforme) the IR was very weak. These findings suggest that Trk A and Trk B are involved in tumour pathogenesis, especially in the early stage, and may respond to signals that elicit glial proliferation, and thus contribute to progression towards malignancy
Inhibiting TRK Proteins in Clinical Cancer Therapy
No full textGene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers. The tropomyosin receptor kinase (TRK) family of tyrosine receptor kinases is emerging as an important target for cancer therapeutics. The TRK family contains three members, TRKA, TRKB, and TRKC, and these proteins are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively. To activate TRK receptors, neurotrophins bind to the extracellular region stimulating dimerization, phosphorylation, and activation of downstream signaling pathways. Major known downstream pathways include RAS/MAPK/ERK, PLCγ, and PI3K/Akt. While being rare in most cancers, TRK fusions with other proteins have been well-established as oncogenic events in specific malignancies, including glioblastoma, papillary thyroid carcinoma, and secretory breast carcinomas. TRK protein amplification as well as alternative splicing events have also been described as contributors to cancer pathogenesis. For patients harboring alterations in TRK expression or activity, TRK inhibition emerges as an important therapeutic target. To date, multiple trials testing TRK-inhibiting compounds in various cancers are underway. In this review, we will summarize the current therapeutic trials for neoplasms involving NTKR gene alterations, as well as the promises and setbacks that are associated with targeting gene fusions.</jats:p
Coexpression of mRNA for the full-length neurotrophin receptor trk-C and trk-A in favourable neuroblastoma
No full textNeuroblastoma, a childhood tumour of the sympathetic nervous system, may sometimes regress spontaneously in infants, or progress to a poor clinical outcome despite intensive therapy. Neuroblastomas express neurotrophin receptors and high levels of mRNA for trk-A correlates with favourable outcome, whereas trk-B mRNA is expressed by more unfavourable tumours. Using a sensitive RNase protection assay, mRNA expression for the neurotrophin receptor trk-C was investigated in 50 tumour samples from 45 children at different stages including metastatic and relapsing tumour tissue, out of which 22 were also investigated for trk-A mRNA. Thirty-seven of 43 primary tumours (86%) showed trk-C mRNA with more than 300-fold difference between the highest and the lowest values. A higher trk-C index (trk-C mRNA/GAPDH mRNA) was associated with favourable features such as younger age (P = 0.009-0.003), favourable tumour stage (1, 2 or 4S; P < 0.001) and favourable prognosis (P = 0.044). Better survival probability was shown in children with intermediate or high trk-C index compared with patients with low or undetectable levels (P = 0.031). All localised tumours co-expressed mRNA for trk-A and trk-C receptors. RT-PCR analysis detected mRNA encoding the cytoplasmic trk-C tyrosine kinase region only in favourable neuroblastomas. We conclude that favourable neuroblastoma may express the full-length trk-C receptor while unfavourable tumours, especially those with MYCN amplification, seem to either express no trk-C or truncated trk-C receptors with unknown biological function. Trk-C and possibly its preferred ligand NT-3 may be involved in the biology of favourable neuroblastomas showing apoptosis or differentiation. (C) 1997 Elsevier Science Ltd
On Trk for Retrograde Signaling
No full textAbstractTarget-derived neurotrophins like nerve growth factor (NGF) mediate biological effects by binding to and activating Trk neurotrophin receptors at nerve terminals. The activated Trk receptors then stimulate local effects at nerve terminals, and retrograde effects at neuronal cell bodies that often reside at considerable distances from the terminals. However, the nature of the retrograde signal has been mysterious. Recent experiments suggest that the major retrograde signal required for survival and gene expression consists of activated Trk itself. Remarkably, signaling by Trk may differ at the terminal versus the neuronal cell body as a consequence of the retrograde transport mechanism, thereby allowing NGF to not only promote growth locally, but to specifically support survival and gene expression retrogradely
- …
