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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In addition to the ALK-related agents described above, many other types of similar kinases might be targeted with potential clinical benefit, and the list of potential targets is growing. For example, entrectinib has Orphan Drug and Rare Pediatric Disease designations for the treatment of neuroblastoma, and Orphan Drug designation for TrkA-, TrkB-, TrkC-, ROS1-, and ALK-positive NSCLC cancers. NPM-ALK is a different variation/fusion of ALK that drives anaplastic large-cell lymphomas (ALCLs) and is the target of other ALK inhibitors.
Effects of sex steroids on brain cells
Published in Barry G. Wren, Progress in the Management of the Menopause, 2020
L. M. Garcia-Segura, M. C. Fernandez-Galaz, J. A. Chowen, F. Naftolin
A putative estrogen-receptor element has been identified also in the gene encoding brain-derived neurotrophic factor (BDNF)48. The receptor (trkB) for this neurotrophin is expressed in neurons from hypothalamic neuroendocrine areas, as well as trkC, which is the receptor for neurotrophin-342.
Neurotrophic Factors
Published in Martin Berry, Ann Logan, CNS Injuries: Cellular Responses and Pharmacological Strategies, 2019
Neurotrophic factors with structural and functional homology to NGF have been found and together form the neurotrophin family that consists of NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3, -4/5, and -6 (NT-3, NT-4, NT-6).20,21 Neurotrophins are homodimers of approximately 120 amino acid protein strands (∼13 kDa), and any two neurotrophins are 50 to 60% identical. Disulfide bonds in the monomers provide a three-dimensional structure with several loops that are important for specific receptor binding. The neurotrophins activate high-affinity transmembrane tyrosine kinase (Trk) receptors that activate various intracellular signaling pathways.21–24 NGF binds specifically to and activates TrkA, BDNF and NT-4 preferentially activate TrkB, and NT-3 primarily activates TrkC and in some cell types TrkB. TrkB and TrkC also exist in truncated forms without an intracellular domain that can bind the neurotrophins, but do not transduce intracellular signals. The function of such binding proteins is still unclear. Through targeted mutations of the amino acid composition of the neurotrophins and the determination of the crystal structure of NGF, various binding domains of the neurotrophins have been identified.25 Such information may help in the rational design of neurotrophin mimics or their antagonists.
Advances in pharmacotherapy for neuroblastoma
Published in Expert Opinion on Pharmacotherapy, 2021
Parmida Sadat Pezeshki, Aysan Moeinafshar, Faezeh Ghaemdoust, Sepideh Razi, Mahsa Keshavarz-Fathi, Nima Rezaei
Before the exact analysis of biochemical and genetic features of the tumor, the vast heterogeneity defied clarification for the wide-ranging responses of the tumors to different therapies. However, some biological features of favorable and unfavorable tumors have been recognized to predict the clinical outcome of the patients. Several somatic genetic modifications such as MYC-N proto-oncogene amplification, loss of heterozygosity (LOH) of chromosome arms 1p or 11q, or 17q unbalanced translocation characterize unfavorable tumors. On the other hand, favorable tumors have near-triploidy karyotype with lower chromosomal rearrangements. The over-expression of tyrosine kinase receptors (TrkA, TrkB, and TrkC), and their ligands can modify the pattern of differentiation and cell death, and subsequently affects the prognosis of the tumor [10].
Transforming approaches to treating TRK fusion cancer: historical comparison of larotrectinib and histology-specific therapies
Published in Current Medical Research and Opinion, 2021
Megan Pollack, Karen Keating, Erika Wissinger, Louis Jackson, Evelyn Sarnes, Brian Cuffel
The tropomyosin receptor kinase (TRK) inhibitor, larotrectinib, marks the first European Medicines Agency (EMA) approval of a tumor-agnostic therapy1. Larotrectinib is a potent and specific inhibitor of all three TRK proteins: TRKA, TRKB, and TRKC2. In addition to the EMA, the Food and Drug Administration (FDA), Agência Nacional de Vigilância Sanitária (ANVISA), Health Canada (HC), Taiwan Food and Drug Administration (TFDA), Saudi Food and Drug Administration (SFDA), and the Swiss Agency for Therapeutic Products (Swissmedic) have approved larotrectinib for use in adult or pediatric patients with solid tumors that display a neurotrophic tyrosine receptor kinase (NTRK) gene fusion who have disease that is locally advanced, metastatic, or where surgical resection is likely to result in severe morbidity, and who have no satisfactory treatment options3. Larotrectinib is the first drug to be approved with a tumor-agnostic indication as the first and only indication. Since the approval of larotrectinib, entrectinib has also received approval in the US and Japan for the treatment of adult and pediatric patients (≥12 years of age) with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy4.
Is neurotrophin-3 (NT-3): a potential therapeutic target for depression and anxiety?
Published in Expert Opinion on Therapeutic Targets, 2020
A. S. de Miranda, J. L. V. M. de Barros, Antonio Lucio Teixeira
In the adult brain, BDNF and NT-3, by binding to their respective cognate receptors TrkB and TrkC, activate signal transduction pathways involved in complex processes like neurogenesis, synaptic transmission, and plasticity. These events are implicated in the pathogenesis of mood disorders [18,44]. However, these neurotrophins present biological differences related to their specific actions in distinct regions of the CNS [14]. In hippocampal neurons, BDNF is stored within the dense-core vesicle and released in response to extracellular stimuli, while NT-3 can be secreted through either constitutive or regulated secretory pathways [14,64]. As a result of being processed in a constitutive secretory pathway, NT-3 is continuously available as a differentiation and survival-promoting factor for neurons [64]. When NT-3 is sorted into large dense-core vesicles and released via the regulated secretory pathway in response to cell depolarization, it acts as a ‘synaptotrophin’ undergoing activity-dependent release at active synapses, enhancing neurotransmitter release and promoting structural changes, such as growth of dendrites [65].