Book ChapterDOI
Neurotrophin Trk Receptors: New Targets for Cancer Therapy.
TLDR
A considerable panel of anti-Trk drugs, developed recently, has been investigated both in vitro and in living mice for their effects on cancer cells, and increased potency and down-regulation of resistance, with no increase of side effects.Abstract:
In the last few years, exciting reports have emerged regarding the role of the two types of neurotrophin receptors, p75NTR and Trks, not only in neurons, where they were discovered, but also in non-neural cells and, especially, in numerous cancers, including breast, lung, colon-rectum, pancreas, prostate, glioblastoma, neuroblastoma, myeloma, and lymphoid tumors. Traditionally, p75NTR, activated by all neurotrophins and their precursors, is an inhibitor. In various cancers, however, activated p75NTR induces variable effects, from inhibition to stimulation of cell proliferation, dependent on their direct or coordinate/indirect mechanism(s) of action. TrkA, TrkB, and TrkC, activated by distinct neurotrophins, are high affinity stimulatory receptors. In cancers, activation of Trks, especially of TrkB, are stimulators of cell proliferation, aggressiveness, and metastases. In rare cancers, these processes are due not to receptor activation but to fusion or mutation of the encoding genes. A considerable panel of anti-Trk drugs, developed recently, has been investigated both in vitro and in living mice for their effects on cancer cells. Many such drugs protect from cancers by preventing cell proliferation and inducing apoptosis. At present, these drugs are under control by trials, to promote introduction in human therapy. Moreover, anti-Trk drugs have been employed also in combination with classical chemotherapeutic drugs. So far, studies in mice have been positive. The chemotherapeutic/anti-receptor combinations exhibited in fact increased potency and down-regulation of resistance, with no increase of side effects.read more
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Journal ArticleDOI
Primary and Metastatic Melanoma With NTRK Fusions
Cecilia Lezcano,Alexander N. Shoushtari,Charlotte E. Ariyan,Travis J. Hollmann,Klaus J. Busam +4 more
TL;DR: The findings document that NTRK kinase fusions can occur in nonspitzoid metastasizing melanomas of adults and may provide a therapeutic opportunity in a small subset of patients with metastatic melanoma.
Journal ArticleDOI
Targeting the BDNF/TrkB pathway for the treatment of tumors (Review)
TL;DR: The present review summarizes recent findings to discuss the role of BDNF in tumors, the underlying molecular mechanism, targeting Trk receptors for treatment of cancers and its potential risk.
Journal ArticleDOI
2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzonitrile as novel inhibitor of receptor tyrosine kinase and PI3K/AKT/mTOR signaling pathway in glioblastoma
Anisha Viswanathan,Dinesh Kute,Aliyu Musa,Saravanan Konda Mani,Vili Sipilä,Frank Emmert-Streib,Fedor I. Zubkov,Atash V. Gurbanov,Olli Yli-Harja,Meenakshisundaram Kandhavelu +9 more
TL;DR: The synthesis of 23 arylhydrazones of active methylene compounds and their anti-proliferative activity against GBM cell lines and R234, being a negative modulator of RTKs and cell cycle inhibitor, may represent a novel class of anti-GBM drugs.
Journal ArticleDOI
Tumor Innervation: Cancer Has Some Nerve
TL;DR: This review aims to address what is currently known about the origin of tumor-infiltrating nerves, how they may be recruited to tumors, and how their presence may give rise to aggressive disease.
Journal ArticleDOI
Glioblastoma: Role of Mitochondria N-acetylserotonin/Melatonin Ratio in Mediating Effects of miR-451 and Aryl Hydrocarbon Receptor and in Coordinating Wider Biochemical Changes.
George M. Anderson,R. J. Reiter +1 more
TL;DR: A plethora of significant, but previously disparate, data on GBM/GSC can be integrated within this framework, including miR-451, AMP-activated protein kinase (AMPK)/mTOR, 14-3-3 proteins, sirtuins, tryptophan 2,3-dioxygenase, and the kynurenine pathways.
References
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Journal ArticleDOI
Neurotrophin-regulated signalling pathways
TL;DR: Three rare human genetic disorders, which result in deleterious effects on sensory perception, cognition and a variety of behaviours, have been shown to be attributable to mutations in brain-derived neurotrophic factor and two of the Trk receptors.
Journal ArticleDOI
Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1).
Alexander Drilon,Salvatore Siena,Sai-Hong Ignatius Ou,Manish Patel,Myung-Ju Ahn,Jeeyun Lee,Todd M. Bauer,Anna F. Farago,Jennifer J. Wheler,Stephen V. Liu,Robert C. Doebele,Laura Giannetta,Giulio Cerea,Giovanna Marrapese,Michele Schirru,Alessio Amatu,Katia Bencardino,Laura Palmeri,Andrea Sartore-Bianchi,Angelo Vanzulli,Sara Cresta,Silvia Damian,Matteo Duca,Elena Ardini,Gang Li,Jason Christiansen,Karey Kowalski,Ann D. Johnson,Rupal Patel,David Luo,Edna Chow-Maneval,Zachary Hornby,Pratik S. Multani,Alice T. Shaw,Filippo de Braud +34 more
TL;DR: Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease, and a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer.
Journal ArticleDOI
Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer.
Aria Vaishnavi,Marzia Capelletti,Anh T. Le,Severine Kako,Mohit Butaney,Dalia Ercan,Sakshi Mahale,Kurtis D. Davies,Dara L. Aisner,Dara L. Aisner,Amanda B. Pilling,Eamon M. Berge,Jhingook Kim,Hidefumi Sasaki,Seung-Il Park,Gregory V. Kryukov,Levi A. Garraway,Levi A. Garraway,Peter S. Hammerman,Julia Haas,Steven W. Andrews,Doron Lipson,Philip J. Stephens,V.A. Miller,Marileila Varella-Garcia,Marileila Varella-Garcia,Pasi A. Jänne,Robert C. Doebele,Robert C. Doebele +28 more
TL;DR: Tumor samples from 3 of 91 patients with lung cancer without known oncogenic alterations assayed by next-generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions.
Journal ArticleDOI
TRKing Down an Old Oncogene in a New Era of Targeted Therapy
TL;DR: The science rationale for the targeting of the TRK oncogene family, which encodes the TRKA, TRKB, and TRKC receptor tyrosine kinases across multiple tumor types, is discussed here.
Journal ArticleDOI
An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101
Robert C. Doebele,Lara E. Davis,Aria Vaishnavi,Anh T. Le,Adriana Estrada-Bernal,Stephen B. Keysar,Antonio Jimeno,Marileila Varella-Garcia,Dara L. Aisner,Yali Li,Philip J. Stephens,Deborah Morosini,Brian B. Tuch,Michele Fernandes,Nisha Nanda,Jennifer A. Low +15 more
TL;DR: A patient with a metastatic soft-tissue sarcoma with an LMNA-NTRK1 fusion had rapid and substantial tumor regression with a novel, highly selective TRK inhibitor, LOXO-101, providing the first clinical evidence of benefit from inhibiting TRK fusions.
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