Abstract：
:The tropomyosin receptor kinase (TRK) family includes TRKA, TRKB, and TRKC proteins, which are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. Binding of neurotrophins to TRK proteins induces receptor dimerization, phosphorylation, and activation of the downstream signaling cascades via PI3K, RAS/MAPK/ERK, and PLC-gamma. TRK pathway aberrations, including gene fusions, protein overexpression, and single nucleotide alterations, have been implicated in the pathogenesis of many cancer types, with NTRK gene fusions being the most well validated oncogenic events to date. Although the NTRK gene fusions are infrequent in most cancer types, certain rare tumor types are predominately driven by these events. Conversely, in more common histologies, such as lung and colorectal cancers, prevalence of the NTRK fusions is well below 5%. Selective inhibition of TRK signaling may therefore be beneficial among patients whose tumors vary in histologies, but share underlying oncogenic NTRK gene alterations. Currently, several TRK-targeting compounds are in clinical development. The ongoing Phase 2 trials with entrectinib and LOXO-101, two of the leading TRK inhibitors, are designed as 'basket trials', inclusive of patients whose tumors harbor NTRK gene fusions, independent of histology. Additional Phase 1 studies of other TRK inhibitors, including MGCD516, PLX7486, DS-6051b, and TSR-011, are underway. Interim data examining NTRK-rearranged tumors treated with entrectinib or LOXO-101 demonstrate encouraging activity, with patients achieving rapid and durable responses. Consequently, both drugs have achieved orphan designation from regulatory agencies, and efforts are underway to further expedite their development.
journal_name
Pharmacol Therjournal_title
Pharmacology & therapeuticsauthors
Khotskaya YB,Holla VR,Farago AF,Mills Shaw KR,Meric-Bernstam F,Hong DSdoi
10.1016/j.pharmthera.2017.02.006subject
Has Abstractpub_date
2017-05-01 00:00:00pages
58-66eissn
0163-7258issn
1879-016Xpii
S0163-7258(17)30020-7journal_volume
173pub_type
杂志文章,评审abstract：:Alcoholism is a chronic relapsing disorder. Major characteristics observed in alcoholics during an initial period of alcohol abstinence are altered physiological functions and a negative emotional state. Evidence suggests that a persistent, cumulative adaptation involving a kindling/allostasis-like process occurs duri...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2010.09.007
更新日期：2011-02-01 00:00:00
abstract：:Nitric oxide (NO) formed via endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) plays crucial roles in the regulation of blood flow through vasodilatation and decreased vascular resistance in various organs and tissues. NO derived from eNOS also contributes to the inhibition of platelet aggregation, adhesi...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2010.04.009
更新日期：2010-09-01 00:00:00
abstract：:Recent epidemiologic studies have shown that aerobic exercise, one of lifestyle modifications, reduces cardiovascular morbidity and mortality in the general population. However, the mechanisms underlying the anti-atherogenic and anti-hypertensive effects of exercise remain unclear. Hypertension is associated with alte...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2004.02.003
更新日期：2004-04-01 00:00:00
abstract：UNLABELLED:Preclinical animal models are useful tools to better understand tumor initiation and progression and to predict the activity of an anticancer agent in the clinic. Ideally, these models should recapitulate the biological characteristics of the tumor and of the related tumor microenvironment (e.g. vasculature,...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2014.01.001
更新日期：2014-06-01 00:00:00
abstract：:The PI3K/Akt/mTOR pathway is the most frequently known activated aberrant pathway in human cancers. Pathologic activation can occur at multiple levels along the signaling pathway by a variety of mechanisms, including point mutations, amplifications, and inactivation of tumor suppressor genes. This pathway is also a kn...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2014.09.006
更新日期：2015-02-01 00:00:00
abstract：:In the search for new approaches to cancer therapy, the first alkyllysophospholipid (ALP) analogs were designed and studied about two decades ago, either as potential immunomodulators or as antimetabolites of phospholipid metabolism. In the meantime, it has been demonstrated that they really act in this way. However, ...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/0163-7258(95)00001-w
更新日期：1995-04-01 00:00:00
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journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2016.04.012
更新日期：2016-08-01 00:00:00
abstract：:The cardiac ryanodine receptor-Ca2+ release channel (RyR2) is an essential sarcoplasmic reticulum (SR) transmembrane protein that plays a central role in excitation-contraction coupling (ECC) in cardiomyocytes. Aberrant spontaneous, diastolic Ca2+ leak from the SR due to dysfunctional RyR2 contributes to the formation...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2009.03.006
更新日期：2009-08-01 00:00:00
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journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2020.107583
更新日期：2020-09-01 00:00:00
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journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/s0163-7258(01)00141-3
更新日期：2001-05-01 00:00:00
abstract：:Cardiac fibrosis is a pathogenic factor of many cardiovascular diseases (CVD), which seriously affects people's life, and health and causes huge economic losses. Increasing evidence has shown that peroxisome proliferator-activated receptors (PPARs) can regulate the progression of cardiac fibrosis. For the first time, ...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2020.107702
更新日期：2020-10-04 00:00:00
abstract：:The organized, tightly regulated signaling relays engaged by the cannabinoid receptors (CBs) and their ligands, G proteins and other effectors, together constitute the endocannabinoid system (ECS). This system governs many biological functions including cell proliferation, regulation of ion transport and neuronal mess...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2017.06.003
更新日期：2017-12-01 00:00:00
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journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/0163-7258(91)90039-o
更新日期：1991-01-01 00:00:00
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journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/0163-7258(94)90008-6
更新日期：1994-04-01 00:00:00
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journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2020.107476
更新日期：2020-04-01 00:00:00
abstract：:Thyroid hormone (TH) is essential for normal brain development and may also promote recovery and neuronal regeneration after brain injury. TH acts predominantly through the nuclear receptors, TH receptor alpha (THRA) and beta (THRB). Additional factors that impact TH action in the brain include metabolism, activation ...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2018.01.007
更新日期：2018-06-01 00:00:00
abstract：:Relationship between inflammation and cancer is now well-established and represents a paradigm that our immune response does not necessarily serves solely to protect us from infections and cancer. Many specific mechanisms that link chronic inflammation to cancer promotion and metastasis have been uncovered in the rece...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2016.09.011
更新日期：2016-12-01 00:00:00
abstract：:Metabolic syndrome has been described as the association of insulin resistance, hypertension, hyperlipidemia and obesity. Its prevalence increased dramatically, mainly in developed countries. Animal models are essential to understand the pathophysiology of this syndrome. This review presents the murine models of metab...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2012.11.004
更新日期：2013-03-01 00:00:00
abstract：:G protein-coupled receptors (GPCR) interact not only with heterotrimeric G proteins but also with accessory proteins called GPCR interacting proteins (GIP). These proteins have important functions. They are implicated in GPCR targeting to specific cellular compartments, in their assembling into large functional comple...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2004.06.004
更新日期：2004-09-01 00:00:00
abstract：:Natriuretic peptides play a critical role in coordination of fluid/electrolyte balance and vascular tone. The renal effects of circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are distinct from the paracrine effects of vascular C-type natriuretic peptide (CNP). CNP is widely expressed t...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2004.08.011
更新日期：2005-02-01 00:00:00
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journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2018.08.002
更新日期：2018-12-01 00:00:00
abstract：:Enhancing the effects of endogenously-released cannabinoid ligands in the brain might provide therapeutic effects more safely and effectively than administering drugs that act directly at the cannabinoid receptor. Inhibitors of fatty acid amide hydrolase (FAAH) prevent the breakdown of endogenous ligands for cannabino...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2013.01.003
更新日期：2013-04-01 00:00:00
abstract：BACKGROUND:Gender differences in cardiac electrophysiology were reported for the first time almost a century ago. The importance for safety pharmacology became significant when modern medicine came into use and women appeared to be more susceptible to drug-induced Torsade de Pointes (TdP). To unravel the underlying mec...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2010.04.002
更新日期：2010-07-01 00:00:00
abstract：:Increasing evidence of a critical role played by the bronchial epithelium in airway homeostasis is opening new therapeutic avenues. Its unique situation at the interface with the environment suggests that the subtle regulation orchestrated by the epithelium between tolerance and specific immune response might be impai...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2013.07.008
更新日期：2013-12-01 00:00:00
abstract：:Nerve growth factor (NGF) and other members of the neurotrophin family are critical for the survival and differentiation of neurons and have been implicated in the pathophysiology of numerous disease states. Although the therapeutic potential of neurotrophins has generated much excitement over the past decade, inconve...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2007.03.005
更新日期：2007-08-01 00:00:00
abstract：:Purinergic signaling, mediated mainly by G protein-coupled P2Y receptors (P2YRs), is now attracting attention as a new therapeutic target for preventing or treating cardiovascular diseases. Observations using mice with genetically modified P2YRs and/or treated with a pharmacological P2YR inhibitor have helped us under...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2017.06.010
更新日期：2017-12-01 00:00:00
abstract：:Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with a high mortality rate. Genetic and biochemical studies have shown that RAS signaling mediated by KRAS plays a pivotal role in disease initiation, progression and drug resistance. RAS signaling affects several cellular processes in PDAC, includ...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2016.09.003
更新日期：2016-12-01 00:00:00
abstract：:Targeted therapies have changed the landscape of treatments for non-small cell lung cancer (NSCLC). Specific targeted therapies have been approved for NSCLC patients harboring genetic alterations in four oncogenes, and agents targeting additional oncogenic drivers are under investigation. Standard first-line chemother...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2018.08.007
更新日期：2019-01-01 00:00:00
abstract：:Angiotensin II (Ang II) is the main effector hormone of the renin-angiotensin system (RAS). The pathogenesis of many cardiovascular diseases, including heart failure and hypertension, appear to be related to Ang II production. The generation of Ang II involves angiotensin-converting enzyme (ACE) in circulating and tis...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/s0163-7258(97)00021-1
更新日期：1997-01-01 00:00:00
abstract：:In the last decade, there have been considerable advances in the understanding of the pathophysiology of malignant ventricular tachyarrhythmias (VT) and sudden cardiac death (SCD). Over 80% of SCD occurs in patients with organic heart disease. However, approximately 10%-15% of SCD occurs in the presence of structurall...
journal_title：Pharmacology & therapeutics
pub_type： 杂志文章,评审
doi：10.1016/j.pharmthera.2015.09.002
更新日期：2015-11-01 00:00:00
