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Cancer Cell Jan 2021Should lorlatinib be the standard first-line treatment in advanced ALK-rearranged lung cancer? In the New England Journal of Medicine, Shaw et al. present interim...
Should lorlatinib be the standard first-line treatment in advanced ALK-rearranged lung cancer? In the New England Journal of Medicine, Shaw et al. present interim analysis results from CROWN, a randomized, phase 3 study comparing lorlatinib with crizotinib as initial therapy in patients with advanced ALK-rearranged NSCLC.
Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Crizotinib; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Pyrazoles
PubMed: 33434512
DOI: 10.1016/j.ccell.2020.12.017 -
Scientific Reports May 2023F508del, the most frequent mutation in cystic fibrosis (CF), impairs the stability and folding of the CFTR chloride channel, thus resulting in intracellular retention...
F508del, the most frequent mutation in cystic fibrosis (CF), impairs the stability and folding of the CFTR chloride channel, thus resulting in intracellular retention and CFTR degradation. The F508del defect can be targeted with pharmacological correctors, such as VX-809 and VX-445, that stabilize CFTR and improve its trafficking to plasma membrane. Using a functional test to evaluate a panel of chemical compounds, we have identified tricyclic pyrrolo-quinolines as novel F508del correctors with high efficacy on primary airway epithelial cells from CF patients. The most effective compound, PP028, showed synergy when combined with VX-809 and VX-661 but not with VX-445. By testing the ability of correctors to stabilize CFTR fragments of different length, we found that VX-809 is effective on the amino-terminal portion of the protein that includes the first membrane-spanning domain (amino acids 1-387). Instead, PP028 and VX-445 only show a stabilizing effect when the second membrane-spanning domain is included (amino acids 1-1181). Our results indicate that tricyclic pyrrolo-quinolines are a novel class of CFTR correctors that, similarly to VX-445, interact with CFTR at a site different from that of VX-809. Tricyclic pirrolo-quinolines may represent novel CFTR correctors suitable for combinatorial pharmacological treatments to treat the basic defect in CF.
Topics: Humans; Cystic Fibrosis Transmembrane Conductance Regulator; Chloride Channels; Quinolines; Cystic Fibrosis; Benzodioxoles; Aminopyridines; Mutation
PubMed: 37165082
DOI: 10.1038/s41598-023-34440-0 -
International Journal of Molecular... Jun 2022The development of HER2-targeted therapies has dramatically improved patient survival and patient management and increased the quality of life in the HER2+ breast cancer... (Review)
Review
The development of HER2-targeted therapies has dramatically improved patient survival and patient management and increased the quality of life in the HER2+ breast cancer patient population. Due to the activation of compensatory pathways, patients eventually suffer from resistance to HER2-directed therapies and develop a more aggressive disease phenotype. One of these mechanisms is the crosstalk between ER and HER2 signaling, especially the CDK4/6-Cyclin D-Rb signaling axis that is commonly active and has received attention for its potential role in regulating tumor progression. CDK 4/6 inhibitors interfere with the binding of cell-cycle-dependent kinases (CDKs) with their cognate partner cyclins, and forestall the progression of the cell cycle by preventing Rb phosphorylation and E2F release that consequentially leads to cancer cell senescence. CDK 4/6 inhibitors, namely, palbociclib, ribociclib, and abemaciclib, in combination with anti-estrogen therapies, have shown impressive outcomes in hormonal receptor-positive (HR+) disease and have received approval for this disease context. As an extension of this concept, preclinical/clinical studies incorporating CDK 4/6 inhibitors with HER2-targeted drugs have been evaluated and have shown potency in limiting tumor progression, restoring therapeutic sensitivity, and may improving the management of the disease. Currently, several clinical trials are examining the synergistic effects of CDK 4/6 inhibitors with optimized HER2-directed therapies for the (ER+/-) HER2+ population in the metastatic setting. In this review, we aim to interrogate the burden of HER2+ disease in light of recent treatment progress in the field and examine the clinical benefit of CDK 4/6 inhibitors as a replacement for traditional chemotherapy to improve outcomes in HER2+ breast cancer.
Topics: Aminopyridines; Breast Neoplasms; Cell Cycle; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Protein Kinase Inhibitors; Quality of Life
PubMed: 35742993
DOI: 10.3390/ijms23126547 -
Journal of Pharmacy Practice Jun 2022The pharmacology of roflumilast, recent dosing revisions, and the integral roles of pharmacists in effective chronic obstructive pulmonary disease (COPD) management are... (Review)
Review
PURPOSE
The pharmacology of roflumilast, recent dosing revisions, and the integral roles of pharmacists in effective chronic obstructive pulmonary disease (COPD) management are reviewed here.
SUMMARY
COPD is characterized by progressive airflow limitation and intermittent acute exacerbations of symptoms, which contribute to disease progression, worsening of comorbidities, and reduced health-related quality of life. Patients with COPD may use a variety of pharmacotherapies (in combination with nonpharmacological modalities) to prevent exacerbations, reduce the impact of symptoms, and reduce or prevent COPD progression. Given the complex and multifaceted nature of disease management, pharmacists are uniquely positioned to collaborate with other clinicians to improve treatment adherence and efficacy via a number of diverse avenues in patients with COPD. Central to this endeavor is patient education and counseling regarding their treatment regimen.
CONCLUSION
Recent findings from a phase 3 clinical trial demonstrate improved tolerability and reduced treatment discontinuation resulting from the use of an uptitration regimen in patients with severe COPD who initiate therapy with roflumilast. Pharmacists have a central role in effective COPD management, especially with respect to patient education about treatments.
Topics: Aminopyridines; Benzamides; Cyclopropanes; Humans; Pharmacists; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Quality of Life
PubMed: 33267721
DOI: 10.1177/0897190020969286 -
Annals of Oncology : Official Journal... Dec 2021
Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Female; Humans
PubMed: 34815015
DOI: 10.1016/j.annonc.2021.10.214 -
Cardiovascular Research Sep 2022Graft vascular disease (GVD), a clinically important and highly complex vascular occlusive disease, arises from the interplay of multiple cellular and molecular...
AIMS
Graft vascular disease (GVD), a clinically important and highly complex vascular occlusive disease, arises from the interplay of multiple cellular and molecular pathways. While occlusive intimal lesions are composed predominantly of smooth-muscle-like cells (SMLCs), the origin of these cells and the stimuli leading to their accumulation in GVD are uncertain. Macrophages have recently been identified as both potential drivers of intimal hyperplasia and precursors that undergo transdifferentiation to become SMLCs in non-transplant settings. Colony-stimulating factor-1 (CSF1) is a well-known regulator of macrophage development and differentiation, and prior preclinical studies have shown that lack of CSF1 limits GVD. We sought to identify the origins of SMLCs and of cells expressing the CSF1 receptor (CSF1R) in GVD, and to test the hypothesis that pharmacologic inhibition of CSF1 signalling would curtail both macrophage and SMLC activities and decrease vascular occlusion.
METHODS AND RESULTS
We used genetically modified mice and a vascular transplant model with minor antigen mismatch to assess cell origins. We found that neointimal SMLCs derive from both donor and recipient, and that transdifferentiation of macrophages to SMLC phenotype is minimal in this model. Cells expressing CSF1R in grafts were identified as recipient-derived myeloid cells of Cx3cr1 lineage, and these cells rarely expressed smooth muscle marker proteins. Blockade of CSF1R activity using the tyrosine kinase inhibitor PLX3397 limited the expression of genes associated with innate immunity and decreased levels of circulating monocytes and intimal macrophages. Importantly, PLX3397 attenuated the development of GVD in arterial allografts.
CONCLUSION
These studies provide proof of concept for pharmacologic inhibition of the CSF1/CSF1R signalling pathway as a therapeutic strategy in GVD. Further preclinical testing of this pathway in GVD is warranted.
Topics: Aminopyridines; Animals; Macrophage Colony-Stimulating Factor; Mice; Protein Kinase Inhibitors; Pyrroles; Receptor Protein-Tyrosine Kinases; Vascular Remodeling
PubMed: 34478521
DOI: 10.1093/cvr/cvab289 -
European Journal of Medicinal Chemistry Aug 2020Cystic fibrosis (CF) is a monogenic autosomal recessive disorder. The clinical manifestations of the disease are caused by ∼2,000 mutations in the cystic fibrosis... (Review)
Review
Cystic fibrosis (CF) is a monogenic autosomal recessive disorder. The clinical manifestations of the disease are caused by ∼2,000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It is unlikely that any one approach will be efficient in correcting all defects. The recent approvals of ivacaftor, lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor represent the genesis of a new era of precision combination medicine for the CF patient population. In this review, we discuss targeted translational readthrough approaches as mono and combination therapies for CFTR nonsense mutations. We examine the current status of efficacy of translational readthrough/nonsense suppression therapies and their limitations, including non-native amino acid incorporation at PTCs and nonsense-mediated mRNA decay (NMD), along with approaches to tackle these limitations. We further elaborate on combining various therapies such as readthrough agents, NMD inhibitors, and corrector/potentiators to improve the efficacy and safety of suppression therapy. These mutation specific strategies that are directed towards the basic CF defects should positively impact CF patients bearing nonsense mutations.
Topics: Aminophenols; Aminopyridines; Animals; Benzodioxoles; Codon, Nonsense; Cystic Fibrosis; Dose-Response Relationship, Drug; Humans; Indoles; Molecular Structure; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Structure-Activity Relationship
PubMed: 32512483
DOI: 10.1016/j.ejmech.2020.112436 -
Journal of Comparative Effectiveness... Aug 2021Pexidartinib was approved for the treatment of tenosynovial giant cell tumors with a required Risk Evaluation and Mitigation Strategy (REMS) to ensure its safe use. As...
Pexidartinib was approved for the treatment of tenosynovial giant cell tumors with a required Risk Evaluation and Mitigation Strategy (REMS) to ensure its safe use. As required by the REMS, a survey was conducted to document the knowledge, attitudes and behavior (KAB) of patients/caregivers and healthcare providers (HCPs) regarding the risk of serious and potentially fatal liver injury due to pexidartinib, the need for liver testing prior to and during treatment and the need for patient counseling about this risk. The KAB survey was conducted among 40 patients and 18 HCPs enrolled in the pexidartinib REMS. Among patients, 87.5% demonstrated understanding of key risk message (KRM) 1 (risk of serious liver injury), 87.5% demonstrated understanding of KRM2 (liver testing requirement) and 77.5% demonstrated understanding of both KRMs. Among HCPs, 83.3% demonstrated understanding of KRM1, 88.9% demonstrated understanding of KRM2, 100% demonstrated understanding of KRM3 (patient counseling) and 83.3% demonstrated understanding of all three KRMs. The KAB surveys demonstrated that the educational goals of the pexidartinib REMS were being achieved.
Topics: Aminopyridines; Caregivers; Health Knowledge, Attitudes, Practice; Health Personnel; Humans; Pyrroles
PubMed: 34187183
DOI: 10.2217/cer-2020-0253 -
Cancer Immunology, Immunotherapy : CII Jul 2023Acute myeloid leukemia (AML) treatment remains challenging. CD70 was reported as a promising AML-specific antigen. Preclinically, CAR T-cell with single-chain-variable...
BACKGROUND
Acute myeloid leukemia (AML) treatment remains challenging. CD70 was reported as a promising AML-specific antigen. Preclinically, CAR T-cell with single-chain-variable fragment (scFv) or truncated CD27 targeting CD70 has been reported to treat AML. However, various disadvantages including spontaneous exhaustion, proteinase-mediated loss of functional receptors, and high immunogenicity, limited its further application to clinical settings. Alternatively, the single-variable domain on heavy chain (VHH), also known as nanobodies, with comparable binding ability and specificity, provides an optional solution.
METHOD
We generated CD70 knocked-out novel nanobody-based anti-CD70-CAR T-cells (nb70CAR-T) with two different VHHs for antigen detection. Next, we detected the CD70 expression on primary AML blasts by flow cytometry and associated the efficacy of nb70CAR-T with the target antigen density. Finally, epigenetic modulators were investigated to regulate the CD70 expression on AML cells to promote the functionality of nb70CAR-T.
RESULTS
Our nb70CAR-T exhibited expected tumoricidal functionality against CD70-expressed cell lines and primary AML blasts. However, CD70 expression in primary AML blasts was not consistently high and nb70CAR-T potently respond to an estimated 40.4% of AML patients when the CD70 expression level was over a threshold of 1.6 (MFI ratio). Epigenetic modulators, Decitabine and Chidamide can up-regulate CD70 expression on AML cells, enhancing the treatment efficacy of nb70CAR-T.
CONCLUSION
CD70 expression in AML blasts was not fully supportive of its role in AML targeted therapy as reported. The combinational use of Chidamide and Decitabine with nb70CAR-T could provide a new potential for the treatment of AML.
Topics: Humans; Decitabine; Leukemia, Myeloid, Acute; Aminopyridines; Immunotherapy, Adoptive; T-Lymphocytes
PubMed: 36932256
DOI: 10.1007/s00262-023-03422-6 -
American Journal of Hematology Jun 2022Patients with relapsed warm antibody autoimmune hemolytic anemia (wAIHA) have limited treatment options. Fostamatinib is a potent, orally administered spleen tyrosine...
Patients with relapsed warm antibody autoimmune hemolytic anemia (wAIHA) have limited treatment options. Fostamatinib is a potent, orally administered spleen tyrosine kinase inhibitor approved in the United States and Europe for the treatment of adults with chronic immune thrombocytopenia (ITP). This phase 2 study evaluated the response to fostamatinib, administered at 150 mg BID orally with or without food in adults with wAIHA and active hemolysis with hemoglobin (Hgb) <10 g/dL who had failed at least one prior treatment. Hemoglobin levels and safety assessments were performed at visits every 2 weeks. The primary endpoint was Hgb >10 g/dL with an increase of ≥2 g/dL from baseline by week 24 without rescue therapy or red blood cell transfusion. Eleven of 24 (46%) patients achieved the primary endpoint. Increases in median Hgb were detected at week 2 and sustained over time. Median lactate dehydrogenase levels and reticulocyte counts generally declined over time with little change in median haptoglobin levels. The most common adverse events (AEs) were diarrhea (42%), fatigue (42%), hypertension (27%), dizziness (27%), and insomnia (23%). AEs were manageable and consistent with the fostamatinib safety database of over 3900 patients across multiple diseases (rheumatoid arthritis, B-cell lymphoma, COVID-19, and ITP). No new safety signals were detected. Fostamatinib may be a promising therapeutic option for wAIHA. A randomized, double-blind, phase 3 study is nearing completion.
Topics: Adult; Aminopyridines; Anemia, Hemolytic, Autoimmune; COVID-19; Humans; Morpholines; Oxazines; Pyridines; Pyrimidines
PubMed: 35179251
DOI: 10.1002/ajh.26508