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Leukemia & Lymphoma 2023Advances in the treatment of acute myeloid leukemia (AML) over the last 40 years have been limited. With an improved understanding of the pathophysiology of the... (Review)
Review
Advances in the treatment of acute myeloid leukemia (AML) over the last 40 years have been limited. With an improved understanding of the pathophysiology of the disease, the advent of new treatment options has enriched the armamentarium of the physician to combat the disease. Mutations of the isocitrate dehydrogenase (s) genes are common in AML and occur in 20-30% of cases. These mutations lead to DNA hypermethylation, aberrant gene expression, cell proliferation, and abnormal differentiation. Targeting mutant , either as monotherapy or in combination with hypomethylating agents (HMAs) or BCL-2 inhibitors, has opened new avenues of therapy for these patients.This review will outline the function of s and focus on the biological effects of mutations in AML, their prognosis and treatment options.
Topics: Humans; Aminopyridines; Antineoplastic Agents; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Mutation; Triazines
PubMed: 37462435
DOI: 10.1080/10428194.2023.2237153 -
Journal of Oncology Pharmacy Practice :... Jul 2023Cyclin-dependent kinase (CDK) 4/6 inhibitors have shown a different adverse effect. In this case, persistent grade 3 hepatoxicity was observed after ribociclib....
INTRODUCTION
Cyclin-dependent kinase (CDK) 4/6 inhibitors have shown a different adverse effect. In this case, persistent grade 3 hepatoxicity was observed after ribociclib. Therefore, ribociclib therapy was stopped, and then palbociclib was introduced. Transaminase levels returned to normal by switching to palbociclib therapy.
CASE REPORT
71-year-old postmenopausal female patient with luminal subtypes of metastatic breast cancer treated with ribociclib.
MANAGEMENT & OUTCOME
Grade 3 hepatotoxicity secondary to ribociclib developed. She was successfully treated with palbociclib 125 mg.
DISCUSSION
In our case, palbociclib was started with a full dose, to increase treatment success. Starting with a 125 mg dose was not cause any toxicity. Nevertheless, laboratory follow-up is required in terms of neutropenia and increased transaminases.
Topics: Female; Humans; Aged; Aminopyridines; Purines; Breast Neoplasms; Drug-Related Side Effects and Adverse Reactions; Chemical and Drug Induced Liver Injury; Protein Kinase Inhibitors; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36762416
DOI: 10.1177/10781552231154009 -
Neuro-oncology Apr 2024Altered branched-chain amino acid (BCAA) metabolism modulates epigenetic modification, such as H3K27ac in cancer, thus providing a link between metabolic reprogramming...
BACKGROUND
Altered branched-chain amino acid (BCAA) metabolism modulates epigenetic modification, such as H3K27ac in cancer, thus providing a link between metabolic reprogramming and epigenetic change, which are prominent hallmarks of glioblastoma multiforme (GBM). Here, we identified mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase (HMGCL), an enzyme involved in leucine degradation, promoting GBM progression and glioma stem cell (GSC) maintenance.
METHODS
In silico analysis was performed to identify specific molecules involved in multiple processes. Glioblastoma multiforme cells were infected with knockdown/overexpression lentiviral constructs of HMGCL to assess malignant performance in vitro and in an orthotopic xenograft model. RNA sequencing was used to identify potential downstream molecular targets.
RESULTS
HMGCL, as a gene, increased in GBM and was associated with poor survival in patients. Knockdown of HMGCL suppressed proliferation and invasion in vitro and in vivo. Acetyl-CoA was decreased with HMGCL knockdown, which led to reduced NFAT1 nuclear accumulation and H3K27ac level. RNA sequencing-based transcriptomic profiling revealed FOXM1 as a candidate downstream target, and HMGCL-mediated H3K27ac modification in the FOXM1 promoter induced transcription of the gene. Loss of FOXM1 protein with HMGCL knockdown led to decreased nuclear translocation and thus activity of β-catenin, a known oncogene. Finally, JIB-04, a small molecule confirmed to bind to HMGCL, suppressed GBM tumorigenesis in vitro and in vivo.
CONCLUSIONS
Changes in acetyl-CoA levels induced by HMGCL altered H3K27ac modification, which triggers transcription of FOXM1 and β-catenin nuclear translocation. Targeting HMGCL by JIB-04 inhibited tumor growth, indicating that mediators of BCAA metabolism may serve as molecular targets for effective GBM treatment.
Topics: Humans; Acetyl Coenzyme A; Acetylation; Aminopyridines; beta Catenin; Cell Line, Tumor; Cell Proliferation; Forkhead Box Protein M1; Gene Expression Regulation, Neoplastic; Glioblastoma; Histones; Hydrazones; Lyases
PubMed: 38069906
DOI: 10.1093/neuonc/noad232 -
Autophagy Feb 2024Crizotinib, a small-molecule tyrosine kinase inhibitor targeting ALK, MET and ROS1, is the first-line drug for ALK-positive metastatic non-small cell lung cancer and is...
Crizotinib, a small-molecule tyrosine kinase inhibitor targeting ALK, MET and ROS1, is the first-line drug for ALK-positive metastatic non-small cell lung cancer and is associated with severe, sometimes fatal, cases of cardiac failure, which increases the risk of mortality. However, the underlying mechanism remains unclear, which causes the lack of therapeutic strategy. We established in vitro and in vivo models for crizotinib-induced cardiotoxicity and found that crizotinib caused left ventricular dysfunction, myocardial injury and pathological remodeling in mice and induced cardiomyocyte apoptosis and mitochondrial injury. In addition, we found that crizotinib prevented the degradation of MET protein by interrupting autophagosome-lysosome fusion and silence of MET or re-activating macroautophagy/autophagy flux rescued the cardiomyocytes death and mitochondrial injury caused by crizotinib, suggesting that impaired autophagy activity is the key reason for crizotinib-induced cardiotoxicity. We further confirmed that recovering the phosphorylation of PRKAA/AMPK (Ser485/491) by metformin re-activated autophagy flux in cardiomyocytes and metformin rescued crizotinib-induced cardiomyocyte injury and cardiac complications. In summary, we revealed a novel mechanism for crizotinib-induced cardiotoxicity, wherein the crizotinib-impaired autophagy process causes cardiomyocyte death and cardiac injury by inhibiting the degradation of MET protein, demonstrated a new function of impeded autophagosome-lysosome fusion in drugs-induced cardiotoxicity, pointed out the essential role of the phosphorylation of PRKAA (Ser485/491) in autophagosome-lysosome fusion and confirmed metformin as a potential therapeutic strategy for crizotinib-induced cardiotoxicity. AAV: adeno-associated virus; ACAC/ACC: acetyl-Co A carboxylase; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; ATG7: autophagy related 7; CHX: cycloheximide; CKMB: creatine kinase myocardial band; CQ: chloroquine; c-PARP: cleaved poly (ADP-ribose) polymerase; DAPI: 4'6-diamidino-2-phenylindole; EF: ejection fraction; FOXO: forkhead box O; FS: fractional shortening; GSEA: gene set enrichment analysis; H&E: hematoxylin and eosin; HF: heart failure; HW: TL: ratio of heart weight to tibia length; IR: ischemia-reperfusion; KEGG: Kyoto encyclopedia of genes and genomes; LAMP2: lysosomal-associated membrane protein 2; LDH: lactate dehydrogenase; MCMs: mouse cardiomyocytes; MMP: mitochondrial membrane potential; mtDNA: mitochondrial DNA; MYH6: myosin, heavy peptide 6, cardiac muscle, alpha; MYH7: myosin, heavy peptide 7, cardiac muscle, beta; NPPA: natriuretic peptide type A; NPPB: natriuretic peptide type B; PI: propidium iodide; PI3K: phosphoinositide 3-kinase; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; qPCR: quantitative real-time PCR; SD: standard deviation; SRB: sulforhodamine B; TKI: tyrosine kinase inhibitor; WGA: wheat germ agglutinin.
Topics: Mice; Animals; AMP-Activated Protein Kinases; Autophagy; Phosphorylation; Macroautophagy; Crizotinib; Autophagosomes; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Phosphatidylinositol 3-Kinases; Protein-Tyrosine Kinases; Tyrosine Kinase Inhibitors; Lung Neoplasms; Proto-Oncogene Proteins; Metformin; Peptides; Myosins; Lysosomes; Adenosine Monophosphate; Receptor Protein-Tyrosine Kinases
PubMed: 37733896
DOI: 10.1080/15548627.2023.2259216 -
Drugs Dec 2023Iruplinalkib (Trade name: ; Code name: WX-0593), a highly selective oral anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI), is... (Review)
Review
Iruplinalkib (Trade name: ; Code name: WX-0593), a highly selective oral anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI), is being developed by Qilu Pharmaceutical Co., Ltd. for the treatment of ALK-positive (ALK+) or ROS1-positive (ROS1+) non-small cell lung cancer (NSCLC). In June 2023, iruplinalkib was approved in China for the treatment of patients with locally advanced or metastatic ALK+ NSCLC who have progressed after prior crizotinib therapy or are intolerant to crizotinib. This article summarizes the milestones in the development of iruplinalkib leading to this first approval for the treatment of patients with locally advanced or metastatic ALK+ NSCLC.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Crizotinib; Lung Neoplasms; Protein-Tyrosine Kinases; Receptor Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Protein Kinase Inhibitors
PubMed: 38008856
DOI: 10.1007/s40265-023-01970-w -
Skin Therapy Letter Sep 2023Roflumilast is a highly selective phosphodiesterase-4 inhibitor for the treatment of plaque psoriasis. Topical roflumilast 0.3% cream, approved by the US FDA and Health... (Review)
Review
Roflumilast is a highly selective phosphodiesterase-4 inhibitor for the treatment of plaque psoriasis. Topical roflumilast 0.3% cream, approved by the US FDA and Health Canada for use in adolescents and adults, has proven efficacy and tolerability. It is non-steroidal, administered once-daily, and highly potent, with a unique delivery formulation. It can be used on most body areas, including the sensitive intertriginous regions and face. Herein, we review the safety and efficacy of roflumilast 0.3% cream, as demonstrated in clinical trials.
Topics: Adolescent; Adult; Humans; Psoriasis; Aminopyridines; Benzamides; Emollients; Phosphodiesterase 4 Inhibitors
PubMed: 37734074
DOI: No ID Found -
Expert Review of Clinical Immunology 2023New non-steroidal topical agents are needed for the treatment of psoriasis. Roflumilast cream 0.3% is a once daily phosphodiesterase-4 inhibitor that was recently... (Review)
Review
INTRODUCTION
New non-steroidal topical agents are needed for the treatment of psoriasis. Roflumilast cream 0.3% is a once daily phosphodiesterase-4 inhibitor that was recently approved by the FDA for the treatment of plaque psoriasis in adolescents and adults. It is indicated for use on all body surfaces including intertriginous areas.
AREAS COVERED
In this review, we summarize the current knowledge about roflumilast cream for the treatment of psoriasis, highlighting its efficacy and safety profile from published clinical trials. Roflumilast's mechanism of action and pharmacokinetic profile are also discussed.
EXPERT OPINION
Positive results were reported across trials with 48% of patients treated with roflumilast achieving an Investigator Global Assessment score of clear or almost clear at 8 weeks in phase III studies. Most adverse events were mild or moderate in severity and few application-site reactions were reported among participants. Unique advantages of the cream are its success in treating intertriginous areas and its ability to reduce symptoms of itch, results of which may significantly improve quality of life for patients. In the future, real-world data and active comparator trials with existing non-steroidal agents are needed to better understand roflumilast's place in the current treatment landscape.
Topics: Adult; Adolescent; Humans; Quality of Life; Psoriasis; Aminopyridines; Benzamides; Treatment Outcome; Severity of Illness Index
PubMed: 37243575
DOI: 10.1080/1744666X.2023.2219897 -
Journal of Thoracic Oncology : Official... Nov 2023Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, improved outcomes compared with crizotinib in patients with previously untreated ALK-positive advanced...
INTRODUCTION
Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, improved outcomes compared with crizotinib in patients with previously untreated ALK-positive advanced NSCLC in the phase 3 CROWN study. Here, we investigated response correlates using plasma circulating tumor DNA (ctDNA) and tumor tissue profiling.
METHODS
ALK fusions and ALK with or without TP53 mutations were assessed by next-generation sequencing. End points included objective response rate (ORR), duration of response, and progression-free survival (PFS) by blinded independent central review on the basis of EML4::ALK variants and ALK with or without TP53 or other mutation status.
RESULTS
ALK fusions were detected in the ctDNA of 62 patients in the lorlatinib arm and 64 patients in the crizotinib arm. ORRs were numerically higher with lorlatinib versus crizotinib for EML4::ALK variant 1 (v1; 80.0% versus 50.0%) and variant 2 (v2; 85.7% versus 50.0%) but were similar between the arms for variant 3 (v3; 72.2% versus 73.9%). Median PFS in the lorlatinib arm was not reached for EML4::ALK v1 and v2 and was 33.3 months for v3; in the crizotinib arm, median PFS was 7.4 months, not reached, and 5.5 months, respectively. ORRs and PFS were improved with lorlatinib versus crizotinib regardless of TP53 mutation status and in patients harboring preexisting bypass pathway resistance alterations. In the lorlatinib arm, PFS was lower in patients who had a co-occurring TP53 mutation. Results from ctDNA analysis were similar to those observed with tumor tissue samples.
CONCLUSIONS
Patients with untreated ALK-positive advanced NSCLC derived greater clinical benefits, with higher ORRs and potentially longer PFS, when treated with lorlatinib compared with crizotinib, independent of EML4::ALK variant or ALK mutations, TP53 mutations, or bypass resistance alterations.
Topics: Humans; Crizotinib; Lung Neoplasms; Antineoplastic Agents; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Lactams, Macrocyclic; Protein Kinase Inhibitors; Mutation; Tumor Suppressor Protein p53
PubMed: 37541389
DOI: 10.1016/j.jtho.2023.07.023 -
Nature Medicine Apr 2024Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment.... (Randomized Controlled Trial)
Randomized Controlled Trial
Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n = 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n = 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P = 0.003), higher overall response rate (44.0% versus 13.0%, P = 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P = 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8 T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239 .
Topics: Humans; Aminopyridines; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bevacizumab; Colorectal Neoplasms; Histone Deacetylase Inhibitors; Programmed Cell Death 1 Receptor; Tumor Microenvironment; Vascular Endothelial Growth Factor A
PubMed: 38438735
DOI: 10.1038/s41591-024-02813-1 -
JNCI Cancer Spectrum Jul 2023The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib are standard-of-care therapy for hormone receptor-positive advanced or... (Review)
Review
The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib are standard-of-care therapy for hormone receptor-positive advanced or metastatic breast cancer, based on randomized trials showing improved progression-free survival for all 3 drugs and overall survival for ribociclib and abemaciclib. Results in early breast cancer are discordant, with sustained improvement in invasive disease-free survival demonstrated for abemaciclib but not other CDK4/6 inhibitors to date. We review nonclinical studies exploring mechanistic differences between the drugs, the impact of continuous dosing on treatment effect, and translational research into potential resistance mechanisms and prognostic and predictive markers. We focus particularly on how emerging findings may help us understand similarities and differences between the available CDK4/6 inhibitors. Even at late-stage clinical development, there remains much to learn about how agents in this class exert their varying effects.
Topics: Female; Humans; Aminopyridines; Breast Neoplasms; Cyclin-Dependent Kinase 4
PubMed: 37369022
DOI: 10.1093/jncics/pkad045