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Clinical Cancer Research : An Official... May 2024To identify potential predictors of response and resistance mechanisms in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To identify potential predictors of response and resistance mechanisms in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC) treated with the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor abemaciclib ± endocrine therapy (ET), baseline and acquired genomic alterations in circulating tumor DNA (ctDNA) were analyzed and associated with clinical outcomes.
EXPERIMENTAL DESIGN
MONARCH 3: postmenopausal women with HR+, HER2- ABC and no prior systemic therapy in the advanced setting were randomly assigned to abemaciclib or placebo plus nonsteroidal aromatase inhibitor (NSAI). nextMONARCH: women with HR+, HER2- metastatic breast cancer that progressed on/after prior ET and chemotherapy were randomly assigned to abemaciclib alone (two doses) or plus tamoxifen. Baseline and end-of-treatment plasma samples from patients in MONARCH 3 and nextMONARCH (monotherapy arms) were analyzed to identify somatic genomic alterations. Association between genomic alterations and median progression-free survival (mPFS) was assessed.
RESULTS
Most patients had ≥1 genomic alteration detected in baseline ctDNA. In MONARCH 3, abemaciclib+NSAI was associated with improved mPFS versus placebo+NSAI, regardless of baseline alterations. ESR1 alterations were less frequently acquired in the abemaciclib+NSAI arm than placebo+NSAI. Acquired alterations potentially associated with resistance to abemaciclib ± NSAI included RB1 and MYC.
CONCLUSIONS
In MONARCH 3, certain baseline ctDNA genomic alterations were prognostic for ET but not predictive of abemaciclib response. Further studies are warranted to assess whether ctDNA alterations acquired during abemaciclib treatment differ from other CDK4/6 inhibitors. Findings are hypothesis generating; further exploration is warranted into mechanisms of resistance to abemaciclib and ET. See related commentary by Wander and Bardia, p. 2008.
Topics: Humans; Female; Aminopyridines; Benzimidazoles; Breast Neoplasms; Circulating Tumor DNA; Antineoplastic Combined Chemotherapy Protocols; Middle Aged; Aged; Biomarkers, Tumor; Receptor, ErbB-2; Cyclin-Dependent Kinase 4; Receptors, Estrogen; Antineoplastic Agents, Hormonal; Drug Resistance, Neoplasm; Tamoxifen; Aromatase Inhibitors; Mutation; Adult; Cyclin-Dependent Kinase 6
PubMed: 37889120
DOI: 10.1158/1078-0432.CCR-22-3573 -
The Journal of Organic Chemistry Aug 2023Oxoanions such as carboxylates, phosphates, and sulfates play important roles in both chemistry and biology and are abundant on the cell surface. We report on the...
Oxoanions such as carboxylates, phosphates, and sulfates play important roles in both chemistry and biology and are abundant on the cell surface. We report on the synthesis and properties of a rationally designed guanidinium-containing oxoanion binder, 1-guanidino-8-amino-2,7-diazacarbazole (GADAC). GADAC binds to a carboxylate, phosphate, and sulfate in pure water with affinities of 3.6 × 10, 1.1 × 10, and 4.2 × 10 M, respectively. Like 2-azacarbazole, which is a natural product that enables scorpions to fluoresce, GADAC is fluorescent in water (λ = 356 nm, λ = 403 nm, ε = 13,400 M cm). The quantum yield of GADAC is pH-sensitive, increasing from Φ = 0.12 at pH 7.4 to Φ = 0.53 at pH 4.0 as a result of the protonation of the aminopyridine moiety. The uptake of GADAC into live human melanoma cells is detectable in the DAPI channel at low micromolar concentrations. Its properties make GADAC a promising candidate for applications in oxoanion binding and fluorescence labeling in biological (e.g., the delivery of cargo into cells) and other contexts.
Topics: Humans; Guanidine; Water; Phosphates; Carboxylic Acids; Coloring Agents
PubMed: 37530571
DOI: 10.1021/acs.joc.3c00982 -
European Journal of Cancer (Oxford,... Mar 2024In monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no...
BACKGROUND
In monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no expected disease-related symptoms, therapies in the adjuvant setting should preserve quality of life (QoL). With all patients off abemaciclib, we report updated patient-reported outcomes (PROs) for the full 2-year treatment period and follow-up.
METHODS
Patients completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, and 24 months during treatment, and 1, 6, and 12 months after treatment discontinuation. Mixed effects repeated measures model estimated changes from baseline within and between arms for QoL scales and individual items. Meaningful changes were prespecified and no statistical testing was performed. Frequencies of responses to items associated with relevant adverse events and treatment bother were summarized.
RESULTS
At baseline, completion rates for PRO instruments were >96 %. Mean changes from baseline for all QoL scales were numerically similar within and between arms (ie, less than prespecified thresholds). The same was observed for all individual items, except diarrhea. Within abemaciclib arm, meaningful differences for diarrhea were observed at 3 and 6 months (mean increases of 1.19 and 1.03 points on 5-point scale, respectively). During treatment, most patients in both arms (69-78 %) reported being bothered "a little bit" or "not at all" by side effects. Overall, patterns for fatigue were similar between arms. During post-treatment follow-up, PROs in both arms were similar to baseline.
CONCLUSION
PRO findings confirm a tolerable and reversible toxicity profile for abemaciclib. QoL was preserved with the addition of adjuvant abemaciclib to endocrine therapy, supporting its use in patients with HR+, HER2-, high-risk early breast cancer.
Topics: Humans; Female; Breast Neoplasms; Quality of Life; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Patient Reported Outcome Measures; Diarrhea; Receptor, ErbB-2; Benzimidazoles
PubMed: 38244363
DOI: 10.1016/j.ejca.2024.113555 -
Neurobiology of Disease Oct 2023Traumatic brain injury (TBI) involves an acute injury (primary damage), which may evolve in the hours to days after impact (secondary damage). Seizures and cortical...
Traumatic brain injury (TBI) involves an acute injury (primary damage), which may evolve in the hours to days after impact (secondary damage). Seizures and cortical spreading depolarization (CSD) are metabolically demanding processes that may worsen secondary brain injury. Metabolic stress has been associated with mitochondrial dysfunction, including impaired calcium homeostasis, reduced ATP production, and elevated ROS production. However, the association between mitochondrial impairment and vascular function after TBI is poorly understood. Here, we explored this association using a rodent closed head injury model. CSD is associated with neurobehavioral decline after TBI. Craniotomy was performed to elicit CSD via electrical stimulation or to induce seizures via 4-aminopyridine application. We measured vascular dysfunction following CSDs and seizures in TBI animals using laser doppler flowmetry. We observed a more profound reduction in local cortical blood flow in TBI animals compared to healthy controls. CSD resulted in mitochondrial dysfunction and pathological signs of increased oxidative stress adjacent to the vasculature. We explored these findings further using electron microscopy and found that TBI and CSDs resulted in vascular morphological changes and mitochondrial cristae damage in astrocytes, pericytes and endothelial cells. Overall, we provide evidence that CSDs induce mitochondrial dysfunction, impaired cortical blood flow, and neurobehavioral deficits in the setting of TBI.
Topics: Animals; Neurovascular Coupling; Endothelial Cells; Brain Injuries, Traumatic; Brain Injuries
PubMed: 37619791
DOI: 10.1016/j.nbd.2023.106269 -
Revue Neurologique May 2024Genetic cerebellar ataxias are still a diagnostic challenge, and yet not all of them have been identified. Very recently, in early 2023, a new cause of late-onset... (Review)
Review
Genetic cerebellar ataxias are still a diagnostic challenge, and yet not all of them have been identified. Very recently, in early 2023, a new cause of late-onset cerebellar ataxia (LOCA) was identified, spinocerebellar ataxia 27B (SCA27B). This is an autosomal dominant ataxia due to a GAA expansion in intron 1 of the FGF14 gene. Thanks to the many studies carried out since its discovery, it is now possible to define the clinical phenotype, its particularities, and the progression of SCA27B. It has also been established that it is one of the most frequent causes of LOCA. The core phenotype of the disease consists of slowly progressive late-onset ataxia with cerebellar syndrome, oculomotor disorders including downbeat nystagmus, and episodic symptoms such as diplopia. Therapeutic approaches have been proposed, including acetazolamide, and 4-aminopyridine, the latter with a better benefit/tolerance profile.
Topics: Humans; Spinocerebellar Ataxias; Age of Onset; Cerebellar Ataxia; Fibroblast Growth Factors; Spinocerebellar Degenerations
PubMed: 38609751
DOI: 10.1016/j.neurol.2024.03.007 -
Breast Cancer Research and Treatment Sep 2023The monarchE trial showed that the addition of abemaciclib improves efficacy in patients with high-risk early breast cancer (EBC). We analyzed the long-term outcomes of... (Review)
Review
PURPOSE
The monarchE trial showed that the addition of abemaciclib improves efficacy in patients with high-risk early breast cancer (EBC). We analyzed the long-term outcomes of a population similar to the monarchE trial to put into context the potential benefit of abemaciclib.
METHODS
HR-positive/HER2-negative EBC patients eligible for the monarchE study were selected from 3 adjuvant clinical trials and a breast cancer registry. Patients with ≥ 4 positive axillary lymph nodes (N +) or 1-3 N + with tumor size ≥ 5 cm and/or histologic grade 3 and/or Ki67 ≥ 20%, who had undergone surgery with curative intent and had received anthracyclines ± taxanes and endocrine therapy in the neoadjuvant and /or adjuvant setting were included. We performed analysis of Invasive Disease-Free Survival (iDFS), Distant Disease-Free Survival (dDFS) and Overall Survival (OS) at 5 and 10 years, as well as yearly (up to 10) of Invasive Relapse Rate (IRR), Distant Relapse Rate (DRR) and Death Rate (DR).
RESULTS
A total of 1,617 patients were analyzed from the GEICAM-9906 (312), GEICAM-2003-10 (210), and GEICAM-2006-10 (160) trials plus 935 from El Álamo IV. With a median follow-up of 10.1 years, the 5 and 10 years iDFS rates were 75.2% and 57.0%, respectively. The dDFS and OS rates at 5 years were 77.4% and 88.8% and the respective figures at 10 years were 59.7% and 70.9%.
CONCLUSIONS
This data points out the need for new therapies for those patients. A longer follow-up of the monarchE study to see the real final benefit with abemaciclib is warranted.
TRIAL REGISTRATION
ClinTrials.gov: GEICAM/9906: NCT00129922; GEICAM/ 2003-10: NCT00129935 and GEICAM/ 2006-10: NCT00543127.
Topics: Humans; Female; Breast Neoplasms; Chemotherapy, Adjuvant; Neoplasm Recurrence, Local; Aminopyridines; Disease-Free Survival; Antineoplastic Combined Chemotherapy Protocols; Receptor, ErbB-2
PubMed: 37338729
DOI: 10.1007/s10549-023-07002-1 -
International Journal of Molecular... Dec 2023The development of a wider range of therapeutic options is a key objective in drug discovery for chronic obstructive pulmonary disease (COPD). Fundamental advances in... (Review)
Review
The development of a wider range of therapeutic options is a key objective in drug discovery for chronic obstructive pulmonary disease (COPD). Fundamental advances in lung biology have the potential to greatly expand the number of therapeutic targets in COPD. The recently reported successful Phase 3 clinical trial of the first biologic agent for COPD, the monoclonal antibody dupilumab, adds additional support to the importance of targeting inflammatory pathways in COPD. However, numerous other cellular mechanisms are important targets in COPD therapeutics, including airway remodeling, the CFTR ion channel, and mucociliary function. Some of these emerging targets can be exploited by the expanded use of existing COPD drugs, such as roflumilast, while targeting others will require the development of novel molecular entities. The identification of additional therapeutic targets and agents has the potential to greatly expand the value of using clinical and biomarker data to classify COPD into specific subsets, each of which can be predictive of an enhanced response to specific subset(s) of targeted therapies. The author reviews established and emerging drug targets in COPD and uses this as a framework to define a novel classification of COPD based on therapeutic targets. This novel classification has the potential to enhance precision medicine in COPD patient care and to accelerate clinical trials and pre-clinical drug discovery efforts.
Topics: Humans; Precision Medicine; Pulmonary Disease, Chronic Obstructive; Lung; Inflammation; Aminopyridines; Cyclopropanes; Ion Channels
PubMed: 38139192
DOI: 10.3390/ijms242417363 -
The Journal of Antimicrobial... Nov 2023Fosmanogepix (APX001), a first-in-class, intravenous (IV) and oral (PO) antifungal prodrug, is being developed to treat invasive fungal diseases (IFDs). Manogepix...
OBJECTIVES
Fosmanogepix (APX001), a first-in-class, intravenous (IV) and oral (PO) antifungal prodrug, is being developed to treat invasive fungal diseases (IFDs). Manogepix (APX001A; active moiety) targets fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, inhibiting cell wall synthesis causing loss of viability. This open-label, multicentre, Phase 1b study in patients with AML and neutropenia (absolute neutrophil count <500 cells/μL; >10 days) undergoing chemotherapy aimed to assess tolerability, safety and pharmacokinetics (PK) of IV and PO fosmanogepix.
METHODS
Of 21 adult AML patients undergoing remission induction chemotherapy, 10 received IV fosmanogepix (600 mg; q24h) and 11 received oral fosmanogepix (500 mg; q24h) over 14 days, with a 28 day follow-up. Patients also received remission induction chemotherapy [sequential high-dose cytarabine and mitoxantrone (S-HAM) or 7 + 3 regimen] for AML and IFD prophylaxis (posaconazole). A two-compartmental PK model from previous studies in healthy volunteers was fitted to manogepix plasma data.
RESULTS
Of 26 fosmanogepix-related adverse events (AEs; IV: 14; PO: 12) in 9 (42.9%) patients [IV: 5 (50%); PO: 4 (36.4%)], none were serious or resulted in fosmanogepix discontinuation. Most frequently occurring fosmanogepix-related AEs were Grade 1/2 nausea [four events in three patients (14.3%)]; vomiting, ALT increase, and delirium [two events; two patients (9.5%) each]. One patient experienced fosmanogepix-related Grade 3 hypertension. Dose-corrected geometric mean ratio of AUC (PO-to-IV) was 95%. Elimination half-lives (∼2 days) were consistent with prior studies in healthy volunteers.
CONCLUSIONS
Fosmanogepix was safe and well tolerated in AML patients with neutropenia receiving remission induction chemotherapy. Safety and PK profiles were comparable to healthy volunteers.
Topics: Adult; Humans; Antifungal Agents; Aminopyridines; Leukemia, Myeloid, Acute; Neutropenia
PubMed: 37681450
DOI: 10.1093/jac/dkad269 -
Cytokine & Growth Factor Reviews Feb 2024A dysregulated cell division, one of the key hallmarks of cancer, results in uncontrolled cellular proliferation. This aberrant process, mediated by a dysregulated... (Review)
Review
A dysregulated cell division, one of the key hallmarks of cancer, results in uncontrolled cellular proliferation. This aberrant process, mediated by a dysregulated cell-cycle machinery and overactivation of cyclin-dependent kinase (CDK) 4 and 6, can potentially promote tumorigenesis. The clinical application of CDK 4/6 inhibitors, developed to inhibit cell-cycle progression, in the treatment regimens of breast cancer (BC) patients is expanding. Currently, three agents, ribociclib, palbociclib, and abemaciclib, are approved for treating patients with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic BC. In addition, abemaciclib is FDA and EMA-approved for patients with hormone receptor-positive HER2-negative, node-positive, early BC at high risk of recurrence. Emerging data suggest potential anti-tumor effects beyond cell cycle arrest, providing novel insights into the agent's mechanisms of action. As a result, a broader application of the CDK4/6 inhibitors in patients with cancer is achieved, contributing to enhanced optimized treatment in the adjuvant and neoadjuvant settings. Herein, the immunomodulatory activities of CDK4/6 inhibitors, their impact on the cell's metabolic state, and the effect on the decision of the cell to undergo quiescence or senescence are discussed. Moreover, this review provides an update on clinical trial outcomes and the differences in the underlying mechanisms between the distinct CDK4/6 inhibitors.
Topics: Humans; Female; Breast Neoplasms; Cyclin-Dependent Kinase 6; Benzimidazoles; Cell Cycle; Protein Kinase Inhibitors; Cyclin-Dependent Kinase 4; Aminopyridines
PubMed: 37838584
DOI: 10.1016/j.cytogfr.2023.10.001 -
Scientific Reports Feb 2024Individual trials of abemaciclib, palbociclib, and ribociclib show a similar impact on progression-free survival yet differing statistical significance for overall... (Meta-Analysis)
Meta-Analysis
Individual trials of abemaciclib, palbociclib, and ribociclib show a similar impact on progression-free survival yet differing statistical significance for overall survival (OS). A robust comparative evaluation of OS, safety, and tolerability of the three drugs is warranted. A systematic literature search identified phase 3 randomized clinical trials reporting OS of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy in ER-positive/HER2-negative advanced breast cancer. Trial-level data on OS and common and serious adverse events (AE) were extracted for each drug. In the absence of direct comparisons, a network meta-analysis was performed to evaluate pairwise comparative efficacy, safety, and tolerability of each of the CDK4/6i. Seven studies comprising of 4415 patients met the inclusion criteria. Median follow-up was 73.3 months (range: 48.7-97.2 months). There were no statistically significant differences in OS between any of the CDK4/6i. Compared to palbociclib, ribociclib and abemaciclib both showed significantly higher GI toxicity (grade 1-2 vomiting OR 1.87 [95% CI 1.37-2.56] and OR 2.27 [95% CI 1.59-3.23] respectively). Compared to palbociclib, abemaciclib was associated with more grade 3-4 diarrhea OR 118.06 [95% CI 7.28-1915.32]. In contrast, palbociclib was associated with significantly more neutropenia than ribociclib and abemaciclib but significantly lower risk of grade 3-4 infections. Abemaciclib had significantly less grade 3-4 transaminitis and grade 3-4 neutropenia than ribociclib. Treatment discontinuation and death due to AE were significantly higher with abemaciclib than palbociclib and ribociclib. There is no statistically significant difference in OS between CDK4/6i despite differing statistical significance levels of individual trials. Real-world data analyses may help to identify if there is a meaningful inter-drug difference in efficacy. Significant differences between CDK4/6i are observed for safety and tolerability outcomes.
Topics: Female; Humans; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase Inhibitor Proteins; Neutropenia; Purines; Clinical Trials, Phase III as Topic; Randomized Controlled Trials as Topic
PubMed: 38326452
DOI: 10.1038/s41598-024-53151-8