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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 -
Current Treatment Options in Oncology Dec 2023OPINION STATEMENT: Inflammatory myofibroblastic tumor (IMT), characterized by intermediate malignancy and a propensity for recurrence, has presented a formidable... (Review)
Review
OPINION STATEMENT: Inflammatory myofibroblastic tumor (IMT), characterized by intermediate malignancy and a propensity for recurrence, has presented a formidable clinical challenge in diagnosis and treatment. Its pathological characteristics may resemble other neoplasms or reactive lesions, and the treatment was limited, taking chemotherapies as the only option for those inoperable. However, discovering anaplastic lymphoma kinase (ALK) protein expression in approximately 50% of IMT cases has shed light on a new diagnostic approach and application of targeted therapies. With the previous success of combating ALK non-small-cell lung cancers with ALK tyrosine kinase inhibitors (TKIs), crizotinib, a first-generation ALK-TKI, was officially approved by the U.S. Food and Drug Administration in 2020, to treat unresectable ALK IMT. After the approval of crizotinib, other ALK-TKIs, such as ceritinib, alectinib, brigatinib, and lorlatinib, have proven their efficacy on ALK IMT with sporadic case reports. The sequential treatments of targeted therapies in may provide the insight into the choice of ALK-TKIs in different lines of treatment for unresectable ALK IMT.
Topics: Humans; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Lung Neoplasms; Receptor Protein-Tyrosine Kinases; Antineoplastic Agents; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Inflammation
PubMed: 37938503
DOI: 10.1007/s11864-023-01144-6 -
ACS Chemical Biology Oct 2023The human acetyltransferase paralogues EP300 and CREBBP are master regulators of lysine acetylation whose activity has been implicated in various cancers. In the...
The human acetyltransferase paralogues EP300 and CREBBP are master regulators of lysine acetylation whose activity has been implicated in various cancers. In the half-decade since the first drug-like inhibitors of these proteins were reported, three unique molecular scaffolds have taken precedent: an indane spiro-oxazolidinedione (A-485), a spiro-hydantoin (iP300w), and an aminopyridine (CPI-1612). Despite increasing use of these molecules to study lysine acetylation, the dearth of data regarding their relative biochemical and biological potencies makes their application as chemical probes a challenge. To address this gap, here we present a comparative study of drug-like EP300/CREBBP acetyltransferase inhibitors. First, we determine the biochemical and biological potencies of A-485, iP300w, and CPI-1612, highlighting the increased potencies of the latter two compounds at physiological acetyl-CoA concentrations. Cellular evaluation shows that inhibition of histone acetylation and cell growth closely aligns with the biochemical potencies of these molecules, consistent with an on-target mechanism. Finally, we demonstrate the utility of comparative pharmacology by using it to investigate the hypothesis that increased CoA synthesis caused by knockout of PANK4 can competitively antagonize the binding of EP300/CREBBP inhibitors and demonstrate proof-of-concept photorelease of a potent inhibitor molecule. Overall, our study demonstrates how knowledge of the relative inhibitor potency can guide the study of EP300/CREBBP-dependent mechanisms and suggests new approaches to target delivery, thus broadening the therapeutic window of these preclinical epigenetic drug candidates.
Topics: Humans; Pharmaceutical Preparations; Acetyltransferases; Lysine; E1A-Associated p300 Protein; CREB-Binding Protein
PubMed: 37737090
DOI: 10.1021/acschembio.3c00293 -
BMC Medicine Mar 2024There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the...
TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro.
BACKGROUND
There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment.
METHODS
To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models.
RESULTS
Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation.
CONCLUSIONS
Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.
Topics: Humans; Amyotrophic Lateral Sclerosis; Drug Repositioning; Mendelian Randomization Analysis; Protein Serine-Threonine Kinases; Aminopyridines
PubMed: 38443977
DOI: 10.1186/s12916-024-03314-1 -
Journal For Immunotherapy of Cancer Sep 2023Hormone receptor (HR)-positive breast cancer is a disease for which no immune checkpoint inhibitors have shown promise as effective therapies. Cyclin-dependent kinase 4...
Efficacy, safety, and biomarker analysis of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR-positive HER2-negative metastatic breast cancer: a phase II study (WJOG11418B NEWFLAME trial).
BACKGROUND
Hormone receptor (HR)-positive breast cancer is a disease for which no immune checkpoint inhibitors have shown promise as effective therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors synergistically increased the effectiveness of antiprogrammed cell death protein-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibodies in preclinical studies.
METHODS
This non-randomized, multicohort, phase II study evaluated the efficacy and safety of the anti-PD-1 antibody nivolumab 240 mg administered every 2 weeks in combination with the CDK4/6 inhibitor abemaciclib 150 mg twice daily and either fulvestrant (FUL) or letrozole (LET) as a first-line or second-line treatment for HR-positive HER2-negative metastatic breast cancer. The primary end point was the objective response rate (ORR), and secondary end points were toxicity, progression-free survival, and overall survival. Blood, tissue, and fecal samples were collected at multiple points for correlative studies to evaluate immunity biomarkers.
RESULTS
From June 2019 to early study termination due to safety concerns on July 2020, 17 patients were enrolled (FUL: n=12, LET: n=5). One patient with a prior treatment history in the FUL cohort was excluded. ORRs were 54.5% (6/11) and 40.0% (2/5) in the FUL and LET cohorts, respectively. Treatment-emergent (TE) adverse events (AEs) of grade ≥3 occurred in 11 (92%) and 5 (100%) patients in the FUL and LET cohorts, respectively. The most common grade ≥3 TEAEs were neutropenia (7 (58.3%) and 3 (60.0%) in the FUL and LET cohorts, respectively), followed by alanine aminotransferase elevation (5 (41.6%) and 4 (80.0%)). One treatment-related death from interstitial lung disease occurred in the LET cohort. Ten patients developed liver-related grade ≥3 AEs. Liver biopsy specimens from 3 patients showed hepatitis characterized by focal necrosis with predominant CD8+ lymphocyte infiltration. Marked elevation of tumor necrosis factor-related cytokines and interleukin-11, and a decrease in peripheral regulatory T cells (Tregs), were observed in patients with hepatotoxicity. These findings suggest that treatment-related toxicities were immune-related AEs likely caused by proinflammatory cytokine production and suppression of Treg proliferation due to the addition of abemaciclib to nivolumab therapy.
CONCLUSIONS
Although the combination of nivolumab and abemaciclib was active, it caused severe and prolonged immune-related AEs.
TRIAL REGISTRATION NUMBER
JapicCTI-194782, jRCT2080224706, UMIN000036970.
Topics: Humans; Female; Breast Neoplasms; Nivolumab; Aminopyridines; Benzimidazoles; Letrozole; Antibodies
PubMed: 37709297
DOI: 10.1136/jitc-2023-007126 -
Lung Cancer (Amsterdam, Netherlands) May 2024Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic... (Review)
Review
Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). In clinical trials, lorlatinib has shown durable efficacy and a manageable safety profile in treatment-naive patients and in those who have experienced progression while receiving first- and/or second-generation ALK TKIs. Lorlatinib has a distinct safety profile from other ALK TKIs, including hyperlipidemia and central nervous system effects. Clinical trial data showed that most adverse events (AEs) can be managed effectively or reversed with dose modifications (such as dose interruptions or reductions) or with concomitant medications without compromising clinical efficacy or quality of life for patients. A pragmatic approach to managing AEs related to lorlatinib is required. We present patient-focused recommendations for the evaluation and management of select AEs associated with lorlatinib developed by clinicians and nurses with extensive lorlatinib expertise in routine clinical practice. The recommendations follow the general framework of "prepare, monitor, manage, reassess" to streamline AE management and assist in practical, actionable, and personalized patient care.
Topics: Humans; Lactams; Aminopyridines; Carcinoma, Non-Small-Cell Lung; Pyrazoles; Lung Neoplasms; Protein Kinase Inhibitors; Lactams, Macrocyclic; Anaplastic Lymphoma Kinase; Drug-Related Side Effects and Adverse Reactions; Antineoplastic Agents; Disease Management
PubMed: 38554546
DOI: 10.1016/j.lungcan.2024.107535 -
Seminars in Oncology Dec 2023The development of oral cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, including palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment... (Review)
Review
The development of oral cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, including palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for patients with hormone-receptor-positive (HR+) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (BC). When combined with an aromatase inhibitor or fulvestrant, these agents have been approved as first-line therapy in the metastatic setting. Abemaciclib has also gained FDA approval for patients with HR-positive, HER2-negative, node-positive, early BC at high risk of recurrence. Moreover, ribociclib has recently improved disease-free survival in patients with stage II or III HR+/HER2-negative early BC. CDK4/6 inhibitors have favorable safety profiles. However, the available agents have different toxicity profiles that must be clearly discussed with the patients for optimal clinical decisions. This manuscript aims to review CDK4/6 inhibitor-related treatment-associated adverse events, identify risk factors for intolerable adverse events, and assess their safety in special patient populations such as the elderly and those with renal insufficiency. Enhanced knowledge and understanding of CDK4/6 inhibitor-related toxicities can improve treatment strategies and ultimately enhance patient care.
Topics: Humans; Aged; Female; Breast Neoplasms; Protein Kinase Inhibitors; Cyclin-Dependent Kinase 4; Antineoplastic Combined Chemotherapy Protocols; Aminopyridines; Benzimidazoles; Purines
PubMed: 38245458
DOI: 10.1053/j.seminoncol.2024.01.002 -
Journal of Thoracic Oncology : Official... Nov 2023Circulating tumor DNA (ctDNA) has been used as a biomarker for prognostication and response to treatment. Here, we evaluate ctDNA as a potential biomarker for response...
INTRODUCTION
Circulating tumor DNA (ctDNA) has been used as a biomarker for prognostication and response to treatment. Here, we evaluate ctDNA as a potential biomarker for response to lorlatinib, a third-generation ALK tyrosine kinase inhibitor in patients with treatment-naive, advanced, ALK-positive NSCLC in the ongoing phase 3 CROWN study (NCT03052608).
METHODS
Molecular responses were calculated using mean variant allele frequency (VAF), longitudinal mean change in VAF (dVAF), and ratio to baseline. Efficacy assessments (progression-free survival [PFS] and objective response rate) were paired with individual patient ctDNA and analyzed for association.
RESULTS
Compared with baseline, mean VAF at week 4 was decreased in both treatment arms. Considering all detected somatic variants, a reduction in dVAF (≤0) was associated with a longer PFS in the lorlatinib arm. The hazard ratio (HR) for a dVAF less than or equal to 0 versus more than 0 was 0.50 (95% confidence interval [CI]: 0.23-1.12) in the lorlatinib arm. A similar association was not observed for crizotinib (HR = 1.00, 95% CI: 0.49-2.03). Comparing molecular responders with nonresponders, patients treated with lorlatinib who had a molecular response had longer PFS (HR = 0.37, 95% CI: 0.16-0.85); patients treated with crizotinib who had a molecular response had similar PFS as those without a molecular response (HR = 1.48, 95% CI: 0.67-3.30).
CONCLUSIONS
In patients with treatment-naive, advanced, ALK-positive NSCLC, early ctDNA dynamics predicted better outcome with lorlatinib but not with crizotinib. These results suggest that ctDNA may be used to monitor and potentially predict efficacy of lorlatinib treatment.
Topics: Humans; Crizotinib; Lung Neoplasms; Circulating Tumor DNA; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Lactams, Macrocyclic; Protein Kinase Inhibitors; Biomarkers
PubMed: 37295609
DOI: 10.1016/j.jtho.2023.05.021 -
Targeted Oncology Jul 2023Randomized trials have demonstrated that anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) can be safe and efficacious treatments for patients with...
BACKGROUND
Randomized trials have demonstrated that anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) can be safe and efficacious treatments for patients with ALK-positive advanced non-small-cell lung cancer (aNSCLC). However, their safety, tolerability, effectiveness, and patterns of use in real-world patients remain understudied.
OBJECTIVE
We sought to assess the overall treatment pattern characteristics, safety, and effectiveness outcomes of real-world patients with ALK-positive aNSCLC receiving ALK TKIs.
PATIENTS AND METHODS
This retrospective cohort study using electronic health record data included adult patients with ALK-positive aNSCLC receiving ALK TKIs between January 2012 and November 2021 at a large tertiary medical center, University of California, San Francisco (UCSF), with alectinib or crizotinib as the initial ALK TKI therapy. Our primary endpoints included the incidence of treatment changes (treatment dose adjustments, interruptions, and discontinuations) during the initial ALK TKI treatment, the count and type of subsequent treatments, rates of serious adverse events (sAEs), and major adverse events (mAEs) leading to any ALK TKI treatment changes. Secondary endpoints included the hazard ratios (HRs) for median mAE-free survival (mAEFS), real-world progression-free survival (rwPFS), and overall survival (OS) when comparing alectinib with crizotinib.
RESULTS
The cohort consisted of 117 adult patients (70 alectinib and 47 crizotinib) with ALK-positive aNSCLC, with 24.8%, 17.9%, and 6.0% experiencing treatment dose adjustments, interruptions, and discontinuation, respectively. Of the 73 patients whose ALK TKI treatments were discontinued, 68 received subsequent treatments including newer generations of ALK TKIs, immune checkpoint inhibitors, and chemotherapies. The most common mAEs were rash (9.9%) and bradycardia (7.0%) for alectinib and liver toxicity (19.1%) for crizotinib. The most common sAEs were pericardial effusion (5.6%) and pleural effusion (5.6%) for alectinib and pulmonary embolism (6.4%) for crizotinib. Patients receiving alectinib versus crizotinib as their first ALK TKI treatment experienced significantly prolonged median rwPFS (29.3 versus 10.4 months) with an HR of 0.38 (95% CI 0.21-0.67), while prolonged median mAEFS (not reached versus 91.3 months) and OS (54.1 versus 45.8 months) were observed in patients receiving alectinib versus crizotinib but did not reach statistical significance. Yet, it is worth noting that there was a high degree of cross-over post-progression, which could significantly confound the overall survival measures.
CONCLUSIONS
We found that ALK TKIs were highly tolerable, and alectinib was associated with favorable survival outcomes with longer time to adverse events (AE) requiring medical interventions, disease progression, and death, in the context of real-world use. Proactive monitoring for adverse events such as rash, bradycardia, and hepatotoxicity may help further promote the safe and optimal use of ALK TKIs in the treatment of patients with aNSCLC.
Topics: Adult; Humans; Carcinoma, Non-Small-Cell Lung; Crizotinib; Lung Neoplasms; Retrospective Studies; Bradycardia; Anaplastic Lymphoma Kinase; Protein Kinase Inhibitors; Protein-Tyrosine Kinases
PubMed: 37341856
DOI: 10.1007/s11523-023-00973-7 -
Journal of Neuroinflammation Oct 2023The astrocytes in the central nervous system (CNS) exhibit morphological and functional diversity in brain region-specific pattern. Functional alterations of reactive...
BACKGROUND
The astrocytes in the central nervous system (CNS) exhibit morphological and functional diversity in brain region-specific pattern. Functional alterations of reactive astrocytes are commonly present in human temporal lobe epilepsy (TLE) cases, meanwhile the neuroinflammation mediated by reactive astrocytes may advance the development of hippocampal epilepsy in animal models. Nuclear factor I-A (NFIA) may regulate astrocyte diversity in the adult brain. However, whether NFIA endows the astrocytes with regional specificity to be involved in epileptogenesis remains elusive.
METHODS
Here, we utilize an interference RNA targeting NFIA to explore the characteristics of NFIA expression and its role in astrocyte reactivity in a 4-aminopyridine (4-AP)-induced seizure model in vivo and in vitro. Combined with the employment of a HA-tagged plasmid overexpressing NFIA, we further investigate the precise mechanisms how NIFA facilitates epileptogenesis.
RESULTS
4-AP-induced NFIA upregulation in hippocampal region is astrocyte-specific, and primarily promotes detrimental actions of reactive astrocyte. In line with this phenomenon, both NFIA and vanilloid transient receptor potential 4 (TRPV4) are upregulated in hippocampal astrocytes in human samples from the TLE surgical patients and mouse samples with intraperitoneal 4-AP. NFIA directly regulates mouse astrocytic TRPV4 expression while the quantity and the functional activity of TRPV4 are required for 4-AP-induced astrocyte reactivity and release of proinflammatory cytokines in the charge of NFIA upregulation. NFIA deficiency efficiently inhibits 4-AP-induced TRPV4 upregulation, weakens astrocytic calcium activity and specific astrocyte reactivity, thereby mitigating aberrant neuronal discharges and neuronal damage, and suppressing epileptic seizure.
CONCLUSIONS
Our results uncover the critical role of NFIA in astrocyte reactivity and illustrate how epileptogenic brain injury initiates cell-specific signaling pathway to dictate the astrocyte responses.
Topics: Animals; Humans; Mice; 4-Aminopyridine; Astrocytes; Brain; Central Nervous System; Epilepsy; Epilepsy, Temporal Lobe; NFI Transcription Factors; TRPV Cation Channels; Up-Regulation
PubMed: 37880726
DOI: 10.1186/s12974-023-02909-4