Cancer Chemotherapy and Pharmacology最新文献

Introduction: By blocking poly ADP ribose polymerase (PARP), olaparib decreases the proliferation of tumours by preventing DNA damage repair, particularly in tumours that have BRCA1/2 mutations or are BRCA-negative. However, a phase II study of 33 CRC patients receiving mono-olaparib therapy revealed that some of these individuals still had resistance to olaparib therapy but had poor DNA damage repair ability. RAD51C reversion mutation is a frequent reason for the resistance of cancers with BRCA mutations to PARP inhibitors.

Methods: Here, we introduce K(lysine)-acetyltransferase 2B (KAT2B) as a protein involved in the transcription of RAD51C, reducing the expression of RAD51C by lowering the acetylation of histone H3 (H3K27) at the promoter of RAD51C.

Results: We found that a subset of tumour cells expressing RAD51C presented reduced endogenous KAT2B expression, which led to increased accumulation of DNA damage (increased γH2AX accumulation), and lower KA2TB expression decreased PARPi resistance in RAD51C-expressing cells. These findings indicate that colorectal cancer cells with lower KAT2B and RAD51C levels are more vulnerable to olaparib therapy. Our findings indicate that PARPi responses and the expression of RAD51C are significantly regulated by KAT2B and histone acetylation.

Conclusion: These results offer vital and novel insights into the combination of inhibitors in patients who are resistant to olaparib therapy, especially patients with RAD51C reversion mutations.

Purpose: The proteasome inhibitor bortezomib and purine nucleoside analog clofarabine combination had greater than additive activity in the NCI-ALMANAC preclinical screen. We conducted a phase 1 trial (NCT02211755) to evaluate the combination's safety and efficacy in patients.

Experimental design: We administered bortezomib subcutaneously on days 1 and 4, and clofarabine intravenously on days 1-5 of each 21-day cycle. The primary objective was to establish the safety, tolerability, and maximum tolerated dose (MTD) of bortezomib and clofarabine in patients with refractory solid tumors, lymphomas, or MDS. The secondary objective was to determine the effects of the combination on biomarkers of cell death and DNA damage response (DDR) in tumor biopsies.

Results: Of 28 patients enrolled, 11 had a best response of stable disease (median 5 cycles; range 2-10 cycles), including 5 patients (4 from the solid tumor cohort, 2 of which were at MTD) with stable disease for ≥ 6 cycles. The MTD for the solid tumor cohort was 1.3 mg/m² bortezomib on days 1 and 4, and 1.5 mg/m² clofarabine on days 1-5 of each cycle. The MDS cohort closed prior to MTD determination, due to low accrual. The most common study drug related adverse events were hematologic. Two out of 3 patients with evaluable biopsies had increased markers of cell death, and 1 patient also had increased DDR markers after treatment.

Conclusion: The combination of bortezomib with clofarabine demonstrated limited antitumor effects possibly due to the inability to reach the efficacious doses achieved in preclinical models.

Background: High‑dose methotrexate (HD‑MTX) is a cornerstone of pediatric acute lymphoblastic leukaemia (ALL) therapy. However, deviations from protocol-mandated infusion durations need regular monitoring as part of standard quality care. Hence, an observational quality assessment study was planned with a secondary objective to evaluate the acute toxicity in patients who did not receive the infusion within the recommended time period.

Methods: This study enrolled 42 children (75 cycles) who received HD-MTX (3-5 g/m² over 24 h) according to the ICiCLe ALL-14 protocol. The actual infusion duration was recorded, and 48-h MTX levels were measured using an enzyme-multiplied immunoassay technique. Toxicity was graded via CTCAE v5.0.

Results: Only 35% of cycles were completed within the targeted 24-h window [Median (IQR): 23.75 h (21.25, 25.33)]. Prolonged infusions (> 25 h) resulted in significantly higher 48-h MTX levels compared to shortened infusions (median 0.475 vs 0.270 µmol/L; p = 0.015). Multivariable analysis identified male sex (OR, 12.24), T-ALL immunophenotype (OR, 8.36), and the infusion duration (OR, 1.50 per hour) as independent predictors of delayed clearance. A 48-h level > 0.315 µmol/L predicted development of toxicity (AUC 0.686), though no life-threatening event or mortality was recorded in any cycle. Additionally, MTX levels did not differ significantly across the four HD-MTX cycles that each patient received, and elevated levels in one cycle did not predict delayed clearance in subsequent cycles.

Conclusions: Deviations in infusion duration were high and independently drive pharmacokinetic variability and toxicity. Ensuring timely drug delivery is as critical as dose precision.

Purpose: Chemotherapy-induced neutropenia is a serious adverse event. Combination chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) is an effective neoadjuvant therapy for esophageal cancer, but it is associated with a high incidence of Grade 4 neutropenia. In previous study, we identified associations between genetic variants and severe neutropenia. The aim of this study was to explore genetic factors related to pharmacokinetics and endogenous antioxidant defense mechanisms that may be associated with the development of Grade 4 neutropenia in esophageal cancer patients treated with DCF chemotherapy using two independent cohorts.

Methods: We conducted a retrospective pharmacogenetic analysis using DNA samples from the National Cancer Center Biobank in Japan. Two independent cohorts of esophageal cancer patients treated with the DCF chemotherapy were analyzed: an exploratory cohort (n = 157) and a validation cohort (n = 121). Single nucleotide polymorphisms (SNPs) in genes related to docetaxel pharmacokinetics and the Keich-like ECH-associated protein 1-Nuclear factor erythroid2-related factor 2 (Keap1-Nrf2) antioxidant system were examined.

Results: A total 53 (33.8%) and 62 (51.2%) patients developed Grade 4 neutropenia in exploratory and validation cohort, respectively. Multivariate analysis revealed that age, Adenosine triphosphate-binding cassette (ABC) G2 rs2231137G > A and Nuclear factor, erythroid 2 like 2 (NFE2L2) rs35652124C > T were significant in exploratory cohort, while baseline absolute neutrophil count and NFE2L2 rs35652124C > T were significant in the validation cohort.

Conclusions: NFE2L2 rs35652124C > T was identified as an independent predictive genetic factor for Grade 4 neutropenia in esophageal cancer patients treated with DCF chemotherapy.

Purpose: Glioblastoma (GBM) is the most common malignant brain tumor in adults, and durable control or cure with current standard or investigational therapies is rare. Therefore, novel approaches are needed. This exploratory study evaluated whether defactinib and avutometinib, inhibitors of FAK/Pyk2 and RAF/MEK signaling respectively, penetrate GBM and produce measurable effects on their molecular targets.

Methods: Defactinib or avutometinib was administered to six subjects each, in two escalating dose levels: avutometinib at 3.2 mg and 4 mg, and defactinib at 200 mg and 400 mg (three patients per dose level). Administration occurred immediately prior to craniotomy for tumor resection. Tumor tissue, peritumoral brain tissue, and blood were collected during surgery. Drug concentrations were measured by liquid chromatography-mass spectrometry, and effects on the intended molecular targets were assessed by western blot analysis.

Results: Even after a single preoperative dose, both defactinib and, to a lesser extent, avutometinib were detectable in tumor tissue 3-4 h after administration. Peritumoral brain tissue contained lower concentrations of each agent. Exploratory pharmacodynamic analyses suggested target engagement: avutometinib (3.2 mg) reduced Erk1/2 phosphorylation approximately 28-fold, while defactinib (400 mg) reduced Pyk2 phosphorylation by 5.7-fold within tumor tissue. Effects in peritumoral tissue were minimal.

Conclusion: These exploratory findings demonstrate that defactinib and avutometinib can penetrate GBM tissue and produce measurable modulation of their intended molecular targets after a single dose, with limited impact on surrounding brain. While the small sample size and inherent tissue heterogeneity limit definitive conclusions, this study supports the feasibility of presurgical pharmacokinetic and pharmacodynamic evaluation in GBM and provides a rationale for further clinical studies to optimize dosing, target inhibition, and therapeutic efficacy.

Trial registration number: ClinicalTrials.gov NCT05798507. Date of Registration March 3, 2023.

Purpose: OPN-2853 (formerly PLX2853, now dubbed zavabresib) is a potent, oral inhibitor of all four members of the bromodomain and extraterminal (BET) proteins, involved in epigenetic regulation across multiple cancers. This study aimed to determine the recommended Phase 2 dose (RP2D) of OPN-2853 and collect safety, pharmacokinetic and pharmacodynamic data in adults with advanced relapsed/refractory solid tumors or non-Hodgkin lymphoma (NHL).

Methods: This was a first-in-human, open-label, Phase 1b study. Primary endpoints included RP2D, pharmacokinetics and safety. Secondary and exploratory endpoints were efficacy and pharmacodynamics.

Results: Forty-nine patients were enrolled. The RP2D was determined at 80 mg oral once daily (QD). The most common adverse events were nausea (n = 17 [24.7%], all < Grade 3) and fatigue (n = 12 [24.5%], n = 3 Grade 3). No OPN-2853-related deaths occurred. Three patients (6.1%) experienced dose-limiting toxicities: Grade 4 thrombocytopenia at 120 mg QD [n = 2] and a Cycle 1 dose reduction (Grade 3 fatigue with Grade 2 cheilitis and nausea [n = 1]). OPN-2853 has a short half-life (< 3 h). For pharmacodynamic response, gene expression changes in whole blood RNA-seq analysis were observed for up to 9 h. Of the 36 patients (73.4%) with at least one post-baseline assessment, 1 patient (2.8%) achieved a complete response with 18-month progression-free survival (PFS) and 1 patient (2.8%) achieved a partial response (PFS of 5.2 months). Another patient (2.8%) achieved an unconfirmed PR.

Conclusion: OPN-2853 was well tolerated at the RP2D in patients with advanced solid tumors and NHL, with modest clinical activity including two confirmed objective responses.

Purpose: The CIGB-552 peptide is a novel therapeutic alternative for the treatment of cancer. In this study, we aimed to determine the optimal formulation and route of administration for CIGB-552. Other objectives were to characterize the peptide's pharmacokinetic profile in rats and conduct toxicity studies at different dosage regimens.

Methods: The antitumor activity of CIGB-552 was evaluated by different routes of administration (intraperitoneal, subcutaneous) and also with different peptide formulations (Tartrate/mannitol, Tartrate/trehalose) using a TC-1 tumor model in C57BL/6 mice. The pharmacokinetic profile of the peptide was also characterized after subcutaneous administration in Sprague-Dawley rats using PK Solver software. In addition, the safety of the peptide was evaluated following single-dose and repeated-dose administration schedules in healthy BALB/c mice.

Results: In the tumor model, subcutaneous administration of CIGB-552 and its tartrate/trehalose formulation resulted in a significant reduction in tumor volume compared to untreated groups. CIGB-552 exhibited a typical extravascular delivery profile, with rapid absorption, rapid tissue distribution, and rapid blood clearance. The peptide's half-life was 2.5 h, and peak plasma concentration (C_max) was reached in approximately 15 min. Furthermore, CIGB-552 was shown to have nonlinear pharmacokinetics across the evaluated dose and exposure range. On the other hand, CIGB-552 administration in the evaluated regimens was safe, with toxicity and fatal outcomes observed only with the 60 mg/kg dose administered subcutaneously every two days until seven doses were completed in total.

Conclusions: The peptide's safety profile in repeated dosing, combined with evidence of no systemic accumulation, supports the development of new regimens involving higher and more frequent doses to enhance antitumor efficacy in clinical studies.