Cancer Chemotherapy and Pharmacology最新文献

Purpose: Insulin-like growth factor-1 (IGF-1) may play a role in breast cancer (BC) development. Metformin was found to exert anti-cancer function in several studies, partly by interference with the IGF-1 signaling pathway and reducing its blood levels. Therefore, our study aimed primarily to find out how metformin affected both IGF-1 levels and clinical outcomes in metastatic breast cancer patients (MBC) and secondarily to identify the correlation between post-treatment IGF-1 decline rates and BC prognosis and metastasis.

Methods: Fifty MBC female patients were randomly assigned to either the control group (who were administered conventional chemotherapy) and the intervention group (treated with metformin plus chemotherapy). An enzyme-linked immunosorbent assay (ELISA) was used to detect IGF-1 levels at baseline and three months post-treatment.

Results: IGF-1 levels in the metformin group were significantly lower than in the control group (p = 0.011). Furthermore, the percentage of post-treatment drop in IGF-1 levels differed significantly between the control and metformin groups (p = 0.001). Patients whose IGF-1 levels increased after treatment had a statistically significant occurrence of progressive disease (disease progression) in the control group higher than in the metformin group (92.9% versus 87.5%).

Conclusion: The co-administration of metformin with chemotherapy significantly inhibited the IGF-1 signaling pathway, which reduced progressive diseases and reduced mortality in non-diabetic MBC patients. However, while metformin exerts a robust IGF-1 lowering effect, combination chemotherapy and low metastasis burden may further enhance this effect.

Trail registration: Our trial was registered at clinicaltrials.gov (ID no. NCT04143282).

The use of sodium-glucose cotransporter protein 2 (SGLT2) inhibitors, specifically canagliflozin and dapagliflozin, has expanded from diabetes treatment to promising anticancer applications. Epidemiological links between diabetes and certain cancers highlight the potential of these agents in oncology, as SGLT2 is highly expressed in various tumor types. By inhibiting glucose uptake, canagliflozin and dapagliflozin disrupt glycolysis-dependent tumor growth, promoting apoptosis and reducing proliferation across multiple cancer models, including liver, prostate, and lung cancers. Key pathways involved in these effects include PI3K/AKT, mTOR, and AMPK signaling. Importantly, the combination of SGLT2 inhibitors with chemotherapy or radiotherapy has been shown to enhance antitumor efficacy and reduce treatment resistance, underscoring their potential as adjunctive therapies. However, adverse effects, such as increased risk of infection, and the need for more comprehensive mechanistic studies limit current applications. Future research should focus on expanding the understanding of these mechanisms, evaluating efficacy in additional tumor types, and optimizing combination therapies to mitigate side effects. SGLT2 inhibitors thus represent a novel class of metabolic modulators with potential for significant impact in cancer therapeutics.

Introduction: Mechanism underlying resistance to enfortumab vedotin (EV) and prognostication of Nectin-4 expression in muscle-invasive bladder cancer (MIBC) remains unclear.

Methods: We generated gemcitabine-resistant HT-1376 and cisplatin-resistant HT-1376 cells generated from parental HT1376 cells (derived from MIBC). Transcriptome analysis was conducted to explore the biological function of differentially expressed genes detected in chemoresistant HT-1376 cells compared to parental HT-1376. In 70 patients with MIBC undergoing radical cystectomy, unsupervised hierarchical clustering was performed using immunohistochemical staining pattern with GATA3, KRT20, KRT5/6, KRT14, and Nectin-4 expression derived from the gene expression-based Nectin-4-modified NanoString molecular classification: Luminal-Nec4-High, Luminal-Nec4-Low, Basal-Nec4-High, and Basal-Nec4-Low subgroups.

Results: We found significant downregulation of Nectin-4 expression along with epithelial-to-mesenchymal transition in chemoresistant HT-1376 cells. Exogenous expression of NECTIN4 in chemoresistant HT-1376 cells partially restored sensitivity to EV. RNA seq identified differentially expressed genes, including Nectin-4 and small proline-rich proteins, downregulated in chemoresistant HT-1376 cells. Over-representation analysis using GO and KEGG revealed upregulation of gene sets enriched for ribosome biogenesis-related pathways in chemoresistant HT-1376 cells. Nectin-4-modified molecular subtype resulted in better stratification of survival-the Luminal-Nec4-High subgroup had the best and the Basal-Nec4-Low subgroup had the worst prognosis. Comparing molecular subtypes of MIBC cells between transurethral resection specimens and matched radical cystectomy specimens revealed that 43% of neoadjuvant chemotherapy-treated patients with luminal subtype tumors showed a marked shift to the basal subtype in the cystectomy specimens.

Conclusion: The clinical utility of Nection-4, associated molecules, and Nectin-4-modified molecular subtype need to be studied for better management strategies for MIBC.

SLFN11, a DNA/RNA helicase implicated in replication stress response, has recently emerged as a pivotal determinant of chemotherapy sensitivity across multiple cancer types. The expression level of SLFN11 in various cancers is significantly positively correlated with the sensitivity of cancer cell DNA damage agents. SLFN11 exerts its chemosensitizing effects by RPA-coated single-stranded DNA (ssDNA) at stressed replication forks at stalled replication forks, thereby potentiating the cytotoxicity of platinum agents, topoisomerase inhibitors, and PARP inhibitors. Its roles in inhibiting ATR translation, mediating p53-independent apoptosis, sensitizing towards IFN-γ and enhancing chromatin accessibility also remain investigational. The down-regulation of SLFN11 expression is associated with epigenetic silencing including promoter methylation, histone deacetylation, and the histone methylation. In this paper, we reviewed the recent progress of SLFN11 as predictive biomarker and therapeutic target in multiple cancers including medulloblastoma, prostate cancer, breast cancer, ovarian cancer, lung cancer, head and neck cancer, esophageal carcinoma, gastric carcinoma and colorectal cancer. We also summarized 10 active clinical trials conducting molecular analyses to assess SLFN11's role. By bridging mechanistic understanding with translational opportunities, this review provides a roadmap for leveraging SLFN11 to overcome chemoresistance and advance precision oncology.

Objective: This paper aimed to unravel the effect of metformin on vascular endothelial injury in patients with non-small cell lung cancer (NSCLC) treated with chemotherapy combined with bevacizumab.

Methods: We recruited 120 NSCLC patients and then classified into A and B groups (n = 60 cases). A group was treated with chemotherapy + bevacizumab + metformin, and B group was treated with chemotherapy + bevacizumab. The efficacy, pro-inflammatory factors, immune factors, and markers of vascular endothelial injury before and after treatment were compared between the two groups. The incidence of adverse reactions and prognostic 1-year survival status during the treatment period in both groups were counted.

Results: Higher ORR and DCR were observed in Group A relative to Group B. TNF-α, IL-2, IL-12, ET-1, TM, and vWF were elevated in both groups after treatment, but were lower in Group A than in Group B. CD³⁺, CD4⁺, and CD⁴⁺/CD⁸⁺ were reduced in both groups after treatment, but were higher in Group A than in Group B. OS and DFS were higher in Group A than in Group B.

Conclusion: Metformin has some anti-inflammatory and immunoprotective effects on NSCLC patients treated with chemotherapy combined with bevacizumab, which may help to attenuate the vascular endothelial injury induced by chemotherapy and bevacizumab treatment and further improve the prognosis.

Purpose: Indenoisoquinolines are a class of topoisomerase I (TOP1) inhibitors designed to overcome clinical limitations of camptothecins. Three indenoisoquinolines (LMP400, LMP776, and LMP744) demonstrated activity in murine models and a comparative canine lymphoma study. Clinical data for LMP400 were previously reported (NCT01051635). The maximum tolerated dose (MTD), safety, and clinical data from phase 1 studies of LMP776 (NCT01051635) and LMP744 (NCT03030417) are reported herein.

Methods: Patients ≥ 18 years of age with advanced, refractory solid tumors or lymphomas received either LMP776 (n = 34) or LMP744 (n = 35) intravenously following a Simon accelerated titration design. Both LMP776 and LMP744 were administered daily for 5 days (QDx5) in 28-day cycles. Adverse events and clinical responses were evaluated according to CTCAE and RECIST v1.1 criteria, respectively. Pharmacokinetic and pharmacodynamic changes were evaluated.

Results: The MTD of LMP776 was 12 mg/m²/day and that of LMP744 was 190 mg/m²/day. Dose-limiting toxicities (DLTs) for LMP776 included hypercalcemia, anemia, and hyponatremia; DLTs for LMP744 included hypokalemia, anemia, and weight loss. There was 1 confirmed partial response (cPR) among 35 patients receiving LMP744 (overall response rate 3%) and no objective responses in patients receiving LMP776. Tumor biopsies from the patient with cPR demonstrated high baseline expression of SLFN11 and a unique pattern of pharmacodynamic responses, including increased RAD51, phosphorylated KAP1 (pKAP1), γH2AX, and cleaved caspase-3 (cCasp3).

Conclusion: MTDs and safety profiles are reported for LMP776 and LMP744. Target engagement by an indenoisoquinoline was measured for the first time in human samples.

This study investigated the pharmacokinetics, mass balance, and metabolism of [¹⁴C]FCN-437c, a selective and potent CDK4/6 inhibitor, in humans. Six healthy male Chinese subjects were administered a single oral dose of 200 mg [¹⁴C]FCN-437c (120 µCi), and plasma, urine, and feces samples were collected up to 456 h post-dose. The geometric mean C_max of radioactivity in plasma and blood were 706 and 557 ng eq./mL, respectively, with a median T_max of 5.0 h and a geometric mean t_1/2 of 56.5 h in plasma. The primary route of elimination was fecal excretion, accounting for a mean of 77.16% of the dose, whereas urinary excretion constituted a mean of 19.19% of the administered radioactivity. UHPLC-HRMS analysis identified 12 metabolites in human plasma, urine, and feces, with 8 of them being phase I metabolites, and the major metabolic pathways were mono-oxidation and O-dealkylation. Additionally, 4 phase II metabolites were identified, including two glucuronides, one glutathione conjugate, and one cysteine conjugate. The study provides insights into the metabolic stability and clearance mechanisms of FCN-437c in human, which are essential for its further clinical development and dosing regimens.

Purpose: To evaluate single dose pharmacokinetics (PK) of novel reduced-dose film coated Danziten^™ (nilotinib tablets) using a population PK approach, establish bioequivalence vs. Tasigna^® (nilotinib capsules) and investigate food effects on PK of both formulations.

Methods: A population PK model evaluating nilotinib capsules (300 or 400 mg) or tablets (142 or 190 mg) was developed using data from 14 single dose studies and > 30,000 plasma samples from healthy men and women. Steady-state nilotinib concentration-time profiles following twice daily dosing with various treatment and food conditions were simulated using a randomly sampled dataset of 50 subjects.

Results: PK was characterized by a 2-compartment model with linear elimination and zero-order absorption with lag time. Bioequivalence was met for all steady state exposure metrics for both doses under fasted conditions. A milligram strength for nilotinib tablets ~ 50% lower than that for capsules resulted in bioequivalent nilotinib exposures. Administration with a low-fat meal under modified fasting conditions increased the bioavailability (BA) of 142 mg and 190 mg nilotinib tablets by 26.0% and 29.3%, respectively, vs. fasting; values for 300 mg and 400 mg capsules were 56.8% and 60.7%. Administration with a high-fat meal under modified fasting conditions increased the BA of 142 and 190 mg nilotinib tablets by 48.6% and 52.2%, respectively; values for 300 and 400 mg capsules were 180.6% and 183.3%.

Conclusion: Nilotinib tablets 142 and 190 mg provide bioequivalent exposures to 300 mg and 400 mg capsules under fasted conditions and substantially smaller effects of food on exposure.

Purpose: Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). Its inhibition of VEGF signaling may lead to proteinuria due to endothelial dysfunction but the association between endothelial function and clinical outcomes has not been established. This study aimed to investigate vascular endothelial function in patients with HCC receiving atezolizumab plus bevacizumab, and to assess the correlation between reactive hyperemia index (RHI) and adverse renal outcomes.

Methods: This pilot prospective observational study included 20 patients with HCC who received atezolizumab plus bevacizumab. We used reactive hyperemia-peripheral arterial tonometry (RH-PAT) and evaluated vascular endothelial function on the basis of RHI. RHI, blood pressure, and proteinuria were recorded at baseline and at 3 and 6 months after initiation of atezolizumab plus bevacizumab treatment. Statistical analyses were performed to investigate the relationship of RHI to blood pressure and proteinuria.

Results: Following initiation of atezolizumab plus bevacizumab treatment, systolic blood pressure and urine protein-creatinine ratio increased significantly, and RHI decreased. Patients with borderline or low baseline RHI had a higher incidence of grade ≥ 2 proteinuria than those with normal baseline RHI but not hypertension. A significant inverse correlation was found between RHI and urine protein-creatinine ratio.

Conclusion: Bevacizumab administration may cause endothelial dysfunction in patients with HCC. The vascular endothelial function status before and during atezolizumab plus bevacizumab treatment is associated with the risk of bevacizumab-induced proteinuria.