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- Trends in renal function following vascular endothelial growth factor
inhibitor administration in patients with cancer and diabetes mellitus-
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Abstract: Background Vascular endothelial growth factor (VEGF) inhibitors are associated with a high incidence of proteinuria. In patients with diabetes, increased proteinuria is closely associated with decreased renal function; however, the impact of increased proteinuria on renal function in patients with cancer and diabetes mellitus undergoing VEGF inhibitor therapy remains unknown. Methods The incidence of proteinuria and renal function in patients with cancer and a history of diabetes who were treated with VEGF inhibitors at the National Cancer Center Hospital East between January 2018 and December 2019 was retrospectively investigated. Results Among the 49 patients included, 21 (43%) developed proteinuria ≥ 3 + after VEGF inhibitor treatment. In all patients, a decreasing trend in the estimated glomerular filtration rate (eGFR) was observed beginning 2 years after treatment initiation. The decrease in eGFR from baseline was − 6.6% at 1 year, -11% at 2 years, and − 13% at 4 years. Patients who developed proteinuria ≤ 2 + showed no significant decrease in eGFR from baseline to either the end of treatment (p = 0.91) or the latest value during the observation period (p = 0.64). Similarly, no significant decrease in eGFR was observed in those with proteinuria ≥ 3+ (end of treatment, p = 0.91; latest value during the observation period, p = 0.18). Conclusions In patients with cancer and diabetes mellitus, increased proteinuria after VEGF inhibitor therapy suggested that it was not associated with a significant decline in renal function.
PubDate: 2025-07-02
- Peptides derived from the POU domain of BRN2 show antitumor activity
against murine melanoma model cells in vitro and in vivo-
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Abstract: The BRN2 transcription factor controls the protein expression involved in cell motility and is overexpressed in melanoma. Gene mutations involved in cell signaling pathways lead to BRN2 overexpression, tumor formation and metastasis. Peptides derived from the DNA binding domain of transcription factors can compete for the transcription binding and regulate protein expression. In this work, the antitumor activity in vitro and in vivo of the peptide E24G, derived from the DNA-binding POU domain of the BRN2 transcription factor was investigated. This peptide was fragmented into two smaller peptides E12F and A12G, their antitumor activities were characterized and compared with E24G. The E24G at 1 mM significantly reduced cell motility in vitro of B16F10-Nex2 melanoma cells. E12F peptide also inhibited cell motility at a concentration eight times smaller than E24G in murine and human melanoma cells. We observed that the antitumor activity of both E24G and E12F peptides depends on the macropinocytosis displayed by tumor cells. Also, the E24G and E12F peptides induced an increase of the CDH13 expression in 50%, however the treatment with E12F increased the expression already after 12 h by 100%. In vivo assays showed that both peptides reduced the development of metastatic lung nodules without presenting toxicity to normal organs. Our results indicate that E12F and E24G peptides can restore normal expression of BRN2 target genes at the molecular level, inhibiting the cell motility. In addition, we confirmed that the peptide binds to the DNA binding site of the BRN2 transcription factor. Further studies will elucidate their mechanisms of antitumor activity, so far our results pointed out the potential application of E12F and E24G peptides as innovative treatments for metastatic melanoma.
PubDate: 2025-07-02
- ETV1 genetic polymorphisms as a candidate prognosis biomarker of
Gastrointestinal stromal tumor-
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Abstract: Purpose While imatinib is effective for treating Gastrointestinal Stromal Tumors (GISTs), significant variability in patient outcomes exists, highlighting the need for reliable prognostic biomarkers. ETV1, a key transcription factor involved in GIST progression, is implicated in disease biology, but the role of ETV1-related single nucleotide polymorphisms (SNPs) in predicting prognosis remains unclear. Methods This study included 75 GIST patients. We focused on identifying tag SNPs in the ETV1 gene and examined their association with clinical outcomes. Patient characteristics, somatic mutations, and imatinib concentration were also analyzed in a multivariate model. ETV1 expression was assessed using immunohistochemistry, and miRNA interactions with ETV1 transcripts were investigated via the dual-luciferase reporter assay system. Results We found that the rs3735343 SNP, located in the 3’ untranslated region of ETV1, was significantly associated with progression-free survival (PFS) in GIST patients receiving imatinib (P = 0.008). Multivariate analysis identified tumor size (P = 0.032, Hazard Ratio [HR] = 4.173, 95% CI: 1.127–15.454) and rs3735343 (P = 0.009, HR = 8.995, 95% CI: 1.712–47.255) as independent predictors of PFS. The rs3735343 risk allele also correlated with elevated ETV1 expression in GIST tissue (P = 0.04). Additionally, miR-4311 was found to specifically and negatively regulate ETV1 mRNA levels associated with the rs3735343 risk allele in vitro. Conclusion This study reported ETV1 rs3735343 as a novel prognostic candidate biomarker for GISTs treated with Imatinib, providing a potential biomarker for risk assessment of GIST. Additionally, our findings suggest that rs3735343 may act as a miRNA-regulated SNP, with miR-4311 playing a key role in its regulation.
PubDate: 2025-07-02
- Pharmacokinetics, safety, and tolerability of fedratinib in adults with
moderate and severe hepatic impairment: results from the phase 1
FEDR-CP-001 trial-
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Abstract: Purpose The FEDR-CP-001 (NCT03983161) trial evaluated the pharmacokinetics (PK) and safety of a single dose of fedratinib in adults with moderate or severe hepatic impairment (HI) compared with matched healthy participants with normal hepatic function. Methods This was a non-randomized, open-label, multicenter, phase 1 trial. Participants were aged 18–75 years and had a BMI of 18–40 kg/m2. HI was determined by Child–Pugh score. Participants were placed into 1 of the following groups: group 1, moderate HI; group 2, healthy participants matched to group 1; group 3, severe HI; and group 4, healthy participants matched to group 3. Participants received a single dose of fedratinib 300 mg (groups 1 and 2) or 200 mg (groups 3 and 4) and were followed for 21 days. Results All participants (N = 38; groups 1, 3, and 4 [n = 8 each], group 2 [n = 14]) completed the trial. Peak and total fedratinib exposures (Cmax, AUC0−∞) were similar between moderate HI versus matched healthy participants. In participants with severe HI, there were lower total exposures compared to the matched healthy participants where the ratios of geometric means for Cmax, and AUC0−∞ were 0.897 and 0.660, respectively, and with large inter-participant variability. Ten participants experienced a treatment-emergent adverse event (all were considered mild), which were evenly distributed across groups. Conclusion These data indicate that reducing fedratinib starting doses is not necessary for patients with moderate or severe HI, and support clinicians in regular monitoring of patients with HI taking fedratinib.
PubDate: 2025-07-02
- Pazopanib and antacids: insights from the WHO pharmacovigilance database
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Abstract: Pazopanib, a multi-targeted tyrosine kinase inhibitor, is used for advanced renal cell carcinoma and soft tissue sarcoma. However, it is associated with dose-dependent adverse events (AEs), including hypertension, and gastrointestinal issues. Antacids like proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) are often co-administered, raising concerns about potential drug interactions. Pazopanib’s solubility and absorption are pH-dependent, with increased gastric pH potentially reducing its bioavailability. In this study, we analyzed VigiBase® data using multivariate logistic regression models and found significant interactions between pazopanib and antacids (PPIs, H2RAs, and others), suggesting reduced serious AE reporting, possibly due to lower pazopanib exposure. A secondary analysis of CYP3A4 inhibitors showed a non-significant trend for higher serious AEs, aligning with expected pharmacokinetic effects. These findings emphasize the need for caution when combining antacids with pazopanib, as it may reduce both toxicity and efficacy.
PubDate: 2025-07-02
- Targeting insulin-like growth factor-1 (IGF-1) by using metformin in
non-diabetic metastatic breast cancer female patients: a randomized
controlled trial-
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Abstract: 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).
PubDate: 2025-06-28
- Potential anticancer effects of sodium-glucose cotransporter protein 2
(SGLT2) inhibitors Canagliflozin and Dapagliflozin-
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Abstract: 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.
PubDate: 2025-06-26
- Clinical relevance of Nectin-4 downregulation and biological changes
caused by cytotoxic chemotherapy in bladder cancer-
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Abstract: 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.
PubDate: 2025-06-25
- Novel desensitization protocol utilizing conventional formulations to
mitigate Temozolomide-Related skin hypersensitivity-
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PubDate: 2025-06-20
- From predictive biomarker to therapeutic target: the dual role of SLFN11
in chemotherapy sensitivity-
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Abstract: 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.
PubDate: 2025-06-18
- Effect of Metformin on vascular endothelial injury in patients with
non-small cell lung cancer treated with chemotherapy combined with
bevacizumab-
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Abstract: 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.
PubDate: 2025-06-16
- Phase 1 studies of the indenoisoquinolines LMP776 and LMP744 in patients
with solid tumors and lymphomas-
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Abstract: 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.
PubDate: 2025-05-29
- Pharmacokinetics, mass balance, and metabolism of [14C]FCN-437c, a
selective and potent CDK4/6 inhibitor in humans-
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Abstract: 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 Cmax of radioactivity in plasma and blood were 706 and 557 ng eq./mL, respectively, with a median Tmax of 5.0 h and a geometric mean t1/2 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.
PubDate: 2025-05-26
- Pharmacokinetic profile of novel reduced-dose Danziten™ (nilotinib
tablets) versus Tasigna® (nilotinib capsules): in vivo bioequivalence and
population pharmacokinetic analysis-
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Abstract: 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.
PubDate: 2025-05-11
- Potential role of endothelial dysfunction in hypertension and proteinuria
in patients with hepatocellular carcinoma receiving atezolizumab plus
bevacizumab: a pilot prospective observational study-
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Abstract: 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.
PubDate: 2025-04-17
- Neurofilament light chain as a marker for neuronal damage: integrating in
vitro studies and clinical findings in patients with oxaliplatin-induced
neuropathy-
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Abstract: Purpose Oxaliplatin-induced peripheral neuropathy (OIPN) is a chronic, debilitating late effect following oxaliplatin treatment. Neurofilament light chain (NfL) is a structural protein found in nerve axons that was investigated upon oxaliplatin exposure in vitro and in vivo correlated to symptoms of OIPN in colorectal cancer patients receiving oxaliplatin. Methods Human sensory neurons, derived from induced pluripotent stem cells, were exposed to clinically relevant concentrations of oxaliplatin in vitro, with NfL concentrations measured in the cell medium. The prospective clinical study included patients with colorectal cancer undergoing chemotherapy therapy with or without oxaliplatin. Possible OIPN was defined as bilateral presence of numbness and/or presence of pricking sensations in the feet documented in an interview at the time of blood sampling prior to, 3, and 6 months after initiating treatment. Results Oxaliplatin exposure led to a dose-dependent NfL increase in vitro. In the clinical cohort of 30 patients (18 in the oxaliplatin group), NfL levels rose at 3 and 6 months compared to controls. NfL level changes correlated to OIPN symptoms at the 6-month timepoint (rho 0.81, p
PubDate: 2025-04-10
- Pharmacokinetics, metabolism, and excretion of [14C]-valemetostat in
healthy male participants, and in vitro plasma protein binding-
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Abstract: Introduction Valemetostat tosylate (valemetostat) is an oral, selective, dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1. This article reports findings on the mass balance and pharmacokinetics of valemetostat in a phase I study; valemetostat metabolite identification in plasma, urine, and fecal samples; and plasma-protein-binding of valemetostat in vitro. Methods Eight healthy participants received a single 200-mg oral dose of [14C]-valemetostat under fasting conditions. Blood, urine, and feces samples were collected to determine total radioactivity and/or unchanged valemetostat, and for metabolite identification. The binding of valemetostat 600–10,000 ng/mL to plasma, 4% human serum albumin (HSA), and 0.1% alpha-1-acid glycoprotein (AAG) was assessed in vitro. Results Mean cumulative recovery of administered radioactivity was 95.3% by 360 h post-dose, with a mean recovery of 15.6% in urine and 79.8% in feces. Valemetostat accounted for the most radioactivity in the excreta, at 10% and 64.9% of the administered dose in the urine and feces, respectively. CALZ-1809a was the most abundant metabolite, present in all biological samples, and accounted for 5.6% of total radioactivity in the feces. Valemetostat was minimally associated with red blood cells, with a blood-to-plasma total radioactivity ratio of 0.54. In vitro, valemetostat was highly plasma-bound (> 94%) at clinically relevant concentrations, with a higher affinity to AAG than to HSA. Conclusion Valemetostat was rapidly absorbed into the systemic circulation, mainly excreted via the biliary/fecal route, primarily metabolized by CYP3A enzymes to CALZ-1809a, and highly bound to plasma proteins, with a greater affinity to AAG than HSA in vitro.
PubDate: 2025-04-10
- Evolution of computational techniques against various KRAS mutants in
search for therapeutic drugs: a review article-
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Abstract: KRAS was (Kirsten rat sarcoma viral oncogene homolog) revealed as an important target in current therapeutic cancer research because alteration of RAS (rat sarcoma viral oncogene homolog) protein has a critical role in malignant modification, tumor angiogenesis, and metastasis. For cancer treatment, designing competitive inhibitors for this attractive target was difficult. Nevertheless, computational investigations of the protein’s dynamic behavior displayed the existence of temporary pockets that could be used to design allosteric inhibitors. The last decade witnessed intensive efforts to discover KRAS inhibitors. In 2021, the first KRAS G12C covalent inhibitor, AMG 510, received FDA (Food and drug administration) approval as an anticancer medication that paved the path for future treatment strategies against this target. Computer-aided drug designing discovery has long been used in drug development research targeting different KRAS mutants. In this review, the major breakthroughs in computational methods adapted to discover novel compounds for different mutations have been discussed. Undoubtedly, virtual screening and molecular dynamic (MD) simulation and molecular docking are the most considered approach, producing hits that can be employed in subsequent refinements. After comprehensive analysis, Afatinib and Quercetin were computationally identified as hits in different publications. Several authors conducted covalent docking studies with acryl amide warheads groups containing inhibitors. Future studies are needed to demonstrate their true potential. In-depth studies focusing on various allosteric pockets demonstrate that the switch I/II pocket is a suitable site for drug designing. In addition, machine learning and deep learning based approaches provide new insights for developing anti-KRAS drugs. We believe that this review provides extensive information to researchers globally and encourages further development in this particular area of research.
PubDate: 2025-04-07
- Napabucasin targets resistant triple negative breast cancer through
suppressing STAT3 and mitochondrial function-
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Abstract: Chemoresistance in triple negative breast cancer (TNBC) poses a significant challenge in effective treatment, necessitating the exploration of novel therapeutic strategies. This study evaluates the efficacy of napabucasin, a potent STAT3 inhibitor, in two paclitaxel-resistant TNBC cell models (MD-MBA-231-r and BT-549-r). We observed that napabucasin significantly reduced cell viability and colony formation in a dose-dependent manner. Combination index analysis revealed synergistic interactions between napabucasin and paclitaxel, suggesting enhanced cytotoxic effects when used in combination. Mechanistically, napabucasin inhibited STAT3 signaling and impaired mitochondrial function, as evidenced by decreased phosphorylated STAT3 levels, reduced mitochondrial complex I activity, lower oxygen consumption rate and diminished ATP levels. Further analysis indicated that paclitaxel-resistant cells exhibit higher mitochondrial biogenesis and function compared to their sensitive counterparts, with elevated expression of mitochondrial genes and biogenesis regulators, and increased levels of mitochondrial respiration. In vivo, napabucasin significantly inhibited tumor growth in paclitaxel-resistant TNBC xenograft models and reduced the expression of proliferation marker Ki67 and phosphorylation of STAT3. These findings demonstrate that napabucasin effectively targets paclitaxel-resistant TNBC cells by impairing mitochondrial function and inhibiting key signaling pathways, providing a strong rationale for its further clinical investigation as a therapeutic agent to overcome chemoresistance in TBNC.
PubDate: 2025-04-02
- The evaluation of the impact of NUDT15 variants on thiopurine metabolism
in Japanese children with acute lymphoblastic leukemia-
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Abstract: Purpose This study aimed to evaluate the impact of Nudix hydrolase 15 (NUDT15) variants on thiopurine metabolites, DNA-incorporated thioguanine nucleotides (DNA-TG), erythrocyte thioguanine nucleotides (Ery-TGNs) and methyl mercaptopurine nucleotide (Ery-MMPN) levels, and the association among the levels of these 6-MP metabolites in Japanese children with acute lymphoblastic leukemia (ALL). Methods DNA-TG, Ery-TGNs, and Ery-MMPN levels were measured in 20 Japanese patients with childhood ALL (171 sampling points) on consecutive clinical visits, using liquid chromatography with tandem mass spectrometry. NUDT15 was genotyped using Sanger sequencing. Results Three NUDT15 intermediate metabolizers (IM, *1/*2 or *1/*3) and two poor metabolizers (PM, *3/*3) were identified. DNA-TG/dose was significantly higher in PM than in normal metabolizers (NM). Intra-patient coefficients of variation (CV) of DNA-TG levels were similar in NUDT15 genotypes, and inter-patient CV was higher in IM and PM than in NM. The DNA-TG/Ery-TGNs ratio was higher in IM and PM than in NM (p
PubDate: 2025-04-01
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