Current Cancer Drug Targets - Online First

The changing landscape of hepatocellular carcinoma detection and treatment is examined in this study, focusing on recent advancements in therapeutic methods across several stages. Early identification of hepatocellular cancer cells continues to pose a serious threat to human health and is of utmost significance. It is crucial to create a useful signature to diagnose hepatocellular carcinoma early.

Chemotherapy and immunotherapy are high-stage treatment options for hepatocytes cancer. These treatments can be coupled with nanotechnology to increase effectiveness and minimize adverse effects. Furthermore, immunotherapy and chemotherapy might be combined to increase therapeutic efficacy and overcome resistance. Artificial intelligence technologies have the potential to significantly enhance hepatocellular carcinoma diagnosis and management.

Numerous models performed as well as or better than experienced radiologists while indicating the ability to improve radiologists' accuracy, showing encouraging outcomes for applying Artificial Intelligence to hepatocellular carcinoma-related diagnostic tasks.

Treatment for hepatocellular carcinoma has changed dramatically, moving from traditional techniques to cutting-edge technologies. Precision in diagnosis, prognosis, and treatment has increased due to innovations like molecular diagnostics, tailored medicines, and nanotechnology. This change improves patient outcomes and presents encouraging avenues for future research and treatment of hepatocellular cancer.

Recent advances in imaging techniques, biomarkers, and personalized medicine approaches have improved diagnostic accuracy and treatment outcomes. The emergence of immunotherapy, targeted therapies, and combination regimens has expanded treatment options, offering new hope for patients with advanced disease.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the Philadelphia chromosome. Imatinib is considered the standard therapy for CML due to its targeted action against the BCR::ABL1 tyrosine kinase. However, resistance to imatinib often emerges, particularly in the advanced stages of CML. One factor associated with imatinib resistance is the overexpression of survivin (baculoviral IAP repeat-containing 5, BIRC5). YM155 is an innovative survivin inhibitor that suppresses survivin expression and triggers apoptosis. Combination therapy is a strategy used to enhance the effectiveness of cancer treatment and overcome resistance.

Our study explored the in vitro anticancer effects of YM155 as monotherapy and as a combination therapy with imatinib on imatinib-sensitive (K-562) and imatinib-resistant (K562-r) BCR::ABL1+ CML cell lines. Results: Survivin inhibition significantly reduced proliferation in both K-562 and K562-r cells. Combination therapy with YM155 and imatinib produced a synergistic effect. In K562-r cells (imatinib IC50 = 6 µM), the combination reduced the IC50 by 6.2-fold. In K-562 cells, the IC50 decreased by 16.3-fold. Both monotherapy and combination therapy markedly increased apoptosis, with combination therapy inducing significantly greater apoptosis. The combination also downregulated survivin and BCR::ABL1 tyrosine kinase expression and significantly reduced BCR::ABL1 mRNA levels.

YM155 enhances imatinib’s efficacy against both sensitive and resistant CML cells, overcoming resistance through synergistic inhibition of proliferation, increased apoptosis, and suppression of survivin and BCR::ABL1 expression. These results support further investigation of YM155-Imatinib combination therapy as a potential strategy for resistant CML.

Single-nucleotide polymorphisms (SNPs) are the major source of attraction for researchers as they significantly contribute to an individual's susceptibility to various diseases, as well as provide an insight into new diseases associated with a particular gene.

In this study, the data were retrieved from dbSNP till July 2021. DbSNP showed 103738 total SNPs in the human ERG gene, and out of them, 377 missense SNPs were selected for analysis. Twenty-six missense SNPs were found to be deleterious in all five SNP tools (SIFT, PolyPhen-2, Condel, PHD-SNP, SNPs&GO). These 26 SNPs were further checked for protein stability by iStable, I-Mutant, and MuPro. Collectively, 23 SNPs showed to decrease the protein stability. A comparison of the 3D structures of the wild type (predicted by trRosetta) and the mutated type was visualized using the Chimera tool.

Post-translational modifications identified T180, R302, S356, and Y452 as clinically significant sites, as they were involved in phosphorylation and methylation.

In this study, in silico SNP analysis was performed on the human ERG gene. ERG’s involvement in various types of diseases, as well as cancer, has made it a source of interest. It is an oncogene that is not only involved in the germ line differentiation of hemopoietic stem cells, but is also involved in cell proliferation, embryonic development, angiogenesis, inflammation, and apoptosis.

This study has provided detailed information on missense SNPs of the ERG gene. This work can be significant in the detection of genetic diseases and drug discovery, as it has shown involvement of the ERG gene.

Agonists of CD137, a co-stimulatory receptor expressed on activated lymphocytes, are under investigation, including their use in combination with immune checkpoint blockade. FS222 is a tetravalent bispecific antibody targeting both CD137 and programmed death-ligand 1 (PD-L1).

Fragment crystallizable regions with antigen-binding (Fcab™) domains with high avidity to CD137 were engineered and matured. A resulting Fcab was introduced into a human high-affinity PD-L1 monoclonal antibody, generating FS222. Valency variants of FS222 and its mouse surrogate (FS222m) were generated. Antibody properties were assessed in vitro, while antitumor efficacy and T-cell proliferation were evaluated in vivo.

FS222 could bind to two copies of each antigen concurrently (‘2+2’ binding). In T-cell activation assays, FS222 and a variant that is bivalent for CD137 and monovalent for PD-L1 activated T cells, whereas monovalent variants for CD137 did not. FS222 had no hook effect up to 300 nM and was superior to a heterodimeric ‘1+1’ CD137/PD-L1 bispecific antibody. In mixed lymphocyte reaction assays, FS222 and another bivalently linked antibody for PD-L1 were more potent than monovalent antibodies for PD-L1. In syngeneic mouse models, FS222m was associated with more peripheral T-cell proliferation and antitumor efficacy than all MC38 or most CT26.WT valency variants.

FS222 could potently target and activate high CD137-expressing tumor-infiltrating lymphocytes due to its high avidity for CD137. FS222 demonstrates activity when PD-L1 levels are limited, highlighting its potential activity in tumors insensitive to PD-1 blockade, and in situations requiring both PD-L1 and CD137 binding. This may have clinical relevance.

In this study, it was found that the ‘2+2’ structure of FS222 is superior to that of a ‘1+1’ CD137/PD-L1 antibody.

Enhanced angiogenesis and impaired vascular integrity facilitate cancer metastasis. There is accumulating evidence that cancer-derived exosomes take a functional role in these processes. In our previous study, we revealed that Golgi Membrane protein 1 (GOLM1) can promote metastasis of Hepatocellular Carcinoma (HCC), and miRNAs can modulate angiogenesis and vascular permeability in HCC. The objective is to reveal that GOLM1 can promote HCC progression in an exosomal miRNA-dependent way.

Comprehensive bioinformatics analysis and experiments were conducted to associate GOLM1 expression with angiogenesis in HCC. The effect of hepatoma cell-derived exosomes on Human Umbilical Vein Endothelial Cells (HUVEC) was tested. Exosomal miRNA expression was profiled and validated in GOLM1-knockdown HCC cells. Targets of miR-4449 and miR-3651 were predicted with online tools and validated in vitro. Correlation between miR-4449/miR-3651 and microvascular invasion or recurrence in HCC was assessed.

GOLM1 correlated with angiogenesis in HCC. HCC cell-derived exosomes can be transferred to endothelial cells, and GOLM1 can regulate exosome-induced angiogenesis and vascular permeability. In vitro experiments showed that GOLM1 knockdown reduced exosomal abundance of miR-4449 and miR-3651, which target KEAP1 and ZO-1, respectively. Elevated miR-4449 and miR-3651 expression were correlated with microvascular invasion and recurrence in HCC patients.

We demonstrated that GOLM1 can promote HCC progression independent of its role in modulating EGFR/RTK cell-surface recycling, indicating that patients with high GOLM1 expression may benefit more from anti-angiogenic drugs and highlighting the potential of targeting miR-4449 and miR-3651 to prevent angiogenesis and vascular leakiness in HCC. However, in vivo studies are further needed to validate the effect of miR-4449 and miR-3651 inhibitors in compromising angiogenesis and vascular permeability. Besides, a larger validation cohort is indispensable for establishing the correlation between miR-4449/miR-3651 expression and microvascular invasion and tumor recurrence in HCC.

Our findings suggest that, under the control of GOLM1, HCC cell-derived exosomal miR-4449 and miR-3651 increase angiogenesis and vascular permeability by targeting KEAP1 and ZO-1, highlighting the potential of exosomal miRNAs as promising therapeutic targets for HCC.

Thiazolidinedione (TZD) derivatives have gained significant attention as anti-cancer agents due to their diverse biological activities. The objective of the research was to investigate the potential of thiazolidine derivatives as inhibitors of Carbonic anhydrase XII, an isoform overexpressed in hypoxic tumor environments, to explore their application as anticancer agents targeting breast cancer.

The study employed a computational approach to evaluate thiazolidine derivatives as potential CA XII inhibitors. Acute toxicity and safety were evaluated using ProTox 3.0. Molecular docking was conducted to study interactions with the zinc-bound active site of CA XII. Molecular dynamics simulations were performed to validate the stability of the ligand-enzyme complex over 250 ns.

TZD derivatives demonstrated favorable physicochemical properties, high gastrointestinal absorption, and low toxicity risks. Molecular docking studies showed strong binding affinities with key hydrogen bonding and zinc coordination at the CA XII active site. Toxicity predictions indicated that most compounds had acceptable safety margins, reinforcing their potential as safe and effective CA XII inhibitors.

The findings suggest that thiazolidine scaffolds could serve as promising small-molecule inhibitors of CA XII by targeting its zinc-bound catalytic site, a mechanism consistent with previously reported CA inhibitor pharmacology.

The study demonstrates that TZD derivatives possess promising characteristics as CA XII inhibitors, with favorable physicochemical properties, strong binding affinity, stable ligand-protein interactions, and acceptable safety profiles. These findings highlight their potential for further in vitro and in vivo validation, supporting the continued exploration of thiazolidinedione scaffolds in the development of targeted anticancer therapies.

Epidermal Growth Factor Receptor (EGFR) is a well-established therapeutic target in cancer treatment. In this study, a novel N-phenylacetamide derivative of theobromine, designated as T-1-PA, was designed as a potential semisynthetic EGFR inhibitor.

The 3D structure, stability, and electronic reactivity of T-1-PA were determined using Density Functional Theory (DFT) analyses. Molecular docking, molecular dynamics (MD) simulations, Molecular Mechanics Generalized Born Surface Area (MM-GBSA), Protein–Ligand Interaction Profiler (PLIP), and Principal Component Analysis of Trajectories (PCAT) were employed to evaluate the binding affinity and inhibitory potential of T-1-PA against EGFR. Computational ADMET profiling was conducted to predict drug-likeness and safety. Subsequently, T-1-PA was semisynthesized and subjected to in vitro biological evaluation.

Computational analyses demonstrated a strong binding affinity of T-1-PA to EGFR. The compound exhibited favorable ADMET properties. In vitro assays revealed potent EGFR inhibition with an IC50 of 0.736 ± 0.005 μM. T-1-PA also inhibited the proliferation of HepG2 and MCF7 cancer cell lines with IC50 values of 0.88 ± 0.01 μM and 1.13 ± 0.01 μM, respectively. Flow cytometry analysis indicated induction of apoptosis and G1 phase cell cycle arrest in HepG2 cells. Additionally, T-1-PA significantly impaired HepG2 cell migration and wound-healing capacity.

The results validate the computational predictions and highlight the anticancer potential of T-1-PA through EGFR inhibition and antiproliferative activity. The compound's favorable pharmacokinetic and safety profiles further support its therapeutic promise.

T-1-PA is a promising semisynthetic compound with selective antiproliferative activity mediated via EGFR inhibition. These findings encourage further preclinical investigation of T-1-PA as a novel candidate for EGFR-targeted cancer therapy.

There is no consensus on the impact of young age (≤ 35 or 40) on breast cancer prognosis. In this study, a meta-analysis was carried out on the prognosis of breast cancer in young women.

We searched PubMed, Embase, Web of Science, Cochrane, and key cancer-related international conference proceedings, from their inception to 1st June, 2023, with an update on 15th July, 2023. Studies were included if they reported hazard ratios (HRs) with 95% confidence intervals (CIs) or presented Kaplan–Meier survival curves. The main outcomes were overall survival (OS), disease-free survival (DFS), breast cancer–specific survival (BCSS), local recurrence–free survival (LRFS), distant disease–free survival (DDFS), progression-free survival (PFS), and pathological complete response (pCR). This meta-analysis was registered in PROSPERO (CRD42023459282).

The meta-analysis, including 129 studies with approximately 1,065,000 patients, reported that young breast cancer (YBC) patients had worse OS (HR = 1.30; 95% CI: 1.17 - 1.43; I² = 93%; P < 0.01), DFS (HR = 1.58; 95% CI: 1.47 - 1.70; I² = 68%; P < 0.01), BCSS (HR = 1.28; 95% CI: 1·09 - 1.49; I² = 95%; P < 0.01), LRFS (HR = 2.05; 95% CI: 1.59 - 2.59; I² = 70%; P < 0.01), DDFS (HR = 1.44; 95% CI: 1.11 - 1.87; I² = 91%; P < 0.01), and PFS (HR = 1.54; 95% CI: 1.16 - 2·03; I² = 90%; P < 0.01) and a greater pCR rates than non-young breast cancer (NYBC) patients (odds ratio (OR) = 1.45; 95% CI: 1.16 - 1.82; I² = 87%; P < 0.01). Subgroup analysis demonstrated that, compared with NYBC patients, certain differences were found in the prognoses of YBC patients with different molecular subtypes, regions, and stages.

This meta-analysis confirmed that YBC patients have worse survival outcomes than NYBC patients, despite having higher pCR rates. Subgroup analyses demonstrated that outcomes varied by molecular subtype, region, and disease stage. These findings underscore the importance of early screening, enhanced patient education, and tailored treatment strategies for YBC patients.

Patients with YBC had worse OS, DFS, BCSS, LRFS, DDFS, PFS, and greater pCR rates than NYBC patients.

Esophageal squamous cell carcinoma (ESCC) stands as one of the deadliest cancers globally. Given the urgent clinical need for more precise and comprehensive therapeutic strategies, the phytocompound methylophiopogonanone A (MO-A) demonstrates the potential as a candidate for ESCC treatment. This study aimed to verify the therapeutic effect of MO-A against ESCC and unveil its underlying mechanism.

Three compound-protein interaction databases were utilized to predict the molecular targets of MO-A. Subsequently, potential therapeutic targets of ESCC were identified based on the GEO database. KEGG pathway and GO function enrichment analyses were then performed by using these two sets of targets, respectively. Through the integrative analysis of these two target sets, core targets of MO-A with therapeutic potential against ESCC were determined. Protein-protein interaction network analyses and molecular dockings were executed by using these targets. Two human-derived ESCC cell lines were enrolled for biological validation, including cell viability, colony formation, and cell cycle assays.

This study predicted 200 potential targets of MO-A and uncovered 138 key targets associated with the progression of ESCC. Enrichment analyses and PPI networks underscored the involvement of cell cycle-related genes in ESCC development. Four proteins were determined as core MO-A targets for ESCC treatment, including AURKA, AURKB, CDC25B, and TOP2A, which partake in the regulation of the cell cycle. Finally, the inhibitory effect of MO-A on ESCC cell proliferation was validated in vitro, primarily through inducing cell cycle arrest at the G2/M phase in ESCC cells.

These results revealed the anti-ESCC potential of MO-A, a plant-derived flavonoid, using integrated bioinformatics and biological experiments. While findings provide a mechanistic basis for the efficacy of MO-A, limitations include reliance on computational and in vitro models. Further studies should be conducted to evaluate the pharmacological properties and safety of MO-A across multiple models, alongside more comprehensive structure-activity relationship studies to inform drug optimization prior to clinical translation.

MO-A can impede ESCC growth by triggering cell cycle G2/M arrest, positioning it as a novel and promising phytocompound for ESCC therapy.