Cervical cancer, a common malignant tumor of the female reproductive system, ranks fourth in incidence and mortality among female cancers globally, which highlights the urgent need for new therapeutic agents to improve treatment outcomes. In this study, 16 new erlotinib-1,2,3-triazole derivatives were synthesized via click chemistry and evaluated for their anti-proliferative activities against HeLa cells using the MTT assay. Compound 3h exhibited the most potent antitumor activity, with a half-maximal inhibitory concentration (IC50) value of 1.35 ± 0.74 µM, significantly lower than that of erlotinib (IC50 = 25.91 ± 1.35 µM). Further assays showed that compound 3h reduced cell viability, inhibited colony formation, and suppressed migration. It arrested the cell cycle at the G2/M phase and induced mitochondrial apoptosis, marked by decreased Bcl-2, increased Bax, and downregulated Caspase-9, Caspase-3, and PARP-1. Additionally, compound 3h promoted ROS accumulation, induced γ-H2AX expression, and regulated the phosphorylation of ERK, JNK, and p38. Molecular docking studies suggested direct binding to these MAPKs. Overall, compound 3h inhibited HeLa cell proliferation by inducing ROS-mediated DNA damage and mitochondrial apoptosis via the MAPK pathway. This study provides evidence for the therapeutic potential of erlotinib-1,2,3-triazole derivatives in cervical cancer treatment, offering new strategies for developing effective and low-toxicity drugs.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that urgently needs more effective therapies. Cancer-associated fibroblasts (CAFs) contribute to the aggressive and chemo-resistant nature of the disease by creating a drug-impeding fibrotic microenvironment. We developed novel compounds, the racemate CRO-05 and its active enantiomer CRO-67, which target both pancreatic tumor and CAF cells with robust anti-cancer activity. These compounds were designed using rational medicinal chemistry based on chromans, a class of anti-cancer drugs. Their therapeutic potential and efficacy were assessed in a clinically relevant patient-derived PDAC tumor explant model, which mimics the disease's 3-dimensional complexity. CRO-67 treatment in these explants significantly reduced tumor cell and αSMA+ CAF frequency, decreased cell proliferation and increased cell death. CRO-67 also significantly decreased cell proliferation and enhanced apoptosis by inhibiting cell cycle progression through G2/M phase in PDAC cells and patient-derived CAFs in vitro. CRO-67 treatment of orthotopic PDAC tumors in mice significantly reduced tumor growth in tumors with active growth (> 150% growth at endpoint), and remodeled tumor stroma (reduced αSMA+ CAF frequency, loosened tumor fibrosis and normalized tumor vasculature). Finally, CRO-67 sensitized PDAC cells to multiple standard-of-care chemotherapeutics in vitro, paving the way for future combination therapy development and validation.

The dysfunction of HDACs is closely related to tumorigenesis and development, which has emerged as an attractive target for cancer therapy. In this study, a series of thiazole-containing hydroxamate derivatives were designed and synthesized as novel HDAC inhibitors. Among these inhibitors, compounds 15a and 15d showed excellent inhibitory activities against HDAC1 and HepG2 cancer cell line, these two compounds increased the levels of acetylated histone H3 and H4. Moreover, 15a and 15d significantly arrested HepG2 cells at the G0/G1 phase. Additionally, these two compounds could induce apoptosis and pyroptosis. Moreover, 15a exhibited significant antitumor activity in the HepG2 xenograft model. Molecular docking and molecular dynamics simulation studies revealed the possible interaction mode of compound 15a with HDAC1. Besides, the preliminary pharmacokinetics study of compound 15a in vivo was evaluated. These results suggested that these novel thiazole-based HDAC inhibitors might become a promising scaffold for further structural optimization.

Cancer cells that survive chemotherapy achieve full DNA duplication despite the accumulation of damaged DNA triggered by chemotherapy. This happens because the synthesis of DNA at damaged sites is granted by tolerance events including translesion DNA synthesis (TLS), a process that promotes the use of specialized DNA polymerases (S-Pols) for DNA synthesis. Such a crucial role of S-Pols in the promotion of damaged DNA replication prompted analyses of the cell killing effects of individual S-Pols inhibitors. Because S-Pols can compensate for each other, a global inhibition of S-Pols needs to be designed and tested. Given that S-Pols are recruited to the replisome through their PCNA binding motif, we reasoned that global displacement of S-Pols will occur when delivering a peptide with a strong PCNA binding motif. The cyclin kinase inhibitor p21 contains the strongest PCNA binding motif. Therefore, we designed a peptide representing this C-terminal, PCNA interacting region (PIR) of p21. As hypothesized by us, the PIR peptide achieved global S-Pol displacement from PCNA-associated replication factories and enhanced the cancer cell killing potential of DNA damaging agents including cisplatin, hydroxyurea, olaparib and UV irradiation. Demonstrating strong versatility, the peptide also enhanced the cytotoxicity caused by agents that do not directly provoke DNA damage such as Chk1, ATR and Wee1 inhibitors. In all cases, disrupting the PCNA binding site within the PIR peptide was sufficient to dismantle its cell killing potential. Strengthening the concept, a less potent PIR, namely derived from S-Pol eta, efficiently displaced S-Pols from replication factories exacerbating cell killing by all agents tested. These results collectively indicate that simultaneous displacement of S-Pols from PCNA can be enforced by excess levels of PIR peptides. This strategy is demonstrably valid to enhance the cancer cell killing by different DNA-damaging agents.

Reovirus type 3 Dearing (RT3D) is an oncolytic, double-stranded RNA virus. To identify potential RT3D drug-viral sensitizer, here we use a high-throughput screen of therapeutic agents and find a PARP-1 inhibitor, talazoparib, as a top hit. RT3D interacts with retinoic acid-induced gene-1 (RIG-I) and activates PARP-1, with consequent PARylation of components of the extrinsic apoptosis pathway. Pharmacological or genetic inhibition of PARP-1 abrogates this PARylation and enhances extrinsic apoptosis, NF-kB signalling and pro-inflammatory cell death. Interaction between PARP-1 and RIG-I induced by treating RT3D-infected cells with talazoparib activates downstream IFN-β and TNF/TRAIL production to amplify the therapeutic effect through positive feedback. Furthermore, the effect of RT3D-talazoparib combination is phenocopied by non-viral ds-RNA therapy and RIG-I agonism. In vivo, mouse tumour model results show that RT3D/talazoparib combination regimen induces complete control of inoculated tumour as well as protection from subsequent tumour rechallenge with the, with accompanied innate and adaptive immune activation.

Renal angiomyolipomas (AMLs) are a common renal manifestation in tuberous sclerosis complex (TSC), occurring in 50%-85% of cases. Even in asymptomatic individuals, treatment is often initiated based on AML size, with mTOR inhibitors being the primary medical therapy. AMLs tend to enlarge with age, and treatment during school age is rare. Secondary AML shrinkage in paediatric TSC patients has been reported who received everolimus for subependymal giant cell astrocytomas (SEGA) or epilepsy, but studies on its direct use for AMLs in paediatric cases remain limited. A 9-year-old girl born to a mother with TSC was diagnosed at birth due to cardiac rhabdomyomas, cortical tubers, and Shagreen patches. At the age of 4, ultrasound detected multiple AMLs in both kidneys, with the largest lesions measuring 2.3 cm in the right kidney and 1.6 cm in the left. By the age of 7, MRI showed further growth to 4.8 cm. Despite the absence of symptoms, the risk of haemorrhage led to treatment initiation. Everolimus was started at 1.0 mg/day (1.3 mg/m2/day), significantly lower than the standard 4.5 mg/m2/day. Trough levels remained below the target range, yet AMLs showed a shrinking tendency, with MRI at age 9 revealing a reduction in the largest AML to 2.4 cm. Stomatitis occurred intermittently, but no serious adverse effects were observed. This case suggests that low-dose everolimus can effectively reduce AML size while minimising adverse effects, highlighting its potential as a treatment option for AMLs in paediatric TSC patients.

Recent studies have demonstrated functional and cosmetic benefits with the use of hedgehog pathway inhibitors in the neoadjuvant setting for basal cell carcinoma (BCC). This study investigated the current use of neoadjuvant therapy by Mohs surgeons for the treatment of BCC with an anonymous REDcap survey distributed to members of the American College of Mohs Surgery. In the study population, a considerable percentage (22%) of Mohs surgeons reported current use of neoadjuvant hedgehog inhibitors for BCC prior to Mohs surgery. Among this group, there is wide variation in BCC size, location, target tumor size reduction, and average length of therapy for their use of neoadjuvant hedgehog inhibitors prior to Mohs surgery. Concerns about adverse effects and creating a discontinuous tumor were the most cited reasons not to treat patients with neoadjuvant hedgehog inhibitors prior to Mohs surgery. Given there is better tolerability of hedgehog pathway inhibitors when used for shorter treatment duration, hedgehog pathway inhibitors may be most useful in the neoadjuvant setting to maximize clinical benefit and minimize toxicity.

Aim     To monitor the dynamics of biomarkers during chemotherapy, targeted chemotherapy and targeted monotherapy in patients with HER2-positive breast cancer (BC); to analyze the emergence timing of these changes; to compare early biochemical and echocardiographic criteria; and to determine the best time for assessing latent subclinical cardiac dysfunction.Material and methods            Patients with BC (229 women aged 57±11 years) treated sequentially with anthracyclines, a combination of docetaxel and trastuzumab, and trastuzumab monotherapy were examined during three blocks of BC therapy until the development of clinical cardiotoxicity. Time-related changes in high-sensitivity cardiac troponin I, N-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular (LV) global longitudinal strain (GLS) and LV ejection fraction (EF) (up to 12 speckle-tracking echocardiograms/up to 12 laboratory tests) were analyzed. Clinical cardiotoxicity was defined as a symptomatic decrease in LV EF ≥10% from the baseline value of 54% or more.Results            Clinically significant cardiotoxicity developed in 6.3-10.9% of cases depending on the treatment option for BC. Early manifestations of cardiotoxicity were detected already at 3 weeks after the start of the first course of chemotherapy. For the BC treatment with anthracyclines and targeted chemotherapy with docetaxel and trastuzumab, the markers of clinical cardiotoxicity were high-sensitivity cardiac troponin I, NT-proBNP and GLS LV. For the trastuzumab monotherapy, only GLS LV had a prognostic value. No statistically significant changes in the concentrations of high-sensitivity troponin I and NT-proBNP were found.Conclusion      For timely detection of clinical cardiotoxicity, laboratory tests (high-sensitivity troponin I, NT-proBNP) and echocardiography (GLS LV) are recommended to be performed every 3 weeks before the next course of BC therapy. While doing so, their sensitivity will depend on the treatment option for BC.

Aim     To determine the array of metabolomic profiles and structural and functional parameters of the vascular wall associated with the risk of cardiovascular toxicity of antitumor therapy (ATT) in oncohematological patients.Material and methods            This study included 59 patients, among them 34 patients with lymphomas (non-Hodgkin and Hodgkin lymphoma) and 25 with multiple myeloma. Before and after 3 courses of ATT (anthracyclines, proteasome inhibitors), finger photoplethysmography and transthoracic echocardiography were performed as well as metabolomic profiling (98 metabolites) by high-performance liquid chromatography in combination with tandem mass spectrometry. Statistical analysis of the results included parametric and nonparametric tests, logistic regression, and cross-validation.Results            The study showed that even before the initiation of ATT, cancer patients had signs of endothelial dysfunction and increased vascular wall stiffness (increased aSI, RI, and IO indices), which significantly worsened after the specific treatment. Metabolomic profiling identified a set of metabolites associated with the risk of cardiovascular toxicity, including increased concentrations of amino acids (asparagine, serine, glutamate, glutamine, taurine, citrulline), short-chain acylcarnitines (C18:1 OH-carnitine, C16:1 OH-carnitine, C14OH-carnitine, C2 carnitine), choline metabolism intermediates (TMAO, dimethylglycine, choline), tryptophan metabolites (hydroxyindoleacetic acid, kynurenic acid). Additionally, a logistic regression model was developed based on the analysis of the metabolomic profile, which showed a high prognostic power (AUC = 0.84) for predicting cardiovascular toxicity of ATT.Conclusion      The study identified key metabolites and structural and functional parameters of blood vessels that allow detection of an increased risk of cardiovascular complications of ATT in patients with lymphomas and multiple myeloma before the initiation of a specific treatment. Increased concentrations of amino acids, acylcarnitines, and choline metabolites may serve as an additional risk factor for the onset/progression of cardiovascular complications. The proposed integrative approach, including both metabolomic profiling and non-invasive assessment of the vascular wall condition, opens broad prospects for personalized cardioprotection of cancer patients and more accurate monitoring of the cardiovascular status during ATT.

The purpose of this study was to investigate the frequency and characteristics of Bruch's membrane (BM) breaks, and their relationship with clinically relevant outcomes in neovascular age-related macular degeneration (nAMD).

Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, but their use is limited by the development of autoimmunity in healthy tissues as a side effect of treatment. Such immune-related adverse events (IrAE) contribute to hospitalizations, cancer treatment interruption, and even premature death. ICI-induced autoimmune diabetes mellitus (ICI-T1DM) is a life-threatening IrAE that presents with rapid pancreatic β-islet cell destruction leading to hyperglycemia and life-long insulin dependence. While prior reports have focused on CD8+ T cells, the role for CD4+ T cells in ICI-T1DM is less understood. We identify expansion of CD4+ T follicular helper (Tfh) cells expressing IL-21 and IFN-γ as a hallmark of ICI-T1DM. Furthermore, we show that both IL-21 and IFN-γ are critical cytokines for autoimmune attack in ICI-T1DM. Because IL-21 and IFN-γ both signal through JAK/STAT pathways, we reasoned that JAK inhibitors (JAKi) may protect against ICI-T1DM. Indeed, JAKi provide robust in vivo protection against ICI-T1DM in a mouse model that is associated with decreased islet-infiltrating Tfh cells. Moreover, JAKi therapy impaired Tfh cell differentiation in patients with ICI-T1DM. These studies highlight CD4+ Tfh cells as underrecognized but critical mediators of ICI-T1DM that may be targeted with JAKi to prevent this grave IrAE.

A significant proportion of patients fail to respond adequately to the standard R-CHOP regimen for diffuse large B-cell lymphoma (DLBCL). Rapid proliferation requires energy and the interaction between H+ ions and mitochondria suggests that regulating acid secretion in tumor cells may be a therapeutic strategy for DLBCL. This study constructed a macrophage membrane-coated liposomal formulation (MM-Lipid@Vpz) for the targeted delivery of vonoprazan to combat DLBCL, which enables the evasion of the reticuloendothelial system, ensuring enhanced specificity in tumor targeting.

Chemodynamic therapy (CDT) is a promising antitumor strategy that damages tumor cells by generating reactive oxygen species (ROS) to induce oxidative stress. However, antioxidant mechanisms in tumor cells greatly reduce CDT efficacy.

The integration of artificial intelligence (AI) into oncology drug discovery is redefining the traditional pipeline by accelerating discovery, optimizing drug efficacy, and minimizing toxicity. AI has enabled groundbreaking advancements in molecular modeling, simulation techniques, and the identification of novel compounds, including anti-tumor and antibodies, while elucidating mechanisms of drug toxicity. Additionally, AI has emerged as a critical tool in precision medicine, driving the formulation and release of targeted therapies and improving the development of treatments for oncology and central nervous system diseases. Furthermore, AI-assisted clinical trial designs have further optimized the recruitment and stratification of patients, reducing the time and cost of trials. Despite these advancements, challenges such as data integration, transparency, and ethical considerations persist. By synthesizing current innovations, this manuscript provides a comprehensive analysis of AI-driven approaches in drug discovery and their potential to advance oncology therapeutics and precision medicine. It examines the transformative role of AI across the drug development continuum, with a focus on its applications in computer-aided drug design (CADD), generative artificial intelligence (GAI), and high-throughput screening (HTS).

Background: Rapid drug desensitizations (RDD) provide a means for patients with a history of acute hypersensitivity reactions (HSR) to platinum-based chemotherapeutics to continue their first-line oncologic treatment. Approximately one third of RDDs have been associated with breakthrough reactions (BTR) but identifying which patients are at risk is challenging. Objective: The objective was to identify factors predictive of patients at risk of developing BTR during their initial RDD. Methods: Forty-three patients who developed HSRs to a platinum drug and subsequently underwent RDDs were included for analysis. A retrospective manual chart review was performed to obtain demographics and information with regard to oncologic history, incident HSR, and RDD. The severity of HSRs and BTRs was determined by using the Brown criteria. Results: BTRs developed in 37% of patients during their initial RDD. Compared with those who tolerated RDDs, the patients who developed BTRs were significantly more likely to have positive allergy skin test results with a platinum drug (100%) than those who tolerated their RDD (47%, p = 0.01). The median (interquartile range) time between incident HSR and initial RDD was significantly shorter among patients who developed BTRs (31 days [21-49 days]) than those who did not develop BTRs (46 days [28-826 days]) (p = 0.04). Only 46% of patients with severe incident HSRs developed a BTR. However, severe BTRs occurred only in patients who had severe incident HSRs (p = 0.02). Conclusion: Severe clinical signs and symptoms of incident HSRs do not always predict if BTRs will occur during initial RDDs. However, patients with severe BTRs are more likely to have had a severe incident HSR.

The role of gut microbial dysbiosis in chemotherapy-induced diarrhea (CID) pathogenesis remains unclear in humans. This study investigates gut microbiota alterations in CID patients and evaluates the therapeutic potential of probiotic supplementation.

Primary ovarian squamous cell carcinoma (POSCC) represents an exceedingly rare subtype of epithelial ovarian cancer (EOC) characterized by a cryptic etiology and insidious onset. The rarity and high mortality associated with pure primary ovarian squamous cell carcinoma (SCC) make it challenging to conduct large randomized controlled studies. Furthermore, there are currently no commercially available ovarian SCC cell lines for research purposes, necessitating the urgent establishment of novel lines. To our knowledge, this study reports the first preclinical model of primary ovarian squamous cell carcinoma (POSCC), denoted as ZOC254. We have detailed the establishment and characterization of ZOC254, derived from a 64-year-old female patient, which preserves the primary tumor's original traits across various levels during prolonged in vitro expansion. Whole-exome sequencing (WES) of both the primary tumor and derived cell line revealed homologous recombination deficiency (HRD) and high tumor mutational burden (TMB). ZOC254 also exhibited the PIK3CA: p.E542K mutation associated with targeted therapy. The effectiveness of olaparib, everolimus, and conventional chemotherapeutic agents for ovarian cancer was preliminarily assessed on the growth of patient-derived cells (PDC). The POSCC cell line and derived xenograft transplantation model reported in this study serve the purpose of broadening the resources accessible for preclinical investigations into ovarian squamous carcinoma.

Biologically active heterocycles hold considerable potential in modulating cellular pathways associated with cancer progression. The present study focuses on the design and synthesis of novel thiadiazole-thiazolidinone hybrid scaffolds aimed at inhibiting the proliferation of cancer cells. The synthesized compounds were evaluated for their cytotoxic efficacy against human cancer cell lines, including HepG2 (hepatocellular carcinoma), MCF-7 (breast adenocarcinoma), HCT-116 (colorectal carcinoma), and W138 (lung fibroblast-derived carcinoma). Doxorubicin was used as a reference standard. Among the synthesized library, compound 7 demonstrated the most potent antiproliferative activity across all tested cell lines, indicating its potential role in targeting molecular pathways involved in tumor growth and survival. To elucidate the underlying mechanism of action, molecular docking studies were conducted to analyze ligand-target interactions at the atomic level, revealing favorable binding conformations within key regulatory proteins implicated in oncogenesis. Furthermore, enzyme kinetics and dose-response inhibition assays were performed to characterize the interaction dynamics and establish potential modes of inhibition. The ADMET profile of the lead compounds was also evaluated in silico, supporting their drug-likeness and safety for further preclinical development. These findings contribute valuable scaffolds for the development of new anticancer agents and highlight the importance of integrating chemical synthesis with molecular biology techniques in the discovery of targeted cancer therapeutics.

Transarterial chemoembolization (TACE) is a common clinical intervention used for unresectable liver tumors, but conventional embolic microspheres generally exhibit slack vascular stacking and suboptimal drug release. Here, we report tumor vessel-adaptable, adhesive, and absorbable microspheres (3Asphere) based on hyaluronic acid developed using microfluidic and radical polymerization techniques for sustained TACE therapy of liver tumors. 3Asphere presents uniform sizes, gradual degradation over two months, and fast encapsulation and sustained release of chemotherapeutics such as epirubicin, irinotecan, and cisplatin. Interestingly, 3Asphere with high elasticity enables robust vascular embolization, effectively blocking rabbit renal blood supply for over one month. In rabbit VX2 orthotopic liver tumors, 3Asphere actively binds to endothelial cells via CD44 and inhibits tumor growth, affording significant survival benefits compared to commercial Embosphere®. TACE with epirubicin-loaded 3Asphere further enhances tumor inhibition and prevents lung metastasis. 3Asphere provides a versatile and advanced TACE therapy that might alleviate liver tumors.

Anticancer drug 5FU is extensively metabolized by dihydropyrimidine dehydrogenase (DPD), an enzyme with high interindividual variability. Poor metabolizer (PM, i.e., DPD deficient) patients are at risk of life-threatening toxicities. Whether ultra-rapid metabolizer (UM) status could conversely compromise 5FU efficacy remains to be investigated.