Significant Antitumor Activity Research Articles

Efficacy and safety of lenvatinib combined with anti-PD-1 antibodies plus GEMOX chemotherapy as non-first-line systemic therapy in advanced gallbladder cancer

BackgroundLenvatinib, programmed cell death 1 (PD-1) antibodies, and gemcitabine and oxaliplatin (GEMOX) chemotherapy have shown significant antitumor activity as first-line therapy against biliary tract cancer. This study evaluated their efficacy and safety as non-first-line therapy in advanced gallbladder cancer (GBC).MethodsPatients with advanced GBC who received lenvatinib combined with anti-PD-1 antibodies and GEMOX chemotherapy as a non-first-line therapy were retrospectively analyzed. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR) and safety.ResultsA total of 36 patients with advanced GBC were included in this study. The median follow-up time was 11.53 (95% confidence interval (CI): 2.2–20.9) months, and the ORR was 36.1%. The median OS and PFS were 15.1 (95% CI: 3.2–26.9) and 6.1 (95% CI: 4.9–7.2) months, respectively. The disease control rate (DCR) and clinical benefit rate (CBR) were 75% and 61.1%, respectively. Subgroup analysis demonstrated that patients with programmed cell death-ligand 1 (PD-L1) expression had significantly longer PFS and OS than those without PD-L1 expression. Additionally, patients with a neutrophil–lymphocyte ratio (NLR) < 5.57 had a longer OS than those with an NLR ≥ 5.57. All patients experienced adverse events (AEs), with 61.1% experiencing grade 3 or 4 AEs, including myelosuppression (13.9%) and fatigue (13.3%), alanine transaminase or aspartate transaminase levels (8.3%), and diarrhea (8.3%). No grade 5 AEs were reported.ConclusionAnti-PD-1 antibodies combined with lenvatinib and GEMOX chemotherapy are effective and well-tolerated as a non-first-line therapy in advanced GBC. PD-L1 expression and baseline NLR may potentially predict treatment efficacy.

A Novel Tryptanthrin Derivative D6 Induces Apoptosis and DNA Damage in Non-small-cell Lung Cancer Cells Through Regulating the EGFR Pathway.

Non-small-cell lung cancer is a prevalent malignancy associated with significant morbidity and mortality rates. Tryptanthrin and its derivatives have exhibited potent antitumor activity. This study aims to investigate the inhibitory effect of a novel synthesized tryptanthrin derivative D6 on proliferation and the possible mechanism of human non-small cell lung cancer cell lines (A549) in vitro. In this study, MTT assay, cell migration, colony formation assay, cell cycle analysis, cell apoptosis, JC- 1 staining assay, reactive oxygen species analysis, proteomics, western blotting, high content screening and absorption titrations analysis were performed. We found that D6 inhibited both the proliferation and migration, induced cell cycle arrest in the G2/M phase, increased levels of ROS, decreased mitochondrial membrane potential, and promoted apoptosis in A549 cells. Further mechanistic studies found that D6 reduced EGFR expression in A549 cells and inhibited the EGFR pathway by decreasing phosphorylation levels of EGFR, Stat3, AKT and Erk1/2. Moreover, DNA damage induced by D6 involved an increase in p53/MDM2 ratio and concentration-dependent accumulation of micronuclei. D6 demonstrated significant antitumor activity against A549 cells by inhibiting the EGFR signaling pathway, inducing DNA damage, and subsequently leading to oxidative stress, apoptosis, and cell cycle arrest. Our findings suggest that D6 exhibits potential as an NSCLC drug, owing to its attributes such as antiproliferative activity and ability to induce apoptosis by attenuating the EGFR-mediated signaling pathway.

Photoredox-Catalyzed Carbamoyl Radical-Initiated Dearomative Spirocyclization To Access Spiro-Cyclohexadiene Oxindoles.

The sustainable construction of spirocyclic compounds is important to the scientific community and the pharmaceutical industries. Herein, we demonstrate a carbamoyl radical-initiated intramolecular dearomative spirocyclization to access the spiro-cyclohexadiene oxindoles under visible light irradiation, which constitutes the first example of accessing the I-substituted derivatives that facilitate diversified transformations. Additionally, the scalability, late-stage modification of drugs, and significant antitumor activity of the products demonstrate the novel spirocyclic synthesis platform for expediting drug development.

Rod-shaped mesoporous silica nanoparticles reduce bufalin cardiotoxicity and inhibit colon cancer by blocking lipophagy

BackgroundBufalin (BA) is a potent traditional Chinese medicine derived from toad venom. It has shown significant antitumor activity, but its use is limited by cardiotoxicity, which necessitates innovative delivery methods, such as rod-shaped mesoporous silica nanoparticles (rMSNs). rMSNs have been extensively employed for reducing drug toxicity and for controlled or targeted drug delivery in tumor therapy. However, their potential in delivering BA has not been completely elucidated. Therefore, in this study, BA-loaded rMSNs (BA-rMSNs) were developed to investigate their potential and mechanism in impairing colon cancer cells.MethodsrMSNs were developed via the sol‒gel method. Drug encapsulation efficiency and loading capacity were determined to investigate the advantages of the rMSN in loading BA. The antiproliferative activities of the BA-rMSNs were investigated via 5-ethynyl-2’-deoxyuridine and CCK-8. To evaluate cell death, Annexin V-APC/PI apoptotic and calcein-AM/PI double staining were performed. Western blotting, oil red O staining, and Nile red solution were employed to determine the ability of BA-rMSNs to regulate lipophagy.ResultsThe diameter of the BA-rMSNs was approximately 60 nm. In vitro studies demonstrated that BA-rMSNs markedly inhibited HCT 116 and HT-29 cell proliferation and induced cell death. In vivo studies revealed that BA-rMSNs reduced BA-mediated cardiotoxicity and enhanced BA tumor targeting. Mechanistic studies revealed that BA-rMSNs blocked lipophagy.ConclusionsrMSNs reduced BA-mediated cardiotoxicity and impaired the growth of colon cancer cells. Mechanistically, antitumor activity depends on lipophagy.

Syntheses of LSD1/HDAC Inhibitors with Demonstrated Efficacy against Colorectal Cancer: In Vitro and In Vivo Studies Including Patient-Derived Organoids.

Precedential evidence ascertaining the overexpression of LSD1 and HDACs in colorectal cancer spurred us to design a series of dual LSD1-HDAC inhibitors. Capitalizing on the modular nature of the three-component HDAC inhibitory model, tranylcypromine as a surface recognition motif was appended to zinc-binding motifs via diverse linkers. A compendium of hydroxamic acids was generated and evaluated for in vitro cytotoxicity against HCT-116 cells (human colorectal cancer cell lines). The most potent cell growth inhibitor 2 (GI50 = 0.495 μMm HCT-116 cells) shows promising anticancer effects by reducing colony formation and inducing cell cycle arrest in HCT-116 cells. It exhibits preferential inhibition of HDAC6, along with potent inhibition of LSD1 compared to standard inhibitors. Moreover, Compound 2 upregulates acetyl-tubulin, acetyl-histone H3, and H3K4me2, indicative of LSD1 and HDAC inhibition. In vivo, it demonstrates significant antitumor activity against colorectal cancer, better than irinotecan, and effectively inhibits growth in patient-derived CRC organoids.

A multi-omic analysis reveals that Gamabufotalin exerts anti-hepatocellular carcinoma effects by regulating amino acid metabolism through targeting STAMBPL1

BackgroundHepatocellular carcinoma (HCC), a prevalent type of liver cancer, is characterized by an unfavorable prognosis and a high mortality rate. Identifying novel treatments to prevent HCC recurrence and metastasis remains crucial for improving patient survival. Gamabufotalin (CS-6), a primary bufadienolide derived from the traditional Chinese medicine Chansu, has demonstrated significant anti-tumor activity. However, the effects and underlying mechanisms of CS-6 on HCC cells are not yet fully understood. PurposeThis study sought to elucidate the anti-HCC effects and potential mechanisms of CS-6. In vitro experiments were conducted using the HCC cell lines MHCC97H and Huh-7, employing CCK-8 assays, colony formation assays, wound healing assays, transwell invasion and migration assays, and flow cytometry to assess apoptosis and cell cycle dynamics. A multi-omics approach, including metabolomics and RNA sequencing analysis, was utilized to identify CS-6′s molecular targets and mechanisms in HCC therapy. Additionally, in vivo assessments were performed using xenografts in nude mice. ResultsCS-6 significantly inhibited HCC cell proliferation, migration, and invasion. Multi-omics analysis suggested that CS-6′s anti-HCC effects may involve the modulation of metabolic pathways, potentially through the downregulation of STAMBPL1, resulting in reduced mTOR signaling, increased apoptosis, and suppression of malignant HCC behavior. In vivo studies further confirmed that CS-6 significantly suppressed tumor growth and enhanced apoptosis and autophagy within tumors. ConclusionThese results underscore the therapeutic potential of CS-6 in HCC treatment. The study offers novel insights into the mechanism of CS-6, suggesting that its therapeutic efficacy may be uniquely mediated by targeting STAMBPL1. This distinct mechanism sets CS-6 apart from existing HCC treatments and positions it as a promising candidate for further clinical investigation.

The Importance of Predictive Biomarkers and Their Correlation with the Response to Immunotherapy in Solid Tumors-Impact on Clinical Practice.

Background/Objectives: Immunotherapy has changed the therapeutic approach for various solid tumors, especially lung tumors, malignant melanoma, renal and urogenital carcinomas, demonstrating significant antitumor activity, with tolerable safety profiles and durable responses. However, not all patients benefit from immunotherapy, underscoring the need for predictive biomarkers that can identify those most likely to respond to treatment. Methods: The integration of predictive biomarkers into clinical practice for immune checkpoint inhibitors (ICI) holds great promise for personalized cancer treatment. Programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), microsatellite instability (MSI), gene expression profiles and circulating tumor DNA (ctDNA) have shown potential in predicting ICI responses across various cancers. Results: Challenges such as standardization, validation, regulatory approval, and cost-effectiveness must be addressed to realize their full potential. Predictive biomarkers are crucial for optimizing the clinical use of ICIs in cancer therapy. Conclusions: While significant progress has been made, further research and collaboration among clinicians, researchers, and regulatory institutes are essential to overcome the challenges of clinical implementation. However, little is known about the relationship between local and systemic immune responses and the correlation with response to oncological therapies and patient survival.

Divergent effects of acute and chronic PPT1 inhibition in melanoma

ABSTRACT Macroautophagy/autophagy-lysosome function promotes growth and survival of cancer cells, making them attractive targets for cancer therapy. One intriguing lysosomal target is PPT1 (palmitoyl-protein thioesterase 1). PPT1 inhibitors derived from chloroquine block autophagy, have significant antitumor activity in preclinical models and are being developed for clinical trials. However, the role of PPT1 in tumorigenesis remains poorly understood. Here we report that in melanoma cells, acute siRNA or pharmacological PPT1 inhibition led to increased ferroptosis sensitivity and significant loss of viability, whereas chronic PPT1 knockout using CRISPR-Cas9 produced blunted ferroptosis that led to sustained viability and growth. Each mode of PPT1 inhibition produced lysosome-autophagy inhibition but distinct proteomic changes, demonstrating the complexity of cellular adaptation mechanisms. To determine whether total genetic loss of Ppt1 would affect tumorigenesis in vivo, we developed a Ppt1 conditional knockout mouse model. We then crossed it into the BrafCA, PtenloxP, Tyr:CreERT2 melanoma mouse model to investigate the impact of Ppt1 loss on tumorigenesis. Loss of Ppt1 had no impact on melanoma histology, time to tumor initiation, or survival of tumor-bearing mice. These results suggest that chemical PPT1 inhibitors produce different adaptations than genetic PPT1 inhibition, and additional studies are warranted to fully understand the mechanism of chloroquine derivatives that target PPT1 in cancer.Abbreviations: 4-HT: 4-hydroxytamoxifen; BRAF: B-Raf proto-oncogene, serine/threonine kinase; cKO: conditional knockout; CRISPR-Cas9: clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9; DC661: A specific PPT1 inhibitor; DMSO: dimethyl sulfoxide; Dox; doxycycline hyclate; Easi-CRISPR: efficient additions with ssDNA inserts-CRISPR; GNS561/ezurpimtrostat: A PPT1 inhibitor; Hug: human guide; iCas: inducible CRISPR-Cas9; KO: knockout; LC-MS/MS: Liquid chromatography-tandem mass spectrometry; LDLR: low density lipoprotein receptor; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NT: non-target; PTEN: phosphatase and tensin homolog; PPT1: palmitoyl-protein thioesterase 1; RSL3: RAS-selective lethal small molecule 3; SCRIB/SCRB1: scribble planar cell polarity protein; Tyr:CreERT2: tyrosinase-driven Cre recombinase fused with the tamoxifen-inducible mutant ligand binding domain of the human estrogen receptor; UGCG: UDP-glucose ceramide glucosyltransferase; WT: wild-type.

Targeted transcriptional downregulation of MYC using epigenomic controllers demonstrates antitumor activity in hepatocellular carcinoma models

Dysregulation of master regulator c-MYC (MYC) plays a central role in hepatocellular carcinoma (HCC) and other cancers but remains an elusive target for therapeutic intervention. MYC expression is epigenetically modulated within naturally occurring DNA loop structures, Insulated Genomic Domains (IGDs). We present a therapeutic approach using an epigenomic controller (EC), a programmable epigenomic mRNA medicine, to precisely modify MYC IGD sub-elements, leading to methylation of MYC regulatory elements and durable downregulation of MYC mRNA transcription. Significant antitumor activity is observed in preclinical models of HCC treated with the MYC-targeted EC, as monotherapy or in combination with tyrosine kinase or immune checkpoint inhibitors. These findings pave the way for clinical development of MYC-targeting epigenomic controllers in HCC patients and provide a framework for programmable epigenomic mRNA therapeutics for cancer and other diseases.

Recommendations from the Galician Oncological Society and the Galician Society of Nuclear Medicine for the use of 177Lu-PSMA-617 radioligand-therapy in prostate cancer.

Theragnostic is a type of precision medicine that uses molecules linked to radioactive isotopes for the diagnosis and treatment of diseases. In recent years, it has gained significant importance to treat neuroendocrine tumors and is currently being used in prostate cancer. Various radiopharmaceuticals have emerged for diagnosing and detecting lesions showing prostate-specific membrane antigen (PSMA) positivity on the Positron emission tomography/computed tomography scan, being the most widely used labeled with [68Ga] and [18F]. Its use as therapy in prostate cancer (PC) has been assessed in the VISION, TheraP, and PSMAfore clinical trials conducted with the radioligand [177Lu]Lu-PSMA-617, demonstrating significant antitumor activity. The aim of this article is to present practical recommendations, based on current available scientific evidence and on a multidisciplinary consensus, for the diagnosis and treatment with [177Lu]Lu-PSMA-617 in patients with PC.

Rationally designed febuxostat-based hydroxamic acid and its pH-Responsive nanoformulation elicits anti-tumor activity

Attempts to furnish antitumor structural templates that can prevent the occurrence of drug-induced hyperuricemia spurred us to generate xanthine oxidase inhibitor-based hydroxamic acids and anilides. Specifically, the design strategy involved the insertion of febuxostat (xanthine oxidase inhibitor) as a surface recognition part of the HDAC inhibitor pharmacophore model. Investigation outcomes revealed that hydroxamic acid 4 elicited remarkable antileukemic effects mediated via HDAC isoform inhibition. Delightfully, the adduct retained xanthine oxidase inhibitory activity, though xanthine oxidase inhibition was not the underlying mechanism of its cell growth inhibitory effects. Also, compound 4 demonstrated significant in-vivo anti-hyperuricemic (PO-induced hyperuricemia model) and antitumor activity in an HL-60 xenograft mice model. Compound 4 was conjugated with poly (ethylene glycol) poly(aspartic acid) block copolymer to furnish pH-responsive nanoparticles (NPs) in pursuit of circumventing its cytotoxicity towards the normal cell lines. SEM analysis revealed that NPs had uniform size distributions, while TEM analysis ascertained the spherical shape of NPs, indicating their ability to undergo self-assembly. HDAC inhibitor 4 was liberated from the matrix due to the polymeric nanoformulation's pH-responsiveness, and the NPs demonstrated selective cancer cell targeting ability.

A Novel Monoclonal Antibody against PD-1 for the Treatment of Viral Oncogene-Induced Tumors or Other Cancer.

Programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) interact to form an immune checkpoint fostering viral infection and viral oncogene-induced tumorigenesis. We generated a novel anti-human PD-1, humanized monoclonal antibody P1801 and investigated its pharmacologic, pharmacokinetic (PK), and pharmacodynamic properties. In vitro binding assays revealed that P1801 uniquely binds to human PD-1 and inhibits its interaction with PD-L1/2. It showed a minor effect on the induction of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). P1801 significantly induced the release of IL-2 from activated T-cells but not from nonactivated T-cells. A dose-dependent linear PK profile was observed for the cynomolgus monkeys treated with repeated doses of P1801 at 5 mg/kg to 200 mg/kg once weekly. A four-week repeat-dose toxicity study revealed that P1801 given weekly was safe and well tolerated at doses ranging from 5 to 200 mg/kg/dose. No pathological abnormalities were noted. In humanized PD-1 mice harboring human PD-L1-expressing colon tumor cells, P1801 administered intraperitoneally twice per week at 12 mg/kg significantly inhibited tumor growth and prolonged mouse survival. P1801 displayed unique binding properties different from pembrolizumab and nivolumab. Therefore, it showed distinctive immunological reactions and significant antitumor activities. We are initiating a Phase 1 clinical study to test its combination use with ropeginterferon alfa-2b, which also has antiviral and antitumor activities, for the treatment of cancer.

New 2,4-diphenylaminopyrimidinothiophene derivatives: Synthesis, Spectroscopic analysis, X-ray, DFT calculation, ADMET prediction, and biological activity

Pyrimidine derivatives have garnered significant attention due to their wide range of biological activities, including anticancer, antimicrobial, and antihypertensive effects. Leveraging the diverse pharmacological potential of pyrimidines, we designed and synthesized a series of novel 2,4-diphenylaminopyrimidinothiophene derivatives. The structures of these target compounds 2a-2h were confirmed using NMR and HRMS techniques, with compound 2 g further characterized by single-crystal X-ray diffraction and FT-IR analysis. Additionally, Density Functional Theory (DFT) calculations for compound 2g were conducted at the B3LYP/6–311++G(d,p) level. Focal adhesion kinase (FAK) inhibitory activity and in vitro antitumor efficacy of compounds 2a-2h against U87-MG cell lines were assessed, revealing that certain compounds exhibited significant antitumor activity. Molecular docking studies indicated that compound 2g effectively occupies the ATP binding site of FAK. Furthermore, the ADMET properties of compounds 2a-2h were predicted, providing valuable insights into their pharmacokinetic profiles. These findings lay a foundation for further exploration of compound 2g as a potential FAK inhibitor.

A combined treatment with Ursolic acid and Solasodine inhibits colorectal cancer progression through the AKT1/ERK1/2-GSK-3β-β-catenin axis

BackgroundConventional chemotherapy medications are inadequate for managing the primary or acquired drug resistance, high toxicity, and adverse effects of colorectal cancer (CRC) treatment. Ursolic acid (UA) and Solasodine (Sol) are natural compounds found in a wide variety of traditional medicinal plants, as well as in many fruits and vegetables, such as Actinidia arguta (Sieb. & Zucc) Planch and Solanum nigrum L.. These compounds exhibit significant anti-tumor activity. Recent investigations have demonstrated that a combination strategy using natural products exhibits greater potential in CRC treatment compared to a single-drug strategy. PurposeThis study aimed to elucidate the potential of UA-Sol synergy against CRC and to investigate the mechanism of action involved in inducing apoptosis and inhibiting metastasis through the AKT1/ERK1/2-GSK-3β-β-catenin axis. MethodsThe optimal ratio of UA-Sol and its synergistic effects were explored using an MTT assay combined with the technique of Chou Talalay. The effects of UA-Sol on the apoptosis, autophagy, and metastasis of CRC cells were assessed using Annexin V-FITC/PI, TUNEL, Immunofluorescence, Wound healing, Transwell migration, and western blotting. The core mechanism of action of UA-Sol against CRC was investigated employing network pharmacology prediction combined with CETSA and plasmid transfection. Finally, in vivo validation was conducted using mouse xenograft tumor and lung metastasis models. ResultsThe combination of UA and Sol synergistically inhibited CRC cell viability at a molar ratio of 6:24. UA-Sol induced the expression of pro-apoptotic and autophagy genes such as Bax/Bcl-2 and LC3, ultimately leading to apoptosis and autophagy in CRC cells in vitro. In addition, this combination inhibited MMP-9 and promoted the expression of the adhesion protein E-cadherin, thereby inhibiting CRC cell metastasis. Mechanistically, UA-Sol regulated the expression of a downstream protein GSK-3β by targeting AKT1 and ERK1/2 inhibition. This induced a cross-talk between the MAPK cascade pathway and the PI3K/AKT pathway, thereby inhibiting the nuclear translocation of β-catenin and participating in the regulation of CRC cell processes. ConclusionUA-Sol inhibited the AKT1/ERK1/2-GSK-3β-β-catenin axis to induce apoptosis, autophagy and anti-metastasis by targeting AKT1 and ERK1/2 inhibition. This dual-target drug combination strategy provides promising insights into the development of novel, safe, and efficient drugs for the treatment of CRC.

CMG901, a Claudin18.2-specific antibody-drug conjugate, for the treatment of solid tumors

Claudin18.2 has been recently recognized as a potential therapeutic target for gastric/gastroesophageal junction or pancreatic cancer. Here, we develop a Claudin18.2-directed antibody-drug conjugate (ADC), CMG901, with a potent microtubule-targeting agent MMAE (monomethyl auristatin E) and evaluate its preclinical profiles. Invitro studies show that CMG901 binds specifically to Claudin18.2 on the cell surface and kills tumor cells through direct cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and bystander killing activity. Invivo pharmacological studies show significant antitumor activity in patient-derived xenograft (PDX) models. Toxicity studies show that the major adverse effects related to CMG901 are reversible hematopoietic changes attributed to MMAE. The highest non-severely toxic dose (HNSTD) is 6mg/kg in cynomolgus monkeys and 10mg/kg in rats once every 3weeks. CMG901's favorable preclinical profile supports its entry into the human clinical study. CMG901 is currently under phase 3 investigation in patients with advanced gastric/gastroesophageal junction adenocarcinoma expressing Claudin18.2 (NCT06346392).

The anti-cancer mechanism of Celastrol by targeting JAK2/STAT3 signaling pathway in gastric and ovarian cancer

BackgroundCelastrol is a natural triterpene exhibiting significant and extensive antitumor activity in a wide range of cancer. Due to unfavorable toxicity profile and undefined mechanism, Celastrol's application in clinical cancer therapy remains limited. Herein, we elucidate the pharmacological mechanism of Celastrol's anticancer effects, with a focus on STAT3 signaling pathway in cancers with high incidence of metastasis. MethodsThe safety profile of Celastrol were assessed in mice. In vitro analysis was performed in gastric cancer and ovarian cancer to assess the cytotoxicity, induction of reactive oxygen species (ROS) of Celastrol using STAT3 knockout cancer cells. Effects of Celastrol on STAT3 activation and transcription activity, JAK2/STAT3 signaling protein expression were assessed. Additionally, proteomic contrastive analysis was performed to explore the molecular association of Celastrol with STAT3 deletion in cancer cells. ResultsCelastrol has no obvious toxic effect at 1.5 mg/kg/day in a 15 days' administration. Celastrol inhibits tumor growth and increases ROS in a STAT3 dependent manner in gastric and ovarian cancer celllines. On molecular level, it downregulates IL-6 level and inhibits the JAK2/STAT3 signaling pathway by suppressing STAT3’ activation and transcription activity. Proteomic contrastive analysis suggests a similar cellular mechanism of action between Celastrol and STAT3 deletion on regulating cancer progression pathways related to migration and invasion. ConclusionOur research elucidates the anti-cancer mechanism of Celastrol through targeting the JAK2/STAT3 signaling pathway in cancer with high incidence of metastasis. This study provides a solid theoretical basis for the application of Celastrol in cancer therapy.

Isoliquiritigenin Modulates the Effect of LINC01503 on Lung Squamous Carcinoma Cells

Isoliquiritigenin (ISL) is an important pharmacological constituent of Glycyrrhiza glabra, which possesses a range of physiological and pharmacological activities, as well as significant antitumor activity, and can be used as a potential drug for targeted cancer therapy. LINC01503 is an oncogene, which has been closely associated with the malignant biological processes of many cancers. The aim of this study was to investigate the effects of ISL on the proliferation, apoptosis, invasion and migration of lung squamous carcinoma cells by regulating LINC01503. Plasma was collected from lung squamous carcinoma patients and healthy individuals treated at Tangshan People's Hospital from January 2021 to December 2022. The expression of LINC01503 in lung squamous carcinoma plasma, tissues and cells was detected by real-time quantitative fluorescence polymerase chain reaction (qRT-PCR). Lung squamous carcinoma cells were treated with different concentrations of ISL for 24 h, and LINC01503 expression was detected by qRT-PCR. The cells were treated in groups: si-NC group, si-LINC01503 group, DMSO (0.1% dimethyl sulfone) group, ISL group, pc DNA3.1(+)-NC group, pc DNA3.1(+)-LINC01503 group, ISL+pc DNA3.1(+)-NC group and ISL+pc DNA3.1(+)- LINC01503 groups. CCK-8 assay, clone formation assay, flow cytometry, Transwell assay and scratch assay were used to explore the effect of LINC01503 on the functional phenotype of lung squamous carcinoma cells. Fluorescence in situ hybridization results showed that the average fluorescence intensity of LINC01503 in tissue microarrays of lung squamous carcinoma patients was higher than that in paracancerous tissues (P<0.05). The expression of LINC01503 in the plasma of patients with lung squamous carcinoma was higher than that in the plasma of healthy individuals (P<0.05). Knockdown of LINC01503 inhibited the proliferation, invasion and migration of lung squamous carcinoma cells and promoted apoptosis (P<0.05). ISL inhibited the proliferation, invasion, migration and promoted apoptosis of lung squamous carcinoma cells (P<0.05). Overexpression of LINC01503 followed by intervention with ISL reversed the promotional effect of overexpression of LINC01503 on the proliferation, invasion and migration of lung squamous carcinoma cells as well as the inhibitory effect on apoptosis (P<0.05). LINC01503 was highly expressed in lung squamous carcinoma, and LINC01503 could promote the proliferation, invasion and migration of lung squamous carcinoma cells and inhibit the apoptosis, ISL could inhibit the proliferation, invasion and migration of lung squamous carcinoma cells and promote apoptosis of lung squamous carcinoma cells by regulating the expression of LINC01503.

Metabolic profiling of triptophenolide in rat plasma, urine, bile and faeces after intragastric administration

Triptophenolide, a major diterpenoid extracted from Tripterygium wilfordii Hook. f., has been reported to possess significant anti-tumour, anti-androgen and anti-inflammatory activities. However, the metabolic fate of triptophenolide remains unknown. Therefore, this study focused on the metabolic profiling of triptophenolide in rat plasma, urine, bile and faeces following intragastric administration. An ultraperformance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry with combination of extracted ion chromatogram strategy based on 71 typical metabolic reactions was established to comprehensively profile the metabolites of triptophenolide. This strategy allowed for the identification of 17 metabolites from the biosamples. Reduction, oxidation, glucuronide conjugation, and hydroxylation were considered as its main metabolic pathways in vivo. The present study will be greatly helpful for the further pharmacological studies on triptophenolide and would provide valuable information for its clinical application.

5 A Phase 1b, Open-Label, Safety, Tolerability, and Efficacy Study of HC-7366 in Combination with Belzutifan (WELIREGTM) in Patients with Advanced or Metastatic Renal Cell Carcinoma, NCT06234605

Abstract Background HC-7366 is a novel, orally administered, highly selective and potent activator of general control nonderepressible 2 (GCN2) kinase, a core regulator of metabolic stress through activation of the integrated stress response (ISR). Activation of GCN2 promotes cell survival, whereas prolonged activation induces apoptosis. GCN2 activation also suppresses general protein synthesis and induces cell cycle arrest, thereby preventing cell growth during nutrient scarcity. Additionally, HC-7366 decreases HIF expression and inhibits glycolysis, oxidative phosphorylation, and TCA cycle function. HC-7366 also inhibits HIF expression in immunosuppressive myeloid cells, including macrophages. These effects of HC-7366 on metabolism, HIF signaling, and immune suppression suggest therapeutic benefit in ccRCC with clear rationale for combinations with HIF2a antagonists and immune checkpoint inhibitors. HC-7366 (0.5-1 mg/kg), combined with belzutifan (1 mg/kg), exhibited combination benefit in HIF-2 dependent A-498 and 786-O RCC xenografts, yielding 90% tumor growth inhibition and a three-fold increase in complete responses, respectively. Additionally, HC-7366 drives significant monotherapy antitumor activity in PDX models that demonstrated belzutifan resistance. Mechanism of action studies have identified several pathway engagement and potential efficacy biomarkers (Stokes, et al., 2024). Trial design/schema This multicenter, open-label phase 1b study will identify the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) of HC-7366 in combination with fixed-dose belzutifan, 120 mg po qd, in patients with advanced or metastatic RCC with renal cell histology irrespective of VHL gene mutation. Monotherapy HC-7366 will be evaluated in parallel. The monotherapy arm, HC-7366, 60 mg p.o. qd, includes patients who have relapsed after 1 to 4 prior lines of standard of care that may include belzutifan or another HIF-2α inhibitor. The combination arm includes patients who have received 1 to 3 prior lines of standard of care and are belzutifan or HIF-2α naïve. HC-7366 dose escalation arm evaluates combination fixed dose belzutifan, 120 mg po qd plus HC-7366 at 20, 40, or 60 mg po qd. Enrollment will start with the HC-7366 monotherapy arm. Subsequently, patients will begin to enroll in the combination therapy HC-7366 dose escalation arm, while the monotherapy arm will continue to enroll. Expansion will evaluate the combination of fixed dose belzutifan with two doses of HC-7366 selected from escalation. Assessments include safety, PK, and anti-tumor activity. The study will enroll up to 80 patients at US study sites. Significance and vision Combination HC-7366 plus belzutifan, supported by preclinical evidence, is being studied to assess antitumor activity in the RCC relapsed setting. Determining safety and evaluation of dose are foundational to this study. Reference Stokes M, Tameire F, Wojnarowicz P, et al. HC-7366, a potent GCN2 activator, complements belzutifan, a HIF-2⍺ antagonist, by providing combination benefit in belzutifan-sensitive models and monotherapy activity in belzutifan-resistant models. Meeting of the American Association for Cancer Research; 2024 Apr 5-10; San Diego (CA); AACR; 2024. Abstract 4615. This study is in collaboration with Merck Sharp &amp; Dohme LLC, a subsidiary of Merck &amp; Co., Inc., Rahway, NJ, USA

A novel shark VNAR antibody-based immunotoxin targeting TROP-2 for cancer therapy

TROP-2, a tumor-associated antigen, has been implicated in the progression of various epithelial tumors. Due to its favorable expression profile, TROP-2 has emerged as a promising target for antibody–drug conjugates (ADCs) based anti-tumor therapies. Although ADCs have shown efficacy in cancer treatment, their application in solid tumors is hindered by their high molecular weight, poor tumor penetration, and release of cytotoxic molecules. Therefore, a recombinant immunotoxin was developed based on a shark-derived variable domain of immunoglobulin new antigen receptor (VNAR) antibody. VNARs are only one-tenth the size of IgG antibodies and possess remarkable tissue penetration capabilities and high stability. In this study, a shark VNAR phage display library was created, leading to the identification of shark VNAR-5G8 that targets TROP-2. VNAR-5G8 exhibited a high affinity and cellular internalization ability towards cells expressing high levels of TROP-2. Epitope analysis revealed that VNAR-5G8 recognizes a hidden epitope consisting of CRD and TY-1 on TROP-2. Subsequently, VNAR-5G8 was fused with a truncated form of Pseudomonas exotoxin (PE38) to create the recombinant immunotoxin (5G8-PE38), which exhibited significant anti-tumor activity in vitro and in vivo. Overall, this study highlights the promise of 5G8-PE38 as a valuable candidate for cancer therapy.