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Aspartate/asparagine-ß-hydroxylase (AspH) is a transmembrane 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes the post-translational hydroxylation of aspartate- and asparagine-residues in epidermal growth factor-like domains (EGFDs) of its substrate proteins. Upregulation of ASPH and translocation of AspH from the endoplasmic reticulum membrane to the surface membrane of cancer cells is associated with enhanced cell motility and worsened clinical prognosis. AspH is thus a potential therapeutic and diagnostic target for cancer. This chapter describes methods for the production and purification of soluble constructs of recombinant human AspH suitable for biochemical and crystallographic studies. The chapter also describes efficient methods for performing turnover and inhibition assays which monitor catalysis of isolated recombinant human AspH in vitro using solid phase extraction coupled to mass spectrometry (SPE-MS). The SPE-MS assays employ synthetic disulfide- or thioether-bridged macrocyclic oligopeptides as substrates; a macrocycle is an apparently essential requirement for productive AspH catalysis and mimics an EGFD disulfide isomer that is not typically observed in crystal and NMR structures. SPE-MS assays can be used to monitor catalysis of 2OG oxygenases other than AspH; the methods described herein are representative for 2OG oxygenase SPE-MS assays useful for performing kinetic and/or inhibition studies.

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The use of breast density as a biomarker for breast cancer treatment has not been well established owing to the difficulty in measuring time-series changes in breast density. In this study, we developed a surmising model for breast density using prior mammograms through a multiple regression analysis, enabling a time series analysis of breast density. We acquired 1320 mediolateral oblique view mammograms to construct the surmising model using multiple regression analysis. The dependent variable was the breast density of the mammary gland region segmented by certified radiological technologists, and independent variables included the compressed breast thickness (CBT), exposure current times exposure second (mAs), tube voltage (kV), and patients' age. The coefficient of determination of the surmising model was 0.868. After applying the model, the correlation coefficients of the three groups based on the CBT (thin group, 18-36 mm; standard group, 38-46 mm; and thick group, 48-78 mm) were 0.913, 0.945, and 0.867, respectively, suggesting that the thick breast group had a significantly low correlation coefficient (p = 0.00231). In conclusion, breast density can be accurately surmised using the CBT, mAs, tube voltage, and patients' age, even in the absence of a mammogram image.

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Existing clinical biomarkers do not reliably predict treatment response or disease progression in patients with advanced intrahepatic cholangiocarcinoma (ICC). Circulating neoplastic-immune hybrid cells (CHCs) have great promise as a blood-based biomarker for patients with advanced ICC. Peripheral blood specimens were longitudinally collected from patients with advanced ICC enrolled in the HELIX-1 phase II clinical trial (NCT04251715). CHCs were identified by co-expression of pan-cytokeratin (CK) and CD45, and levels were correlated to patient clinical disease course. Unsupervised machine learning was then performed to extract their morphological features to compare them across disease courses. Five patients were included in this study, with a median of nine specimens collected per patient. A median of 13.5 CHCs per 50,000 peripheral blood mononuclear cells were identified at baseline, and levels decreased to zero following the initiation of treatment in all patients. Counts remained undetectable in three patients who demonstrated end-of-trial clinical treatment response and conversely increased in two patients with evidence of therapeutic resistance. In the post-trial surveillance period, interval counts increased prior to or at the time of clinical progression in three patients and remain undetectable in one patient with continued long-term disease stability. Using our machine learning platform, treatment-resistant CHCs exhibited upregulation of CK and downregulation of CD45 relative to treatment-responsive CHCs. CHCs represent a promising blood-based biomarker to supplement traditional radiographic and biochemical measures.

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In this paper, we describe a biosensing instrument based on our previously developed photonic resonator absorption microscope (PRAM) that incorporates autofocus, digital representation of the gold nanoparticle (AuNP) accumulation, and the ability to gather time-series image sequences of AuNP attachment and detachment from the photonic crystal (PC) surface. The combined capabilities are used to fully automate PRAM image collection during biomolecular assays to enable tiling of PRAM images to provide millimeter-scale field of view. The instrument can also gather PRAM "movies" that enables digital showcasing and dynamic counting AuNPs as they arrive and depart from the PC surface. We utilize the capabilities in the context of two biomolecular assays for detection of protein biomarkers in a conventional AuNP-tagged sandwich format. Utilizing dynamic counting of AuNP attachment and detachment events during the assay we present a detection for microRNA-375 (miRNA-375) down to 1 aM with a 10-min, room temperature, enzyme-free approach, while revealing characteristics of the binding-rate and unbinding-rate of the biomolecular interactions. Our instrument can potentially find broad applications in multiplexed point-of-care diagnostic testing, and as a general-purpose tool for quantitative characterization of biomolecular binding kinetics with single-molecule resolution.

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Heat shock protein 90 alpha (Hsp90α) is an abundantly expressed and evolutionarily conserved molecular chaperone. Hsp90α is the inducible Hsp90 isoform, and its expression and secretion extracellularly (eHsp90α) can be triggered in response to a variety of cellular stresses to protect/activate client proteins and to facilitate cellular adjustment to the stress. As a result, cancers often have high expression levels of intracellular and extracellular (plasma) Hsp90α, allowing them to support their oncogenesis and progression. In fact, (e)Hsp90α has been implicated in regulating processes such as cell signaling transduction, DNA repair, promotion of the Epithelial-to-Mesenchymal Transition (EMT), promotion of angiogenesis, immune response, and cell migration. Hsp90α levels have been correlated with cancer progression and severity in several cancers, indicating that it may be a useful biomarker or drug-target for cancer. To date, the development of intracellular Hsp90α-targeted therapies include standard N-terminal ATP-competitive inhibitors and allosteric regulators that bind to Hsp90α's middle or C-terminal domain. On-target toxicities and dosing complications as a result of Hsp90α inhibition has driven the development of eHsp90α-targeted therapies. Examples include anti-Hsp90α monoclonal antibodies and cell-impermeable Hsp90α small molecule inhibitors. This review aims to discuss the many roles Hsp90α plays in cancer progression with a focus on the current development of Hsp90α-targeted therapies.

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Long non-coding RNAs (lncRNAs) have garnered significant attention in biomedical research due to their pivotal roles in gene expression regulation and their association with various human diseases. Among these lncRNAs, ArfGAP With RhoGAP Domain, Ankyrin Repeat, And PH Domain 1 - Antisense RNA 1 (ARAP1-AS1) has recently emerged as an novel oncogenic player. ARAP1-AS1 is prominently overexpressed in numerous solid tumors and wields influence by modulating gene expression and signaling pathways. This regulatory impact is realized through dual mechanisms, involving both competitive interactions with microRNAs and direct protein binding. ARAP1-AS1 assumes an important role in driving tumorigenesis and malignant tumor progression, affecting biological characteristics such as tumor expansion and metastasis. This paper provides a concise review of the regulatory role of ARAP1-AS1 in malignant tumors and discuss its potential clinical applications as a biomarker and therapeutic target. We also address existing knowledge gaps and suggest avenues for future research. ARAP1-AS1 serves as a prototypical example within the burgeoning field of lncRNA studies, offering insights into the broader landscape of non-coding RNA molecules. This investigation enhances our comprehension of the complex mechanisms that govern the progression of cancer.

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BUD31, a splicing factor, is linked to various cancers. This study examines BUD31's expression, prognostic value, mutation profile, genomic instability, tumor immune environment, and role in clear cell renal cell carcinoma (ccRCC), focusing on cell cycle regulation via alternative splicing. BUD31 expression was analyzed using TCGA and GTEx databases across 33 cancers. Techniques included IHC staining, survival analysis, Cox regression, and nomogram construction. Mutation landscape, genomic instability, and tumor immune microenvironment were evaluated. Functional assays on ccRCC cell lines involved BUD31 knockdown, RNA sequencing, and alternative splicing analysis. BUD31 was upregulated in multiple tumors, including ccRCC. High BUD31 expression correlated with worse survival outcomes and was identified as an independent predictor of poor prognosis in ccRCC. High BUD31 expression also correlated with increased genomic instability and a less active immune microenvironment. BUD31 knockdown inhibited cell proliferation, migration, and invasion in vitro and reduced tumor growth in vivo. RNA sequencing identified 390 alternative splicing events regulated by BUD31, including 17 cell cycle-related genes. KEGG analysis highlighted pathways involved in cell cycle regulation, indicating BUD31's role in promoting cell cycle progression through alternative splicing. BUD31 is upregulated in various tumors and is associated with poor outcomes, increased genomic instability, and a suppressed immune microenvironment in ccRCC. BUD31 promotes cell cycle progression via alternative splicing, suggesting it as a prognostic biomarker and potential therapeutic target in ccRCC.

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This study investigated the prognostic value of the chemokine C-C motif ligand 2 (CCL2) and its receptor C-C motif chemokine receptor 2 (CCR2) expression in locally advanced prostate cancer treated with radiotherapy and androgen deprivation using the 10-year outcome data from the TROG 03.04 RADAR clinical trial. CCL2 and CCR2 protein expression in prostate cancer biopsies at the time of diagnosis were quantified by immunohistochemistry and digital quantification. CCR2 protein expression was detected in prostate cancer cells and was associated with prostate-specific antigen serum concentration (p = 0.045). However, neither CCL2 nor CCR2 tissue expression could predict prostate cancer progression, or other clinicopathological parameters including perineural invasion and patient outcome. In serum samples, CCL2 concentration at the time of diagnosis, as assayed by enzyme-linked immunosorbent assay, was significantly higher in patients with prostate cancer compared with benign prostatic hyperplasia (median difference 0.22 ng/mL, 95% CI, 0.17-0.30) (p < 0.0001) and normal controls (median difference 0.13 ng/mL, 95% CI, 0.13-0.17) (p < 0.0001). However, circulating CCL2 was not statistically significant as a predictor of disease progression and patient outcome. In conclusion, this study shows that although CCL2 and CCR2 are expressed in prostate cancer, with an increased level of CCL2 in the serum, neither CCL2 nor CCR2 expression has a clinical prognostic value in locally advanced prostate cancer.

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Herein, we report a single step synthesis of highly fluorescent Graphene Quantum Dots (GQDs) using tryptophan and glycerol as precursors via pyrolysis. The morphological and functional characterization of the prepared GQDs was performed using PXRD, FTIR, TEM, XPS and zeta potential measurements. The prepared GQDs found their practical application in ultrasensitive detection of an emerging potential cancer biomarker, H2O2, by exploiting the fluorescence quenching behaviour of H2O2. To evaluate the detection sensitivity, a series of various concentrations of H2O2 was spiked to biomatrices like, serum and MCF-7 (human breast cancer cell line) cell lysate medium. A remarkably low limit of detection (LOD) was found in serum medium (139.5 pM) which further improved in MCF-7 cell lysate medium (LOD 61.43 pM). Moreover, the sensing capacity of the GQDs was further validated in presence of various physiological variables such as glucose, cholesterol, insulin and nitrite. Sensing assay was also carried out in HaCaT (human keratinocyte cell line) cell lysate medium to compare the performance of our prepared sensor but the non-linearity of the F0/F versus H2O2 concentration plot pointed towards the conduciveness of the MCF-7 cell lysate medium for sensitive detection of H2O2.The mechanism behind the sensing was also explored using spectroscopic methods.

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Microsatellite instability (MSI) is a phenomenon seen in several cancer types, which can be used as a biomarker to help guide immune checkpoint inhibitor treatment. To facilitate this, researchers have developed computational tools to categorize samples as having high microsatellite instability, or as being microsatellite stable using next-generation sequencing data. Most of these tools were published with unclear scope and usage, and they have yet to be independently benchmarked. To address these issues, we assessed the performance of eight leading MSI tools across several unique datasets that encompass a wide variety of sequencing methods. While we were able to replicate the original findings of each tool on whole exome sequencing data, most tools had worse receiver operating characteristic and precision-recall area under the curve values on whole genome sequencing data. We also found that they lacked agreement with one another and with commercial MSI software on gene panel data, and that optimal threshold cut-offs vary by sequencing type. Lastly, we tested tools made specifically for RNA sequencing data and found they were outperformed by tools designed for use with DNA sequencing data. Out of all, two tools (MSIsensor2, MANTIS) performed well across nearly all datasets, but when all datasets were combined, their precision decreased. Our results caution that MSI tools can have much lower performance on datasets other than those on which they were originally evaluated, and in the case of RNA sequencing tools, can even perform poorly on the type of data for which they were created.

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BACKGROUND: There are 54,000 new cases of oral cavity and oropharyngeal cancer in the United States and more than 476,000 worldwide each year. Oral cavity and oropharyngeal squamous cell carcinoma make up most tumors with five-year survival rates of 50% due to prevalence of late-stage diagnoses. Improved methods of early detection in high-risk individuals are urgently needed. We aimed to assess the tumorigenic biomarkers soluble CD44 (solCD44) and total protein (TP) measured using oral rinses as affordable convenient screening tools for cancer detection. METHODS: In this prospective cohort study, we recruited 150 healthy current or former smokers through a community screening program. Baseline and four annual visits were conducted from March 2011-January 2016 with records followed until August 2020. Participants provided oral rinses, received head and neck exams, and completed questionnaires. SolCD44 and TP levels were measured and compared across groups and time. Participants were placed in the cancer group if malignancy developed in the study period, the suspicious group if physical exams were concerning for premalignant disease or cancer in the head and neck, and the healthy group if there were no suspicious findings. This analysis used two-sample t-test for comparison of means and two-sample Wilcoxon Test for comparison of medians. For subjects with follow-ups, estimated means of biomarkers were obtained from a fitted Repeated Measures Analysis of Variance (RANOVA) model including group, visit, and their interaction. Pairwise comparisons of mean solCD44 were made, including intergroup and intragroup comparison of values at different years. RESULTS: Most participants were males (58.7%), < 60 years of age. (90.7%), and Black (100%). Baseline mean solCD44 was elevated (2.781 ng/ml) in the cancer group compared to the suspicious group (1.849 ng/ml) and healthy group (1.779 ng/ml). CONCLUSION: This study supports the feasibility of a CD44-based oral rinse test as an affordable and convenient adjunctive tool for early detection of aerodigestive tract and other cancers in high-risk populations.

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Endometrial cancer (EC) is a devastating and common disease affecting women's health. The NCI Surveillance, Epidemiology, and End Results Program predicted that there would be >66,000 new cases in the United States and >13,000 deaths from EC in 2023, and EC is the sixth most common cancer among women worldwide. Regulation of mitochondrial metabolism plays a role in tumorigenesis. In proliferating cancer cells, mitochondria provide the necessary building blocks for biosynthesis of amino acids, lipids, nucleotides, and glucose. One mechanism causing altered mitochondrial activity is mitochondrial DNA (mtDNA) mutation. The polyploid human mtDNA genome is a circular double-stranded molecule essential to vertebrate life that harbors genes critical for oxidative phosphorylation plus mitochondrial-derived peptide genes. Cancer cells display aerobic glycolysis, known as the Warburg effect, which arises from the needs of fast-dividing cells and is characterized by increased glucose uptake and conversion of glucose to lactate. Solid tumors often contain at least one mtDNA substitution. Furthermore, it is common for cancer cells to harbor mixtures of wild-type and mutant mtDNA genotypes, known as heteroplasmy. Considering the increase in cancer cell energy demand, the presence of functionally relevant carcinogenesis-inducing or environment-adapting mtDNA mutations in cancer seems plausible. We review 279 EC tumor-specific mtDNA single nucleotide variants from 111 individuals from different studies. Many transition mutations indicative of error-prone DNA polymerase γ replication and C to U deamination events were present. We examine the spectrum of mutations and their heteroplasmy and discuss the potential biological impact of recurrent, non-synonymous, insertion, and deletion mutations. Lastly, we explore current EC treatments, exploiting cancer cell mitochondria for therapy and the prospect of using mtDNA variants as an EC biomarker.

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Exosomal microRNAs (miRNAs) have great potential in the fight against hepatocellular carcinoma (HCC), the fourth most common cause of cancer-related death worldwide. In this study, we explored the various applications of these small molecules while analyzing their complex roles in tumor development, metastasis, and changes in the tumor microenvironment. We also discussed the complex interactions that exist between exosomal miRNAs and other non-coding RNAs such as circular RNAs, and show how these interactions coordinate important biochemical pathways that propel the development of HCC. The possibility of targeting exosomal miRNAs for therapeutic intervention is paramount, even beyond their mechanistic significance. We also highlighted their growing potential as cutting-edge biomarkers that could lead to tailored treatment plans by enabling early identification, precise prognosis, and real-time treatment response monitoring. This thorough analysis revealed an intricate network of exosomal miRNAs lead to HCC progression. Finally, strategies for purification and isolation of exosomes and advanced biosensing techniques for detection of exosomal miRNAs are also discussed. Overall, this comprehensive review sheds light on the complex web of exosomal miRNAs in HCC, offering valuable insights for future advancements in diagnosis, prognosis, and ultimately, improved outcomes for patients battling this deadly disease.

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Early detection of cancer is vital for increasing patient survivability chances. The three major techniques used to diagnose cancers are instrumental examination, tissue biopsy, and tumor biomarker detection. Circulating tumor DNA (ctDNA) has gained much attention in recent years due to advantages over traditional technology, such as high sensitivity, high specificity, and noninvasive nature. Through the mechanism of apoptosis, necrosis, and circulating exosome release in tumor cells, ctDNA can spread throughout the circulatory system and carry modifications such as methylations, mutations, gene rearrangements, and microsatellite instability. Traditional gene-detection technology struggles to achieve real-time, low-cost, and portable ctDNA measurement, whereas electrochemical biosensors offer low cost, high specificity alongside sensitivity, and portability for the detection of ctDNA. Therefore, this review focuses on describing the recent advancements in ctDNA biomarkers for various cancer types and biosensor developments for real-time, noninvasive, and rapid ctDNA detection. Further in the review, ctDNA sensors are also discussed in regards to their selections of probes for receptors based on the electrode surface recognition elements.

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In the rapidly evolving field of medical diagnostics, biomarkers play a pivotal role, particularly in the early detection of cancer. Cluster of differentiation 5 (CD5), a cell surface glycoprotein found on T cells and B-1a lymphocytes, is instrumental in immune regulation and is associated with both autoimmune diseases and malignancies. Despite its significant diagnostic and therapeutic potential, CD5 detection has been limited by modern methods in the pg/ml range. This study presents a novel multimodal electrochemical immunosensor that employs laser-processed Ti/Au electrodes for the ultra-sensitive detection of CD5 in human blood serum. The "multimodal" approach combines different analytical techniques - differential pulse volctammetry (DPV) and electrochemical impedance spectroscopy (EIS) - to ensure comprehensive analysis, enhancing both the accuracy and reliability of the sensor. This novel sensor significantly outperforms existing commercial ELISA kits, achieving a limit of detection (LOD) of 1.1 ± 0.2 fg/mL with DPV and 3.9 ± 0.5 fg/mL with EIS in phosphate-buffered saline (PBS) and 6.6 ± 3.1 fg/mL and 15.6 ± 3.1 fg/mL in human serum (HS), respectively. These results highlight the immunosensor's potential for improving early-stage cancer diagnosis and broader medical applications.

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Cancer poses a significant public health challenge worldwide, and timely screening has the potential to mitigate cancer progression and reduce mortality rates. Currently, early identification of most tumors relies on imaging techniques and tissue biopsies. However, the use of low-cost, highly sensitive, non-invasive detection methods for early cancer screening has become more attractive. Extracellular Vesicles (EVs) released by all living cells contain distinctive biological components, such as nucleic acids, proteins, and lipids. These vesicles play crucial roles in the tumor microenvironment and intercellular communication during tumor progression, rendering liquid biopsy a particularly suitable method for diagnosis. Nevertheless, challenges related to purification methods and validation of efficacy currently hinder its widespread clinical implementation. These limitations underscore the importance of refining isolation techniques and conducting comprehensive investigations on EVs. This study seeks to evaluate the potential of liquid biopsy utilizing blood-derived EVs as a practical, cost-effective, and secure approach for early cancer detection.

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Ten-eleven translocation (TET) proteins orchestrate deoxyribonucleic acid (DNA) methylation-demethylation dynamics by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and are frequently inactivated in various cancers. Due to the significance of 5hmC as an epigenetic biomarker for cancer diagnosis, pathogenesis, and treatment, its rapid and precise quantification is essential. Here, we report a highly sensitive electrochemical method for quantifying genomic 5hmC using graphene sheets that were electrochemically exfoliated and functionalized with biotin and gold nanoparticles (Bt-AuNPs) through a single-step electrical method. The attachment of Bt-AuNPs to graphene enhances the specificity of 5hmC-containing DNA and augments the oxidation of 5hmC to 5-formylcytosine in DNA. When coupled to a gold electrode, the Bt-AuNP-graphene-based sensor exhibits exceptional sensitivity and specificity for detecting 5hmC, with a detection limit of 63.2 fM. Furthermore, our sensor exhibits a remarkable capacity to measure 5hmC levels across a range of biological samples, including preclinical mouse tissues with varying 5hmC levels due to either TET gene disruption or oncogenic transformation, as well as human prostate cancer cell lines. Therefore, our sensing strategy has substantial potential for cancer diagnostics and prognosis.

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OBJECTIVE: To report long-term efficacy and safety of selinexor maintenance therapy in adults with TP53 wild-type (TP53wt) stage IV or recurrent endometrial cancer (EC) who achieved partial remission (PR) or complete remission (CR) following chemotherapy. METHODS: Analysis of the prespecified, exploratory subgroup of patients with TP53wt EC from the phase 3 SIENDO study was performed. Progression-free survival (PFS) benefit in patients with TP53wt EC and across other patient subgroups were exploratory endpoints. Safety and tolerability were also assessed. RESULTS: Of the 263 patients enrolled in the SIENDO trial, 113 patients had TP53wt EC; 70/113 (61.9%) had TP53wt/proficient mismatch repair (pMMR) EC, and 29/113 (25.7%) had TP53wt/deficient mismatch repair (dMMR) EC. As of April 1, 2024, the median PFS (mPFS) for TP53wt patients who received selinexor compared with placebo was 28.4 versus 5.2 months (36.8-month follow-up, HR 0.44; 95% CI 0.27-0.73). A benefit in mPFS was seen with selinexor versus placebo regardless of MMR status (patients with TP53wt/pMMR EC: 39.5 vs 4.9 months, HR 0.36; 95% CI 0.19-0.71; patients with TP53wt/dMMR EC: 13.1 vs 3.7 months, HR 0.49; 95% CI 0.18-1.34). Selinexor treatment was generally manageable, with no new safety signals identified. CONCLUSION: In the phase 3 SIENDO study, selinexor maintenance therapy showed a promising efficacy signal and a manageable safety profile in the prespecified subgroup of patients with TP53wt EC who achieved a PR or CR following chemotherapy. These results are being further evaluated in an ongoing randomized phase 3 trial (NCT05611931).

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Renal cell carcinoma (RCC) remains incurable in advanced stages. Biomarkers have proven to be quite useful in cancer therapeutics. Herein, we provide a comparative/integrative statistical analysis of seminal immunohistochemistry (IHC) findings for Wilms' Tumor 1 antigen (WT1) and thymine dimers (TDs), emerging as atypical, yet promising, potential biomarkers for RCCs. We assessed WT1/TD reactivity in adult RCC tumor cells, tumor microenvironment (TME), and tumor-adjacent healthy renal tissue (HRT). WT1 positivity was scarce and strictly nuclear in tumor cells, whereas TD-reactive tumor tissues were prevalent. We report statistically significant positive correlations between the density of reactive RCC cellularity and the intensity of nuclear staining for both biomarkers (WT1 - rho = 0.341, p-value = 0.036; TDs - rho = 0.379, p-value = 0.002). RCC stromal TME TD-positivity was much more frequent than WT1 reactivity, apparently proportional to that of the proper RCC cellularity and facilitated by extensive RCC inflammatory infiltration. TDs exhibited nuclear reactivity for most TME cell lines, while RCC TME WT1 expression was rare and inconsistent. In HRTs, TDs were entirely restricted to renal tubular cells, the likely cellular progenitor of most conventional RCC subtypes. In lieu of proper validation, these early findings have significant implications regarding the origins/biology of RCCs and may inform RCC therapeutics, both accounting for the high frequency of immunotherapy-permissive frameshift indels in RCCs, but also hinting at novel predictive clinical tools for WT1-targeted immunotherapy. Overall, the current study represents a meek yet hopefully significant step towards understanding the molecular biology and potential therapeutic targets of RCCs.

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INTRODUCTION: Gastric cancer remains a formidable challenge in oncology with high mortality rates and few advancements in treatment. Claudin-18.2 (CLDN18.2) is a tight junction protein primarily expressed in the stomach and is frequently overexpressed in certain subsets of gastric cancers. Targeting CLDN18.2 with monoclonal antibodies, such as zolbetuximab (IMAB362), has shown promising efficacy results in combination with chemotherapy. AREAS COVERED: The molecular cell biology of CLDN18.2 is discussed along with studies demonstrating the utility of CLDN18.2 expression as a biomarker and therapeutic target. Important clinical studies are reviewed, including Phase III trials, SPOTLIGHT and GLOW, which demonstrate the efficacy of zolbetuximab in combination with chemotherapy in patients with CLDN18.2-positive advanced gastric cancer. EXPERT OPINION: CLDN18.2 is involved in gastric differentiation through maintenance of epithelial barrier function and coordination of signaling pathways, and its expression in gastric cancers reflects a 'gastric differentiation' program. Targeting Claudin-18.2 represents the first gastric cancer specific 'targeted' treatment. Further studies are needed to determine its role within current gastric cancer treatment sequencing, including HER2-targeted therapies and immunotherapies. Management strategies will also be needed to better mitigate zolbetuximab-related treatment side effects, including gastrointestinal (GI) toxicities.

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