Well-established Tumor Research Articles

Real-Time and Ultrasensitive Prostate-Specific Antigen Sensing Using Love-Mode Surface Acoustic Wave Immunosensor Based on MoS2@Cu2O-Au Nanocomposites.

Prostate-specific antigen (PSA) is a well-established tumour marker for prostatic carcinoma. In this study, we present a novel, real-time, and ultrasensitive Love-mode surface acoustic wave (L-SAW) immunosensor for PSA detection enhanced by MoS2@Cu2O-Au nanocomposite conjugation. The MoS2@Cu2O-Au nanocomposites were analyzed by SEM, XRD, and EDS. The experiments show a significant improvement in sensitivity and detection limit compared with the previous detection methods utilizing nanogold alone to detect PSA biomolecules. The experimental results show a good linear relationship when the range of PSA concentrations between 200 pg/mL and 5 ng/mL was tested. The experimental results also show good specificity against alpha 1 fetoprotein and L-tryptophan disruptors.

Role of Serum Alpha-fetoprotein in Assessing the Resectability of Hepatocellular Carcinoma

Background: Serum AFP is a well-established tumor marker of hepatocellular carcinoma (HCC) which has already proved its acceptability in confirming the diagnosis and predicting the prognosis of HCC. Objective: The current study is aimed to evaluate the role of serum alpha-fetoprotein in assessing the resectability of HCC. Methods: This was a single-center, cross-sectional study done from September 2020 to August 2021 at the department of Hepatobiliary, pancreatic, and liver transplantation surgery at BSMMU. A total of 27 HCC patients who met the inclusion criteria were enrolled in the study. Clinical, laboratory, and imaging findings were obtained using a standardized data collecting sheet with the patients' informed agreement. AFP was measured by automated chemiluminescence analyzer (LIAISON XL, DiaSorin, Italy) in the Department of Biochemistry & Molecular Biology, BSMMU. Based on the ROC curve of this study, the patients were divided into group 1 with AFP levels 38.45 ng/ml and group 2 with AFP levels >38.45 ng/ml. According to the resectable criteria (TNM stage: I, II, BCLC stage: 0, A, B, CTP grade: A, B, ECOG PS: 0) established for the study, each AFP group was further subdivided into resectable and unresectable subgroups. Finally, the parameters (tumor size, number, location, CTP grade, fibrosis score, performance status, HBV positive, HBV DNA, BCLC and TNM stage) of the resectable and unresectable patients in each AFP group were evaluated. Statistical analyses were performed using SPSS version 22. Quantitative variables were expressed as mean±standard deviation and examined using an unpaired t-test. The qualitative data were represented by frequencies and percentages, and the Chi-Square test and Fisher exact test (where applicable) were used to determine any correlation. The statistical tests were conducted with a 95% confidence interval, and P0.05 was deemed statistically significant. Results: In this study, thirty seven percent (37%) patients ...........

Raman spectroscopy for classification of neoplastic and non-neoplastic CAM colon tumors

This paper demonstrates the potential of Raman spectroscopy for differentiating neoplastic from non-neoplastic colon tumors, obtained with the CAM (chicken chorioallantoic membrane) model. For the CAM model two human cell lines were used to generate two types of tumors, the RKO cell line for neoplastic colon tumors and the NCM460 cell line for non-neoplastic colon tumors. The Raman spectra were acquired with a 785 nm excitation laser. The measured Raman spectra from the CAM samples (n = 14) were processed with several methods for baseline correction and to remove artifacts. The corrected spectra were analyzed with PCA (principal component analysis). Additionally, machine learning based algorithms were used to create a model capable of classifying neoplastic and non-neoplastic tumors. The principal component scores showed a clear differentiation between neoplastic and non-neoplastic colon tumors. The classification model had an accuracy of 93 %. Thus, a complete methodology to process and analyze Raman spectra was validated, using a rapid, accessible, and well-established tumor model that mimics the human tumor pathology with minor ethical concerns.

High Glycolytic Activity Signature Reveals CCNB2 as a Key Therapeutic Target in Triple-Negative Breast Cancer.

Aerobic glycolysis and the cell cycle are well-established tumor hallmarks. Understanding their relationship could help to unravel the pathogenic mechanisms of breast cancer (BC) and suggest potential new strategies for treatment. Glycolysis-related genes (GRGs) were downloaded from the Reactome database and screened using univariate Cox analysis. The consensus clustering method was employed to identify a glycolytic activity signature (GAS) using the Gene Expression Omnibus (GEO) dataset. A nomogram risk prediction model was constructed using coefficients from univariate Cox analysis. Immune cell infiltration was evaluated using single-sample gene set enrichment analysis (ssGSEA) and the ESTIMATE algorithm. Gene co-expression modules were created using weighted correlation network analysis (WGCNA) to identify hub genes. Gene expression in three BC cell lines was quantified using Quantitative Reverse Transcriptase Polymera (qRT-PCR). Single-cell RNA sequencing (scRNA-seq) data was used to examine the relationship between GAS and hub genes. The sensitivity of different groups to cell cycle-related clinical drugs was also examined. BC with high GAS (HGAS) showed high tumor grade and recurrence rate. HGAS was a prognostic indicator of worse overall survival (OS) in BC patients. HGAS BC showed more abundant immune cells and significantly higher expression of immunomodulators compared to BC with low GAS (LGAS). HGAS BC also showed enhanced cell cycle pathway, with high mRNA and protein expression levels of Cyclin B2 (CCNB2), a key component of the cell cycle pathway. Importantly, scRNA-seq analysis revealed that elevated CCNB2 expression was positively correlated with HGAS in triple-negative BC (TNBC). This was validated in clinical samples from TNBC patients. High expression of CCNB2 was found in three BC cell lines, and was also an indicator of poor prognosis. HGAS BC showed high sensitivity to several cell cycle-related clinical drugs, with 9 of these also showing activity in BC with high CCNB2 expression. HGAS was associated with enhanced cell cycle pathway and immune activity in BC. These results suggest that CCNB2 is a potential key therapeutic target in BC patients.

IMG-28. AUTOMATIC BRAIN TUMOR VOLUMETRIC ANALYSIS IN MAGNETIC RESONANCE IMAGING GENERALIZABLE TO PEDIATRIC NEURO-ONCOLOGY

Abstract BACKGROUND The prognosis of brain tumors is variable in clinical practice if it only relies on human interpretation of magnetic resonance imaging (MRI). The automatic segmentation of brain tumors in MRI enables quantitative analysis in support of clinical trials and personalized patient care. We developed benchmarked deep learning-based tools that are generalizable to the volumetric quantification of various tumor types across diverse populations. METHODS We participated in the well-established international brain tumor segmentation challenge (BraTS 2023) and benchmarking competition. The challenge made available 4,500 multi-national brain tumor cases with multi-sequence MRIs, including pediatric high-grade gliomas (PED), i.e., high-grade astrocytoma and diffuse midline glioma, and adult gliomas, brain metastases (MET) and intracranial meningiomas (MEN). Each case comprises four MRI volumes: T1, contrast-enhanced T1, T2, and T2-FLAIR. Manual segmentations were provided to establish ground truth for enhancing tumor (ET), tumor core (TC), and whole tumor (WT). Our framework used a model ensemble strategy based on two state-of-the-art deep learning models: a convolutional neural network (nnU-Net) and a vision transformer (Swin UNETR) and was tested for broader applicability across multiple tumor types. The framework was trained on 99, 1,000, and 165 cases and validated on 45, 141, and 31 unseen cases for PED, MEN, and MET, respectively. Automatic segmentations were evaluated by lesion-wise volume overlap (Dice similarity score, DSC) and Hausdorff distance (HD). RESULTS In the evaluation on independent unseen test datasets, our automatic tool was ranked first for PED, third for MEN, and fourth for MET volumetric analysis. Our method resulted in PED lesion-wise DSC of 0.733, 0.782, 0.817 and HD (mm) of 75.93, 25.54, 24.18 for ET, TC, and WT, respectively. CONCLUSIONS These brain tumor volumetric analysis tools are readily available to be efficiently tested on diverse datasets. Automatic MRI analysis provides consistent quantitative data for multi-institutional protocols and clinical trials.

Light-Triggered Nanozymes Remodel the Tumor Hypoxic and Immunosuppressive Microenvironment for Ferroptosis-Enhanced Antitumor Immunity.

Cancer immunotherapy holds significant promise for addressing diverse malignancies. Nevertheless, its efficacy remains constrained by the intricate tumor immunosuppressive microenvironment. Herein, a light-triggered nanozyme Fe-TCPP-R848-PEG (Fe-MOF-RP) was designed for remodeling the immunosuppressive microenvironment. The Fe-TCPP-MOFs were utilized not only as a core catalysis component against tumor destruction but also as a biocompatible delivery vector of an immunologic agonist, improving its long circulation and tumor enrichment. Concurrently, it catalyzes the decomposition of H2O2 within the tumor, yielding oxygen to augment photodynamic therapy. The induced ferroptosis, in synergy with photodynamic therapy, prompts the liberation of tumor-associated antigens from tumor cells inducing immunogenic cell death. Phototriggered on-demand release of R848 agonists stimulated the maturation of dendritic cells and reverted the tumor-promoting M2 phenotypes into adoptive M1 macrophages, which further reshaped the tumor immunosuppressive microenvironment. Notably, the nanozyme effectively restrains well-established tumors, such as B16F10 melanoma. Moreover, it demonstrates a distal tumor-inhibiting effect upon in situ light treatment. What is more, in a lung metastasis model, it elicits robust immune memory, conferring enduring protection against tumor rechallenge. Our study presents a straightforward and broadly applicable strategy for crafting nanozymes with the potential to effectively thwart cancer recurrence and metastasis.

Dissecting the Puzzling Roles of FAM46C: A Multifaceted Pan-Cancer Tumour Suppressor with Increasing Clinical Relevance.

FAM46C is a well-established tumour suppressor with a role that is not completely defined or universally accepted. Although FAM46C expression is down-modulated in several tumours, significant mutations in the FAM46C gene are only found in multiple myeloma (MM). Consequently, its tumour suppressor activity has primarily been studied in the MM context. However, emerging evidence suggests that FAM46C is involved also in other cancer types, namely colorectal, prostate and gastric cancer and squamous cell and hepatocellular carcinoma, where FAM46C expression was found to be significantly reduced in tumoural versus non-tumoural tissues and where FAM46C was shown to possess anti-proliferative properties. Accordingly, FAM46C was recently proposed to function as a pan-cancer prognostic marker, bringing FAM46C under the spotlight and attracting growing interest from the scientific community in the pathways modulated by FAM46C and in its mechanistic activity. Here, we will provide the first comprehensive review regarding FAM46C by covering (1) the intracellular pathways regulated by FAM46C, namely the MAPK/ERK, PI3K/AKT, β-catenin and TGF-β/SMAD pathways; (2) the models regarding its mode of action, specifically the poly(A) polymerase, intracellular trafficking modulator and inhibitor of centriole duplication models, focusing on connections and interdependencies; (3) the regulation of FAM46C expression in different environments by interferons, IL-4, TLR engagement or transcriptional modulators; and, lastly, (4) how FAM46C expression levels associate with increased/decreased tumour cell sensitivity to anticancer agents, such as bortezomib, dexamethasone, lenalidomide, pomalidomide, doxorubicin, melphalan, SK1-I, docetaxel and norcantharidin.

Exploring Potential Biomarkers in Oesophageal Cancer: A Comprehensive Analysis.

Oesophageal cancer (OC) is the sixth leading cause of cancer-related death worldwide. OC is highly aggressive, primarily due to its late stage of diagnosis and poor prognosis for patients' survival. Therefore, the establishment of new biomarkers that will be measured with non-invasive techniques at low cost is a critical issue in improving the diagnosis of OC. In this review, we summarize several original studies concerning the potential significance of selected chemokines and their receptors, including inflammatory proteins such as interleukin-6 (IL-6) and C-reactive protein (CRP), hematopoietic growth factors (HGFs), claudins (CLDNs), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), adamalysines (ADAMs), as well as DNA- and RNA-based biomarkers, in OC. The presented results indicate the significant correlation between the CXCL12, CXCR4, CXCL8/CXCR2, M-CSF, MMP-2, MMP-9 ADAM17, ADAMTS-6, and CLDN7 levels and tumor stage, as well as the clinicopathological parameters of OC, such as the presence of lymph node and/or distant metastases. CXCL12, CXCL8/CXCR2, IL-6, TIMP-2, ADAM9, and ADAMTS-6 were prognostic factors for the overall survival of OC patients. Furthermore, IL-6, CXCR4, CXCL8, and MMP-9 indicate higher diagnostic utility based on the area under the ROC curve (AUC) than well-established OC tumor markers, whereas CLDN18.2 can be used in novel targeted therapies for OC patients.

Cancer-associated point mutations within the extracellular domain of PTPRD affect protein stability and HSPG interaction.

PTPRD, a well-established tumor suppressor gene, encodes the protein tyrosine phosphatase-type D. This protein consists of three immunoglobulin-like (Ig) domains, four to eight fibronectin type 3 (FN) domains, a single transmembrane segment, and two cytoplasmic tandem tyrosine phosphatase domains. PTPRD is known to harbor various cancer-associated point mutations. While it is assumed that PTPRD regulates cellular functions as a tumor suppressor through the tyrosine phosphatase activity in the intracellular region, the function of its extracellular domain (ECD) in cancer is not well understood. In this study, we systematically examined the impact of 92 cancer-associated point mutations within the ECD. We found that 69.6% (64 out of 92) of these mutations suppressed total protein expression and/or plasma membrane localization. Notably, almost all mutations (20 out of 21) within the region between the last FN domain and transmembrane segment affected protein expression and/or localization, highlighting the importance of this region for protein stability. We further found that some mutations within the Ig domains adjacent to the glycosaminoglycan-binding pocket enhanced PTPRD's binding ability to heparan sulfate proteoglycans (HSPGs). This interaction is proposed to suppress phosphatase activity. Our findings therefore suggest that HSPG-mediated attenuation of phosphatase activity may be involved in tumorigenic processes through PTPRD dysregulation.

Abstract LB014: The role of genetic alterations in metastatic development insights from a large-scale genomic database

Abstract Metastasis remains a major challenge in cancer treatment, with somatic genetic alterations being a crucial feature in progression. This study harnesses the whole genome sequencing data in the Genomics England biobank (GEL), cataloging of somatic alterations in the context of cancer metastasis. Our research aims to uncover the genetic underpinnings that facilitate the spread of cancer from its primary site to secondary locations by analyzing clinicogenomic data from 3047 cancer patients with metastatic progression. In this study, we analyzed the complex relationship between somatic alterations and cancer progression to uncover significant interactions among these alterations in a broad distribution of common tumor types among well-established oncogenic and tumor suppressor genes. In our study, we employed a Bayesian network approach, enabling us to not only pinpoint crucial genetic contributors to metastasis but also to consider other clinical variables, including patient treatment, sex, age, tumor grade and cancer types. In our analysis, LILRB2 was found to directly increase metastatic risk in hematologic cancer, with prior evidence suggesting its potential as a therapeutic biomarker in colorectal cancer and adversely related to patient prognosis in lung cancer. Similarly, MYL1, initially linked to tumor metastasis and immune infiltration in head and neck squamous cell carcinoma, was also found to increase the risk of metastasis in renal cancer, while interacting with the transcription factor E2F4, marker of poor prognosis in hepatocellular carcinoma. Our study not only confirmed the numerous key somatic gene alterations significantly linked to metastatic behavior across various cancers, but also established their significant roles.Our work highlights the potential of leveraging extensive genomic databases such as GEL to enhance our understanding of cancer metastasis. GEL’s paired germline and somatic data allows us to not only identify mutations unique to cancer cells but also to uncover germline variants that are associated with an elevated risk of cancer and the presence of more aggressive tumor characteristics. By characterizing metastatic risk features, we can explore the opportunities to stratify high-risk patients in clinical trials, with similar effort has been applied to brain metastasis in lung adenocarcinoma. Although tumor heterogeneity poses a treatment challenge due to cell diversity, previous work has demonstrated value in targeting the metastatic potential. For instance, trastuzumab target HER2-positive breast cancers prone to metastasis, markedly improving patient outcomes. Similarly, vemurafenib effectively controls metastatic Melanoma progression by targeting specific mutations like BRAFV600E. Understanding the genetic basis of metastasis could help identify high risk patients and lead to personalized combination therapies addressing various tumor subpopulations. Future research based on these findings could lead to the development of personalized combination treatment strategies that improve patient outcomes. Citation Format: Songjun Xu, Danyang Yu, Shuwei Li, Christopher Moy, Julio Molineros. The role of genetic alterations in metastatic development insights from a large-scale genomic database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB014.

Abstract 2371: BGB-B167, a first-in-class 4-1BB/CEACAM5 bispecific antibody, exhibits potent in vitro and < for vivo antitumor activity and < for superior safety profile in preclinical models

Abstract 4-1BB (CD137) is a key costimulatory immunoreceptor and a promising therapeutic target in cancer. CEACAM5 (CEA) is a well-established tumor associated antigen overexpressed in many cancers, including colorectal, gastric, lung, pancreatic cancer, liver, breast and thyroid cancers. BGB-B167 is a novel immunoglobulin G (IgG)-based bispecific antibody targeting 4-1BB and CEA and is under clinical development for the treatment of advanced or metastatic solid tumors in humans. BGB-B167 binds to its target proteins with high specificity and affinity. Potent and CEA-dependent functional activities were demonstrated using peripheral blood mononuclear cell (PBMC)-based immune cell activation and cytotoxicity assays. In humanized 4-1BB knock-in mice bearing human CEA-expressing tumors, BGB-B167 exhibited potent, dose-associated single-agent efficacy as well as synergistic antitumor activity in combination with anti-PD-1 antibody. BGB-B167 was well tolerated in 1-month repeat-dose toxicology study in cynomolgus monkeys. Here, we describe the characterization of BGB-B167 with regard to preclinical proof-of-concept and basic drug-like properties. The combined dataset provides an overview on the design, mode of action, preclinical pharmacology and safety profile of BGB-B167. Citation Format: Zhuo Li, Liang Qu, Xin Chen, Liu Xue, Jie Li, Qi Liu, Jian Sun, Hanzi Sun, Yun Chen, Yuanyuan Xie, Wanyi Wang, Lin Zhu, Penghao Wang, Xiaosui Zhou, Hongjia Hou, Jie Chen, Xinyi Liu, Yilu Zhang, Ning Liu, Xinyi Liang, Shuo Zhang, Xiaoyan Tang, Jing Song, Tong Zhang, Xiaomin Song, Xuesong Liu, Kang Li, Chichi Huang. BGB-B167, a first-in-class 4-1BB/CEACAM5 bispecific antibody, exhibits potent in vitro and < for vivo antitumor activity and < for superior safety profile in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2371.

Abstract 744: Novel conditionally active biologic (CAB) tetravalent T-cell engagers targeting solid tumors

Abstract The use of T-cell engagers (TCEs) has great therapeutic potential in oncology. This potential, however, is diminished due to severe toxicity (cytokine release effects, as well as on-target off-tumor toxicities). We leveraged BioAtla’s Conditionally Active Biologic (CAB) technology (1) to develop bispecific antibodies which have no or very little binding to CD3 and to the tumor target antigen (TAA) in healthy tissue (normal physiological conditions), yet have strong binding in diseased tissues (i.e. tumor microenvironment, TME) derived from glycolytic tumor metabolism, which supports tumor growth (Warburg effect). The conditional activity in the TME is achieved by optimizing the sequences of the binding domains and does not require masking and subsequent activation of the binding domain as used in pro-drugs. We have developed dual-CAB T-cell engagers targeting serval well-established tumor associated antigens. Data demonstrating superior potency with reduced off-target binding through in vitro and in vivo characterization of three new DualCAB TCEs, targeting PSMA, Trop2, and Tissue Factor (TF) will be presented.(1) Chang HW, Frey G, Liu H, Xing C, Steinman L, Boyle WJ and Short, JM Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches. Proc Natl Acad Sci U S A 2021;118. Citation Format: Ana Paula Cugnetti, Haizhen Liu, Patricia McNeeley, Charles Xing, Kathryn Woodard, Hwai Chang, Gerhard Frey, William J. Boyle, Jay M. Short. Novel conditionally active biologic (CAB) tetravalent T-cell engagers targeting solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 744.

OsGADD45a1: a multifaceted regulator of rice architecture, grain yield, and blast resistance.

The homolog gene of the Growth Arrest and DNA Damage-inducible 45 (GADD45) in rice functions in the regulation of plant architecture, grain yield, and blast resistance. The Growth Arrest and DNA Damage-inducible 45 (GADD45) family proteins, well-established stress sensors and tumor suppressors in mammals, serve as pivotal regulators of genotoxic stress responses and tumorigenesis. In contrast, the homolog and role of GADD45 in plants have remained unclear. Herein, using forward genetics, we identified an activation tagging mutant AC13 exhibited dwarf characteristics resulting from the loss-of-function of the rice GADD45α homolog, denoted as OsGADD45a1. osgadd45a1 mutants displayed reduced plant height, shortened panicle length, and decreased grain yield compared to the wild-type Kitaake. Conversely, no obvious differences in plant height, panicle length, or grain yield were observed between wild-type and OsGADD45a1 overexpression plants. OsGADD45a1 displayed relatively high expression in germinated seeds and panicles, with localization in both the nucleus and cytoplasm. RNA-sequencing analysis suggested a potential role for OsGADD45a1 in the regulation of photosynthesis, and binding partner identification indicates OsGADD45a1 interacts with OsRML1 to regulate rice growth. Intriguingly, our study unveiled a novel role for OsGADD45a1 in rice blast resistance, as osgadd45a1 mutant showed enhanced resistance to Magnaporthe oryzae, and the expression of OsGADD45a1 was diminished upon blast fungus treatment. The involvement of OsGADD45a1 in rice blast fungus resistance presents a groundbreaking finding. In summary, our results shed light on the multifaceted role of OsGADD45a1 in rice, encompassing biotic stress response and the modulation of several agricultural traits, including plant height, panicle length, and grain yield.

Revolutionizing cancer therapy: nanoformulation of miRNA-34 - enhancing delivery and efficacy for various cancer immunotherapies: a review.

Despite recent advancements in cancer therapies, challenges such as severe toxic effects, non-selective targeting, resistance to chemotherapy and radiotherapy, and recurrence of metastatic tumors persist. Consequently, there has been considerable effort to explore innovative anticancer compounds, particularly in immunotherapy, which offer the potential for enhanced biosafety and efficacy in cancer prevention and treatment. One such avenue of exploration involves the miRNA-34 (miR-34) family, known for its ability to inhibit tumorigenesis across various cancers. Dysregulation of miR-34 has been observed in several human cancers, and it is recognized as a tumor suppressor microRNA due to its synergistic interaction with the well-established tumor suppressor p53. However, challenges have arisen with the therapeutic application of miR-34a. These include its susceptibility to degradation by RNase in serum, limiting its ability to penetrate capillary endothelium and reach target cells, as well as reports of immunoreactive adverse reactions. Furthermore, unexpected side effects may occur, such as the accumulation of therapeutic miRNAs in healthy tissues due to interactions with serum proteins on nano-vector surfaces, nanoparticle breakdown in the bloodstream due to shearing stress, and unsuccessful extravasation of nanocarriers to target cells owing to interstitial fluid pressure. Despite these challenges, miR-34a remains a promising candidate for cancer therapy, and other members of the miR-34 family have also shown potential in inhibiting tumor cell proliferation. While the in vivo applications of miR-34b/c are limited, they warrant further exploration for oncotherapy. Recently, procedures utilizing nanoparticles have been developed to address the challenges associated with the clinical use of miR-34, demonstrating efficacy both in vitro and in vivo. This review highlights emerging trends in nanodelivery systems for miR-34 targeting cancer cells, offering insights into novel nanoformulations designed to enhance the anticancer therapeutic activity and targeting precision of miR-34. As far as current knowledge extends, no similar recent review comprehensively addresses the diverse nanoformulations aimed at optimizing the therapeutic potential of miR-34 in anticancer strategies.

Enhanced anticancer synergy of LOM612 in combination with selinexor: FOXO1 nuclear translocation-mediated inhibition of Wnt/β-catenin signaling pathway in breast cancer.

The intricate relationship between Forkhead box O1 (FOXO1), a well-established tumor suppressor, and breast cancer (BC) remains partially elucidated. This study aims to investigate the mechanistic role of FOXO1 nuclear localization in the context of BC. In vitro experiments employed BC cell lines MCF-7 and MDA-MB-175 treated with LOM612, a small molecule activator of FOXO nuclear-cytoplasmic shuttling, and selinexor, an exportin 1 inhibitor. Nuclear accumulation of FOXO1, its interaction with β-catenin, and expressions of key proteins like V-Myc avian myelocytomatosis viral oncogene homolog (c-Myc), cyclin D1 and apoptosis markers were assessed. In vivo, the effects of LOM612 and selinexor were studied using MCF-7 cell-derived xenografts (CDX). Treatment with LOM612 exhibited a significant enhancement in nuclear accumulation of FOXO1 within BC cells. This effect coincided with suppressed migratory behavior and heightened apoptosis susceptibility in these cells. Mechanistically, LOM612 orchestrated FOXO1 to compete with transcription factors (TCF) for binding to β-catenin in the nucleus, leading to reduced c-Myc and cyclin D1 expressions, along with elevated levels of apoptosis-related proteins. Similar trends were observed in CDX models, where LOM612 effectively suppressed tumor growth, increased FOXO1 nuclear localization, and downregulated c-Myc and cyclin D1 expressions. Importantly, selinexor synergistically reinforced the therapeutic effects of LOM612 both in vitro and in vivo. Collectively, this study underscores the potential of combining LOM612 and selinexor as an efficacious anti-BC strategy. The underlying mechanism involves FOXO1's nuclear translocation, which disrupts TCF-β-catenin interactions, thus indirectly inhibiting the Wnt/β-catenin signaling pathway.

P11.70.A EQUITY IN GENOMIC TESTING: LESSONS LEARNT FOLLOWING THE ROLLOUT OF AN AMBITIOUS GENOMIC TESTING STRATEGY FOR NEUROLOGICAL TUMOUR PATIENTS IN THE UNITED KINGDOM

Abstract BACKGROUND The NHS England Genomic Test Directory now offers extensive genomic testing to brain tumour patients including whole genome sequencing (WGS), methylation arrays, gene panels, and other targeted mutation tests. Comprehensive genomic testing enables precise diagnosis and prognosis, tailoring of treatment, and research into new actionable targets. Despite the ambitious plans and potential for significant patient benefits, the Tessa Jowell Brain Cancer Mission (TJBCM) identified variation in deployment of these tests across Neuro-Oncology Centres in the UK. Based on these findings, we aimed to further understand the variation. We aimed to uncover drivers to delivering a successful genomic testing programme and identify local and national barriers to rolling out extensive genomic testing. MATERIAL AND METHODS As part of the TJBCM Centre of Excellence Programme, 90% of Neuro-Oncology Centres in the UK provided self-reported data on volumes of genomic testing for brain tumour patients. Subsequently, structured interviews were conducted with neuro-oncologists, neuropathologists, neurosurgeons, clinical scientists and other stakeholders from these Centres to further evaluate the state of genomic testing. RESULTS Accessibility to WGS varied from no access, to Centres where WGS was available in a limited capacity, to Centres where WGS was accessible but not scalable or timely. Bottlenecks were identified throughout the WGS pathway including inadequate tumour tissue, sample processing and transport delays, and insufficient clinical scientists to interpret results. As such, no UK Centre interviewed had sufficient capacity to offer WGS to all neurological tumour patients in a timely manner using NHS-accredited pathways. Interviews showed geographic variability in access to basic molecular tests such as methylation array and CDKN2A/B which are required for diagnostics and prognostics. There was also a strong reliance on a small number of laboratories to provide methylation array, resulting in backlogs. Common drivers to effective delivery of genomic testing included funded posts for research nurses, innovative systems for delivery of tumour samples from surgery to the laboratory, dedicated staff who advocated for genomic testing, and well-established Genomic Tumour Advisory Boards for test interpretation. CONCLUSION Impressive progress has been made in the last two years yet there remains a mismatch between what the National Genomic Test Directory dictates, and what can currently be delivered in a manageable timeframe. Inconsistencies in infrastructure, funding and training are preventing UK Centres from delivering the intended world-leading genomic testing. Barriers to address vary from simple changes at a local level, to national coordination and funding so that genomic testing will be equally accessible to all brain tumour patients in the UK.

Serum CXCL8 and CXCR2 as diagnostic biomarkers for noninvasive screening of cervical cancer.

Cervical cancer (CC) is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer-related death in women. Identifying new biomarkers for the early detection of CC is an essential requirement in this field. CXCL8 was originally discovered because of its role in inflammation by binding to CXCR1 and CXCR2; however, it is now known to play an important role in cancer. In this study, we aimed to evaluate the expression levels of potential biomarkers (CXCL8, CXCR1, and CXCR2) and to explore their diagnostic potential in CC. The expression levels of serum CXCL8, CXCR1, and CXCR2 were investigated by kit method on Immulite-1000 in 30 healthy volunteers, 30 precancerous patients and 70 CC patients. The results indicated that the expression of CXCL8 and CXCR2 was significantly higher in the serum of CC patients than in healthy volunteers, similar to the well-established tumor marker (squamous-cell cancerantigen [SCC]). Receiver operating characteristic analyses showed that the combination of CXCL8, CXCR2, and SCC had the highest diagnostic sensitivity and area under the curve value. Meanwhile, the positive predictive value and negative predictive value were not very low. Moreover, high concentrations of CXCL8 and CXCR2 are associated with an increased risk of CC. In conclusion, our data demonstrated that combined serum CXCL8, CXCR2, and SCC measurements are helpful for CC diagnosis and can be used as potential biomarkers for the early detection of CC. Cytokines, such as CXCL8 and CXCR2, can be easily measured in most university hospital laboratories and in some private laboratories with a routine test.

The Significance of CXCL1 and CXCR1 as Potential Biomarkers of Colorectal Cancer.

The CXCL1/CXCR2 and CXCL8-CXCR1/CXCR2 axes are under intensive investigation as they appear to regulate the progression and invasion of colorectal cancer (CRC). Growing evidence demonstrates the elevated expression of these proteins in CRC. However, a majority of relevant studies have been performed on CRC tissues using immunohistochemical techniques. Our study is the first to evaluate the diagnostic significance of serum CXCL1 and CXCR1 levels in CRC patients in comparison to well-established tumor markers, such as the carcinoembryonic antigen (CEA), and markers of inflammation, such as C-reactive protein (CRP). Thus, the aim of our study was to assess whether circulating serum levels of CXCL1 and CXCR1 might be candidates for novel biomarkers in the diagnosis and progression of CRC. The study was performed on 76 subjects, including patients with CRC and healthy volunteers as a control group. Serum concentrations of CXCL1, CXCR1, and the classical tumor marker (CEA) were measured using immunoenzyme assays, while CRP levels were assessed with the immunoturbidimetric method. Serum CXCL1 levels were statistically significantly increased in CRC patients when compared to healthy subjects, and similar results were found for CEA and CRP levels. The percentage of elevated concentrations of CXCL1 and CXCR1 was higher than that of the classical tumor biomarker and increased in the combined measurement of these proteins with CEA. In addition, among all proteins tested, serum CXCL1 seems to be the best indicator in the differentiation between CRC patients with nodal involvement and patients without the presence of lymph node metastasis. Our preliminary results indicate the role of serum CXCL1 and CXCR1 in the diagnosis of CRC, particularly in the combined measurement with CEA.

The Comprehensive Analysis of Specific Proteins as Novel Biomarkers Involved in the Diagnosis and Progression of Gastric Cancer.

Gastric cancer (GC) cases are predicted to rise by 2040 to approximately 1.8 million cases, while GC-caused deaths to 1.3 million yearly worldwide. To change this prognosis, there is a need to improve the diagnosis of GC patients because this deadly malignancy is usually detected at an advanced stage. Therefore, new biomarkers of early GC are sorely needed. In the present paper, we summarized and referred to a number of original pieces of research concerning the clinical significance of specific proteins as potential biomarkers for GC in comparison to well-established tumor markers for this malignancy. It has been proved that selected chemokines and their specific receptors, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), specific proteins such as interleukin 6 (IL-6) and C-reactive protein (CRP), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), as well as DNA- and RNA-based biomarkers, and c-MET (tyrosine-protein kinase Met) play a role in the pathogenesis of GC. Based on the recent scientific literature, our review indicates that presented specific proteins are potential biomarkers in the diagnosis and progression of GC as well as might be used as prognostic factors of GC patients' survival.

Allogeneic chimeric antigen receptor-T cells with CRISPR-disrupted programmed death-1 checkpoint exhibit enhanced functional fitness

Background aimsTherapeutic disruption of immune checkpoints has significantly advanced the armamentarium of approaches for treating cancer. The prominent role of the programmed death-1 (PD-1)/programmed death ligand-1 axis for downregulating T cell function offers a tractable strategy for enhancing the disease-modifying impact of CAR-T cell therapy. MethodsTo address checkpoint interference, primary human T cells were genome edited with a next-generation CRISPR-based platform (Cas9 chRDNA) by knockout of the PDCD1 gene encoding the PD-1 receptor. Site-specific insertion of a chimeric antigen receptor specific for CD19 into the T cell receptor alpha constant locus was implemented to drive cytotoxic activity. ResultsThese allogeneic CAR-T cells (CB-010) promoted longer survival of mice in a well-established orthotopic tumor xenograft model of a B cell malignancy compared with identically engineered CAR-T cells without a PDCD1 knockout. The persistence kinetics of CB-010 cells in hematologic tissues versus CAR-T cells without PDCD1 disruption were similar, suggesting the robust initial debulking of established tumor xenografts was due to enhanced functional fitness. By single-cell RNA-Seq analyses, CB-010 cells, when compared with identically engineered CAR-T cells without a PDCD1 knockout, exhibited fewer Treg cells, lower exhaustion phenotypes and reduced dysfunction signatures and had higher activation, glycolytic and oxidative phosphorylation signatures. Further, an enhancement of mitochondrial metabolic fitness was observed, including increased respiratory capacity, a hallmark of less differentiated T cells. ConclusionsGenomic PD-1 checkpoint disruption in the context of allogeneic CAR-T cell therapy may provide a compelling option for treating B lymphoid malignancies.