Liver Cancer Patients Research Articles

One-step polymerization of functionalized ionic liquid as polymer microspheres for highly specific enrichment of phosphopeptides from cell lysate and serum

A Ti4+-functionalized ionic liquid polymer microsphere was proposed and prepared through free radical precipitation polymerization. The polymer microsphere demonstrates excellent performance on phosphopeptide enrichment, with a low detection limit (0.5 fmol) and good selectivity (1:2500). Through the analysis of HepG2 cell lysate using nano LC-MS/MS after material enrichment, a total of 1100 phosphopeptides and 733 phosphoproteins were identified. Additionally, in the serum of liver cancer patients, 69 phosphopeptides, 47 phosphoproteins, and 52 phosphorylation sites were identified, while healthy controls exhibited 55 phosphopeptides, 31 phosphoproteins, and 40 phosphorylation sites. Label-free quantification revealed 10 differentially expressed proteins (DEPs), with five proteins (FN1, SERPIND1, SERPINF2, IGFBP3, and MENT) being up-regulated and five proteins (SELENOP, PLG, SPP2, SERPINC1, and GP1BB) being down-regulated. These findings highlight the potential of the MBA-VImDOPA-Ti4+ polymer microsphere in specifically enriching phosphopeptides from clinical biological samples.

An immune sandwich electrochemical biosensor based on triple-modified zirconium derivatives for detection of CD146 in serum

CD146, also known as melanoma cell adhesion molecule (MCAM), is overexpressed in various cancer patients, making it a valuable predictor for early diagnosis. In this work, an immune sandwich electrochemical biosensor is proposed for sensitive and non-invasive quantitative detection of CD146 in serum. Zirconium-based MOF (UIO-66) was modified by simultaneous copper atom doping, in situ growth carbon-based support and physical embedding of platinum nanoparticles (PtNPs). Triple-modified Cu-UIO-66@SWCNT/PtNPs nanocomposites with high stability and excellent electrochemical properties, serve as surface modification materials for glassy carbon electrodes. Anti-CD146 antibody (Ab1) was grafted onto the electrode surface via Pt-S bond. Meanwhile, the secondary antibody (Ab2) was conjugated with silver nanoparticles (AgNPs) to cooperate for CD146 capture and achieve secondary electrical signal amplification. Under optimal conditions, square wave voltammetry was employed to determine CD146 in the concentration range of 10−9–10−4 mg/mL and a limit of detection of 12 fg/mL was obtained. Finally, it was successfully applied to the analysis of CD146 in lung and liver cancer patients’ serum samples.

Validation of Core Ingredients and Molecular Mechanism of Cinobufotalin Injection Against Liver Cancer.

Cinobufotalin injection has obvious curative effects on liver cancer patients with less toxicity and fewer side effects than other therapeutic approaches. However, the core ingredients and mechanism underlying these anti-liver cancer effects have not been fully clarified due to its complex composition. Multidimensional network analysis was used to screen the core ingredients, key targets and pathways underlying the therapeutic effects of cinobufotalin injection on liver cancer, and in vitro and in vivo experiments were performed to confirm the findings. By construction of ingredient networks and integrated analysis, eight core ingredients and ten key targets were finally identified in cinobufotalin injection, and all of the core ingredients are tightly linked with the key targets, and these key targets are highly associated with the cell cycle-related pathways, supporting that both cinobufotalin injection and its core ingredients exert anti-liver cancer roles by blocking cell cycle-related pathways. Moreover, in vitro and in vivo experiments confirmed that either cinobufotalin injection or one of its core ingredients, cinobufagin, significantly inhibited cell proliferation, colony formation, cell cycle progression and xenograft tumor growth, and the key target molecules involved in the cell cycle pathway such as CDK1, CDK4, CCNB1, CHEK1 and CCNE1, exhibit consistent changes in expression after treatment with cinobufotalin injection or cinobufagin. Interestingly, some key targets CDK1, CDK4, PLK1, CHEK1, TTK were predicted to bind with multiple of core ingredients of cinobufotalin injection, and the affinity between one of the critical ingredients cinobufagin and key target CDK1 was further confirmed by SPR assay. Cinobufotalin injection was confirmed to includes eight core ingredients, and they play therapeutic effects in liver cancer by blocking cell cycle-related pathways, which provides important insights for the mechanism of cinobufotalin injection antagonizing liver cancer and the development of novel small molecule anti-cancer drugs.

Clinical Characteristics of Non-B and Non-C Biopsy-Proven Primary Liver Cancers in an HBV- Endemic Area: A Retrospective Study.

To explore the distribution of probable causes and clinical characteristics of non-B and non-C (NBNC) primary liver cancer (PLC) patients in the HBV-endemic region. A total of 86 individuals with biopsy-proven NBNC-PLC were enrolled. NBNC-PLC patients were defined as negative for both anti-HCV antibodies and five serum hepatitis B markers. Patients' characteristics were collected from medical records. Among them, most of the NBNC-PLC patients had intrahepatic cholangiocarcinoma (ICC) (81.4%), and 12.8% had hepatocellular carcinoma (HCC). The NBNC ICC group had more platelet count, GGT, and CA199 levels; approximately two-thirds were female, and it was more often present in patients with biliary inflammatory diseases, especially intrahepatic biliary lithiasis. The NBNC HCC group was older and had a higher proportion of dyslipidemia, obesity, cirrhosis, and AFP levels. Our data revealed that most of the NBNC PLC patients were ICC. Female patients with biliary inflammatory diseases and higher CA199 levels had an increased risk of ICC, and patients with metabolic risk factors and elevated AFP levels were more likely to develop HCC. Additional research should be performed to verify this finding.

Sterigmatocystin induces autophagic and apoptotic cell death of liver cancer cells via downregulation of XIAP

XIAP, or the X-linked Inhibitor of Apoptosis Protein, is the most extensively studied member within the IAP gene family. It possesses the capability to impede apoptosis through direct inhibition of caspase activity. Various kinds of cancers overexpress XIAP to enable cancer cells to avoid apoptosis. Consequently, the inhibition of XIAP holds significant clinical implications for the development of anti-tumor medications and the treatment of cancer. In this study, sterigmatocystin, a natural compound obtained from the genus asperigillus, was demonstrated to be able to induce apoptotic and autophagic cell death in liver cancer cells. Mechanistically, sterigmatocystin induces apoptosis by downregulation of XIAP expression. Additionally, sterigmatocystin treatment induces cell cycle arrest, blocks cell proliferation, and slows down colony formation in liver cancer cells. Importantly, sterigmatocystin exhibits a remarkable therapeutic effect in a nude mice model. Our findings revealed a novel mechanism through which sterigmatocystin induces apoptotic and autophagic cell death of liver cancer cells by suppressing XIAP expression, this offers a promising therapeutic approach for treating liver cancer patients.

Effect of Family Music Therapy on Patients with Primary Liver Cancer Undergoing Palliative Care and their Caregivers: A Retrospective Study.

The effectiveness of family music therapy for patients with advanced palliative care hepatocellular carcinoma and their main caregivers was investigated. The clinical data of liver cancer patients and their main caregivers admitted to Wuwei City People's Hospital from August 2022 to April 2023 were retrospectively analysed. Patients were divided into observation group A and control group A according to whether they received family music therapy, and caregivers were divided into control group B and observation group B. The general demographic data, self-rating depression scale (SDS), self-rating anxiety scale (SAS), cancer-related fatigue scale (CFS), Pittsburgh sleep quality index (PSQI), anticipatory grief scale (AGS), and caregiver burden inventory (CBI) scores of the patients and their primary caregivers were collected. Propensity score matching (PSM) was used to balance the baseline data of the two groups. Then, data were analysed using t-test and chi-squared (χ2) test. After 1:1 PSM, 45 samples were included in each group. Before management, no significant differences in SDS, SAS, AGS, CFS, PSQI and CBI scores were found among the groups (P > 0.05). After management, the SDS, SAS and CFS scores of observation group A were lower than those of control group A (P < 0.05). The AGS, PSQI and CBI scores of observation group B were lower than those of control group B (P < 0.05). The effect of family music supplement therapy is ideal, which can relieve the negative emotions of patients, reduce the degree of cancer-related fatigue, enhance the sleep quality of the main caregivers and reduce anticipatory grief and the burden of care.

Stigmatization of drinking patients with liver cancer: The role of socioeconomic status

Patients with liver cancer may face stigmatization due to cancer, alcohol consumption, or both. This study addresses gaps in the existing literature regarding stigmatization of alcohol-related liver cancer patients, particularly its connection with socioeconomic status (SES). The study explores whether the SES of a fictional character with alcohol addiction and liver cancer influences stigma levels reported by participants. Additionally, it investigates how participants' personal characteristics, such as alcohol consumption and healthcare professional status, impact stigmatization. This study aims to provide new insights regarding the role of stigmatization in liver cancer treatment and management, emphasizing in socioeconomic determinants. The method is based on three scenarios describing a woman character with alcohol abuse and liver cancer. The scenarios depicted a woman character with either low, medium or high SES. Each participant (N = 991) was randomly assigned to one of the three scenarios. After reading it, each participant answered questionnaires assessing negative attitudes towards the character. Four scales were used: “Negative attributions about people with health problems”, “Causality of cancer”, “Controllability of drinking” and “Reluctance to helping behavior”. Data were analyzed using ANOVA and t-tests. The scenario describing a character with a low SES significantly received more “Negative attributions about people with health problems” than the character with medium or high SES. Participants having higher alcohol consumption themselves showed lower stigma scores for three out of four scales than participants with lower consumption. In addition, participants identified as health professionals had lower stigma scores regarding the scales “Negative attributions about people with health problems” and “Controllability of drinking”, and higher scores for the subscale “Reluctance to helping behavior”, compared with non-professionals. A character with low SES received more negative attributions than the one with higher SES. Participants’ own alcohol consumption and professional status (being health professional or not), influenced their stigmatizing attitudes.

Combined effects of smoking and alcohol consumption on the risk of liver cancer according to metabolic syndrome: A nested case-control study in South Korea.

Tobacco and alcohol may interact to increase the risk of liver cancer, which might be modified by other risk factors. Their combined effects in the context of metabolic syndrome (MetS) remain unclear. Given the increasing prevalence of MetS, this nested case-control study was conducted to evaluate the combined effects of smoking and alcohol consumption on liver cancer risk with stratification by MetS. We included 15,352 liver cancer patients and 92,112 matched controls who attended the nationwide general health examination during 2009-2019, using a customized database (N = 5,545,835) from the Korean National Health Insurance Service. Liver cancer risk according to smoking and alcohol consumption was estimated using conditional multivariable logistic regression. Additive and multiplicative interactions between these two factors were assessed. Results showed that in men, dual current users were at a significantly higher risk of liver cancer compared with dual nonusers, adjusted odds ratio (aOR) = 1.61, 95% confidence interval: (1.50, 1.72). Interactions were detected between light-to-moderate alcohol consumption (0.1-28 g/day) and heavy smoking (>20 pack-years) on additive scale, relative excess risk due to interaction = 0.34 (0.16, 0.51), attributable proportion = 0.22 (0.11, 0.33), synergy index = 2.75 (1.85, 3.66), and multiplicative scale, aOR for the product term = 1.28 (1.11, 1.49). An additive interaction was also revealed between light-to-moderate drinking and light-to-moderate smoking in the MetS subgroup. In women, light-to-moderate drinking/nonsmoking was negatively associated with the risk in the non-MetS subgroup. In conclusion, a holistic health promotion program should target male dual users of tobacco cigarettes and alcohol, including light-to-moderate users, especially those with MetS.

Potential of Using qFibrosis Analysis to Predict Recurrent and Survival Outcome of Patients with Hepatocellular Carcinoma after Hepatic Resection

Background: There remains a lack of studies addressing the stromal background and fibrosis features and their prognostic value in liver cancer. qFibrosis can identify, quantify, and visualize the fibrosis features in biopsy samples. In this study, we aim to demonstrate the prognostic value of histological features by using qFibrosis analysis in liver cancer patients. Methods: Liver specimens from 201 patients with hepatocellular carcinoma (HCC) who underwent curative resection were imaged and assessed using qFibrosis system and generated a total of 33 and 156 collagen parameters from tumor part and non-tumor liver tissue, respectively. We used these collagen parameters on patients to build two combined indexes, RFS index and OS index, in order to differentiate patients with early recurrence and early death, respectively. The models were validated using the leave-one-out method. Results: Both combined indexes had significant prediction value for patients’ outcome. The RFS index of 0.52 well differentiates patients with early recurrence (p p = 0.02). Conclusions: Combined index calculated with qFibrosis from a digital readout of the fibrotic status of peri-tumor liver specimen in patients with HCC has prediction values for their disease and survival outcomes. These results demonstrated the potential to transform histopathological features into quantifiable data that could be used to correlate with clinical outcome.

Abstract 27: A single amino acid mutated AFP specific T cell receptor uniting synergistic functionalities of CD4 and CD8 T Cells with no cross-activity

Abstract Background: Genetically engineered T cells with T cell receptor (TCR-T) cell therapy have shown great potential for cancer treatment by targeting tumor-associated antigens. Despite its success in treating various tumor types, such as synovial sarcoma, head and neck tumors, and cervical cancer, its application in liver cancer is limited. Alpha-fetoprotein (AFP), a highly expressed tumor-associated antigen in liver cancer, is an ideal target for TCR-T cell therapy. Although early human trials have confirmed the safety of AFP-targeting TCR-T products, their efficacy is still modest, highlighting the need for further research and development. Methods: We developed a robust strategy combining ex vivo stimulation and single-cell paired TCR sequencing to identify AFP-recognizing TCRs in liver cancer patients. To optimize TCR expression and minimize mispairing, we employed codon optimization and replaced the constant regions with murine counterparts. Furthermore, structural analysis guided the affinity optimization of the CDR3 region to enhance the antitumor function of the selected TCR. The anti-tumor efficacy of TCR-T cells was rigorously evaluated through in vitro cytotoxicity assays using the Real-Time Cell Analyzer (RTCA) system and in vivo antitumor assessment in immunodeficient mouse xenograft models. Antigen specificity, HLA restriction, and other potential toxicity were carefully evaluated in both in vitro and in vivo models. Results: We successfully cloned a highly effective TCR that recognizes the AFP158-166 epitope presented by HLA-A*0203. After sequence optimization, we further changed a single amino acid on the TCR vβ chain based on AI prediction. The expression and functionality of this TCR was significantly improved. When introduced into human T cells, the single amino acid mutated TCR demonstrated robust and specific anti-tumor activity in various models, including cultured tumor cells, patient-derived organoids, and mouse xenografts models. Notably, this TCR also redirected CD4 T cells to recognize tumor cells, induced the secretion of multiple cytokines, and maintained long-lasting anti-tumor effects. Our rigorous screening assays confirmed that the TCR showed no cross-reactivity with the human proteome or major HLA subtypes. Additionally, extensive preclinical safety assessments in tumor-bearing animals treated with ST08A01-AM14 TCR-T cells showed no significant safety concerns. Conclusion: In this study, we have developed an HLA-A*0203 restrict AFP158-166 specific TCR-T therapy, which exhibits exceptional anti-tumor effects while ensuring a favorable safety profile. The promising results support the further investigation against AFP-positive solid tumors in clinic. Citation Format: Chen-Song Huang, shudan Ou, Jun Li, Junjun Chu, Yanyan Han. A single amino acid mutated AFP specific T cell receptor uniting synergistic functionalities of CD4 and CD8 T Cells with no cross-activity [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 27.

Abstract 1896: Therapeutic potential of TORL-4-500, an antibody-drug conjugate directed against delta like non-canonical notch ligand 1 (DLK1)

Abstract Delta like non-canonical Notch ligand 1 (DLK1) is a transmembrane protein that belongs to the NOTCH non-canonical ligand family. It has been implicated in adipogenesis, the regulation of stem cell pools, tissue differentiation during development, cancer differentiation, and cancer stem-like cell maintenance. DLK1 is highly expressed in adrenocortical, uterine, and testicular cancers as well as in a large portion of pancreatic, sarcoma, liver and squamous lung cancer patient samples. In contrast there is limited normal tissue expression beyond the normal adrenal gland, pituitary, and ovarian tissue samples. This expression profile makes DLK1 an attractive target for development of a therapeutic antibody-drug conjugate (ADC). This study describes the generation and preclinical characterization of TORL-4-500, an ADC consisting of a humanized anti-DLK1 monoclonal antibody coupled to monomethyl auristatin E (MMAE) via a cleavable linker. TORL-4-500 showed strong binding to DLK1 by flow cytometry in DLK1 native and artificial overexpressing cell lines. In contrast no binding was observed in DLK1 non-expressing cell lines. TORL-4-500 exhibits nanomolar binding affinity for both human and cynomolgus monkey DLK1 and is rapidly internalized in DLK1 expressing cells. TORL-4-500 exhibited selective efficacy in cell line xenograft models of DLK1 positive human cancers. Treatment with TORL-4-500 induced significant regressions in four DLK1 expressing human cancer cell line xenograft studies encompassing liver, small cell lung cancer (SCLC) and sarcoma cancer. Furthermore, anti-tumor responses were sustained in each of the DLK1 expressing models for several weeks post-final dose. In the case of the two SCLC cell lines, complete regressions of xenograft tumors were measured out past 100 days in the TORL-4-500 treated animals. No significant impact on xenograft tumor growth was observed in either a DLK1 non-expressing colon cell line xenograft or in a DLK1 non-expressing melanoma xenograft study. Each of the doses tested in this study was well tolerated in mice with no dose-limiting toxicity observed. The nonclinical pharmacokinetics and toxicokinetics of TORL-4-500 were characterized in mice and monkeys and results support dosing in humans. In summary, TORL-4-500 is a novel therapeutic for DLK1 positive cancers and on the basis of these promising preclinical efficacy results, a first in human trial to evaluate safety, tolerability, pharmacokinetics, and antitumor activity of TORL-4-500 has been launched in patients with advanced cancer and is currently ongoing (NCT06005740). Citation Format: Martina S. McDermott, Neil A. O'Brien, Ming Lu, Jun Zhang, KeWei Gong, Benjamin Hoffstrom, Tong Luo, Min Liang, Weiping Jia, Kevin Chau, Leonard Presta, John Glaspy, Dennis J. Slamon. Therapeutic potential of TORL-4-500, an antibody-drug conjugate directed against delta like non-canonical notch ligand 1 (DLK1) [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 1896.

Abstract 4449: Hepatic steatosis induced by bioactive lipids

Abstract Introduction: HCC is the most common form of liver cancer and is the sixth most common cancer globally. Despite the clinical advancement of immune checkpoint inhibitors, median survival continues to be less than twenty months and most patients develop resistance making it one of the deadliest malignancies. The rate of liver cancer continues to rise, which is coupled to the high prevalence of steatosis and steatohepatitis that accounts for about 25% in the general population. Pathologically, 80% of liver cancer occurs in patients with an underlying liver disease that displays liver steatosis. Thus, it is paramount to better characterize the transition from steatosis to HCC. Methods: Utilizing a Pten deleted mouse model (PtenloxP/loxP; Alb-Cre+) that recapitulates HCC progression, protein and lipid fractions were isolated to explore differentially expressed proteins and their correlations with bioactive lipid metabolism. Global untargeted differential proteomics was done with fractionation using a qExactive. Lipid fractions were analyzed using a Sciex 6500 for targeted lipidomic analysis. In addition, genetic knockout hepatocyte cell lines of each AKT isoform were used to explore the involvement of the PI3K/AKT signal. Further, a phosphoproteomic enrichment was performed to discover downstream signaling targets. Results: The PTEN regulated PI3K/AKT signal is induced in 54% of all liver cancers and represents the dominant signaling pathway regulating liver cancer progression. Untargeted differential proteomic analysis of Pten deleted mice livers revealed significant dysregulation in oxidative stress and eicosanoid metabolism among the top enriched disease and biological functions when the phenotype progressed from steatosis to HCC. Analysis of publicly available liver cancer patient samples from the NCI Proteomic Data Commons further shows strong correlation between PTEN protein abundance and the expression of enzymes involved in eicosanoid metabolism. Our analysis using a bio-active lipid multi reaction monitoring panel of Pten deleted mouse livers further validates significant decreases in resolving eicosanoid levels along with increases in proinflammatory eicosanoid precursors as steatosis progress to HCC. These data suggest a potential hepatic AKT-dependency in regulating the shift towards proinflammatory eicosanoids. Primary isolated hepatocytes from mouse livers lacking either AKT1 or AKT2 were analyzed to elucidate AKT’s regulatory role in hepatic eicosanoid metabolism. Proteomic and lipidomic analysis of these hepatocytes supported a unique AKT isoform specific role in the regulation of eicosanoids via potential isoform specific signaling interactions with MAPK. Conclusion: Eicosanoid metabolism dysregulation plays a key role in the progression from steatosis to HCC and appears to be regulated in an AKT isoform specific manner via interactions with MAPK signaling. Citation Format: Mario Alba, Ielyzaveta Slarve, Brandon Ebright, Yiren Zhou, Whitaker Cohn, Yunyi Jia, Elizabeth Elton, Jared Khan, Aditi Datta, Lina He, Qi Tang, Pranav Pammidimukkala, Taojian Tu, Phillip Nguyen, Jonathan Katz, Julian Whitelegge, Stan Louie, Bangyan Stiles. Hepatic steatosis induced by bioactive lipids [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 4449.

Abstract 4662: High-throughput screening identifies potential combinatorial therapies to overcome lenvatinib resistance in liver cancer

Abstract Liver cancer has seen an increase in mortality rate over recent decades due to limited targeted therapies and growth in specific etiologies. Lenvatinib, a multi-TKI inhibitor, is used as a first-line therapy for liver cancer patients who cannot receive immunotherapy, which is a component of the current standard of care. Unfortunately, lenvatinib efficacy is short. Understanding why liver cancers become resistant and identifying interventions to restore sensitivity can help prolong the clinical efficacy of lenvatinib. A panel of 20 liver cancer lines was screened to identify four lenvatinib-sensitive lines. These lines were subsequently conditioned to grow under increasing lenvatinib concentrations to generate lenvatinib-resistant (LR) models. One such model, Hep3B LR, exhibited a stable resistance to lenvatinib for up to 12 weeks in culture. Hep3B LR showed cross-resistance to selective inhibitors of FGFR4 and FGFR1 but not of MAPK14 and PDGFR, suggesting that the resistance phenotype may result from FGFR dysfunction. Unlike parental Hep3B, Hep3B LR exhibited a 3.4X increase in migration. Western blot detected an increase in pAKT, a survival marker. Additionally, proteins associated with cancer drug resistance were higher in Hep3B LR cells: Notch receptors and ligands, pStat3, and Axl. To identify means of overcoming lenvatinib resistance in Hep3B LR, a Cell-Titer Glo high-throughput assay was developed to measure the growth inhibition of candidate drugs in the presence and absence of lenvatinib. Preliminary results from the first 24 drugs screened reproduced known drug sensitivities associated with lenvatinib resistance (i.e., MEK/ERK, EGFR, GPX4 inhibition) but also identified novel sensitivities to inhibition of PKMYT1 or γ-secretase, the latter a cleavage enzyme involved in Notch signaling activation. Validation of these candidate hits using a grid-based titration of both drugs showed additive growth inhibition of lenvatinib in combination with ERK, EGFR, or GPX4 inhibitors but not with PKMYT1 or γ-secretase inhibitors in resistant cells. Interestingly, EGFRi and lenvatinib were substantially synergistic in parental cells, suggesting that an upfront combination of these inhibitors could potentially be used before the emergence of lenvatinib resistance in liver cancer. We have established a lenvatinib-resistant liver cancer cell model and validated a drug screening assay to identify potential combinatorial therapies to overcome lenvatinib resistance in liver cancer. Citation Format: Kevin Chau, Martina S. McDermott, KeWei Gong, Dennis J. Slamon. High-throughput screening identifies potential combinatorial therapies to overcome lenvatinib resistance in liver cancer [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 4662.

Abstract 6395: Metabolic dysregulation as a determinant of prognosis and response to sorafenib in liver cancer

Abstract Background &amp; Aims: Elevated metabolic activity is a defining characteristic of liver cancer. Nevertheless, our understanding of the molecular underpinnings of high metabolic activity in liver cancer and its impact on clinical outcomes and treatment responses remains limited. We aimed to elucidate the metabolic features of liver cancer associated with clinical outcomes, particularly overall survival and responsiveness to sorafenib treatment. Methods: Utilizing cross-species comparisons of genomic data, we integrated gene expression profiles from liver tissues in metabolically challenged mice and from patients with cirrhosis and liver cancer. To categorize patients, we developed a genomic predictor and applied it to gene expression data from a cirrhosis cohort (n=216) and large liver cancer cohorts (n=1390). Comprehensive statistical and informatics analyses were conducted to evaluate clinical significance, including overall survival and responses to standard treatments. Moreover, we integrated genomic data derived from patient-derived xenograft (PDX) models into our analytical framework. Results: Our integrated data analysis unveiled three distinct metabolic subtypes of tissues: high, moderate, and low metabolic subtypes. In the cirrhosis cohort, the high metabolic subtype was significantly associated with early liver cancer development. Among liver cancer cohorts, the high metabolic subtype exhibited characteristics such as poor survival, heightened hepatic stem cell features, increased genomic instability, and elevated expression of AFP, KRT19, EPCAM, and SALL4. Notably, when liver cancer patients undergoing systemic sorafenib treatment were stratified using our genomic predictor, those with low and moderate metabolic activity derived significant benefits from sorafenib therapy. Conversely, the high metabolic subtype displayed substantial resistance to sorafenib, suggesting that metabolic activity may dictate the response of liver cancer cells to sorafenib treatment. Gene network analysis of the metabolic expression signature identified multiple signaling pathways that potentially contribute to sorafenib resistance in liver cancer cells. Our analysis predicted the activation of pathways such as the TGF-β pathway (TGFB1), consistent with previous findings of TGF-β pathway activation in highly metabolic cancer cells. Additionally, our analysis identified YAP1, HIF1A, and MAPK pathways as activated pathways in sorafenib-resistant liver cancer. Conclusions: This study identifies clinically and metabolically distinct subtypes of liver cancer, biomarkers associated with these subtypes, and mechanisms underlying metabolic-mediated resistance of liver cancer cells to sorafenib. Furthermore, the metabolic subtypes observed in PDX models provide valuable tools for selecting appropriate preclinical models for future research endeavors. Citation Format: Hyewon Park, Sowon Park, Sung-Hwan Lee, Yun Seong Jeong, Bohwa Sohn, Sun Young Yim, Ju-Seog Lee. Metabolic dysregulation as a determinant of prognosis and response to sorafenib in liver cancer [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 6395.

Mechanisms and therapeutic prospect of the JAK-STAT signaling pathway in liver cancer.

Liver cancer (LC) poses a significant global health challenge due to its high incidence and poor prognosis. Current systemic treatment options, such as surgery, chemotherapy, radiofrequency ablation, and immunotherapy, have shown limited effectiveness for advanced LC patients. Moreover, owing to the heterogeneous nature of LC, it is crucial to uncover more in-depth pathogenic mechanisms and develop effective treatments to address the limitations of the existing therapeutic modalities. Increasing evidence has revealed the crucial role of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in the pathogenesis of LC. The specific mechanisms driving the JAK-STAT pathway activation in LC, participate in a variety of malignant biological processes, including cell differentiation, evasion, anti-apoptosis, immune escape, and treatment resistance. Both preclinical and clinical investigations on the JAK-STAT pathway inhibitors have exhibited potential in LC treatment, thereby opening up avenues for the development of more targeted therapeutic strategies for LC. In this study, we provide an overview of the JAK-STAT pathway, delving into the composition, activation, and dynamic interplay within the pathway. Additionally, we focus on the molecular mechanisms driving the aberrant activation of the JAK-STAT pathway in LC. Furthermore, we summarize the latest advancements in targeting the JAK-STAT pathway for LC treatment. The insights presented in this review aim to underscore the necessity of research into the JAK-STAT signaling pathway as a promising avenue for LC therapy.

Low-abundance proteins-based label-free SERS approach for high precision detection of liver cancer with different stages

BackgroundSurface-enhanced Raman scattering (SERS) technology have unique advantages of rapid, simple, and highly sensitive in the detection of serum, it can be used for the detection of liver cancer. However, some protein biomarkers in body fluids are often present at ultra-low concentrations and severely interfered with by the high-abundance proteins (HAPs), which will affect the detection of specificity and accuracy in cancer screening based on the SERS immunoassay. Clearly, there is a need for an unlabeled SERS method based on low abundance proteins, which is rapid, noninvasive, and capable of high precision detection and screening of liver cancer. ResultsSerum samples were collected from 60 patients with liver cancer (27 patients with stage T1 and T2 liver cancer, 33 patients with stage T3 and T4 liver cancer) and 40 healthy volunteers. Herein, immunoglobulin and albumin were separated by immune sorption and Cohn ethanol fractionation. Then, the low abundance protein (LAPs) was enriched, and high-quality SERS spectral signals were detected and obtained. Finally, combined with the principal component analysis-linear discriminant analysis (PCA-LDA) algorithm, the SERS spectrum of early liver cancer (T1-T2) and advanced liver cancer (T3-T4) could be well distinguished from normal people, and the accuracy rate was 98.5% and 100%, respectively. Moreover, SERS technology based on serum LAPs extraction combined with the partial least square-support vector machine (PLS-SVM) successfully realized the classification and prediction of normal volunteers and liver cancer patients with different tumor (T) stages, and the diagnostic accuracy of PLS-SVM reached 87.5% in the unknown testing set. SignificanceThe experimental results show that the serum LAPs SERS detection combined with multivariate statistical algorithms can be used for effectively distinguishing liver cancer patients from healthy volunteers, and even achieved the screening of early liver cancer with high accuracy (T1 and T2 stage). These results showed that serum LAPs SERS detection combined with a multivariate statistical diagnostic algorithm has certain application potential in early cancer screening.

Identification of an immune-related gene signature for predicting prognosis and immunotherapy efficacy in liver cancer via cell-cell communication.

Liver cancer is one of the deadliest malignant tumors worldwide. Immunotherapy has provided hope to patients with advanced liver cancer, but only a small fraction of patients benefit from this treatment due to individual differences. Identifying immune-related gene signatures in liver cancer patients not only aids physicians in cancer diagnosis but also offers personalized treatment strategies, thereby improving patient survival rates. Although several methods have been developed to predict the prognosis and immunotherapeutic efficacy in patients with liver cancer, the impact of cell-cell interactions in the tumor microenvironment has not been adequately considered. To identify immune-related gene signals for predicting liver cancer prognosis and immunotherapy efficacy. Cell grouping and cell-cell communication analysis were performed on single-cell RNA-sequencing data to identify highly active cell groups in immune-related pathways. Highly active immune cells were identified by intersecting the highly active cell groups with B cells and T cells. The significantly differentially expressed genes between highly active immune cells and other cells were subsequently selected as features, and a least absolute shrinkage and selection operator (LASSO) regression model was constructed to screen for diagnostic-related features. Fourteen genes that were selected more than 5 times in 10 LASSO regression experiments were included in a multivariable Cox regression model. Finally, 3 genes (stathmin 1, cofilin 1, and C-C chemokine ligand 5) significantly associated with survival were identified and used to construct an immune-related gene signature. The immune-related gene signature composed of stathmin 1, cofilin 1, and C-C chemokine ligand 5 was identified through cell-cell communication. The effectiveness of the identified gene signature was validated based on experimental results of predictive immunotherapy response, tumor mutation burden analysis, immune cell infiltration analysis, survival analysis, and expression analysis. The findings suggest that the identified gene signature may contribute to a deeper understanding of the activity patterns of immune cells in the liver tumor microenvironment, providing insights for personalized treatment strategies.

Polyphenol consumption and Nonalcoholic fatty liver disease risk in adults

In this cross-sectional investigation, the primary objective was to explore the correlation between the consumption of polyphenols and the likelihood of non-alcoholic fatty liver disease (NAFLD) in the adult population participating in the Hoveyzeh cohort. Data from the Hoveyzeh cohort study, part of the Persian Cohort Study, involving 10,009 adults aged 35–70, were analyzed. Exclusions were made for missing data, extreme energy intake, and liver cancer patients. Dietary habits were assessed using a food frequency questionnaire, and polyphenol intake was calculated using the Phenol Explorer database. Logistic regression analyses, adjusted for confounders, were performed to assess the relationship between polyphenol subclasses (total polyphenols, total flavonoids, phenolic acid, and lignin) and NAFLD. Among 9894 participants, those in the highest quintile of total polyphenol (OR 0.65, CI 0.5–0.84; P = 0.007), phenolic acid (OR 0.67, CI 0.52–0.86; P < 0.001), and lignin intake (OR 0.69, CI 0.52–0.87; P = 0.001) demonstrated lower odds of NAFLD compared to the lowest quintile, even after adjusting for confounding factors. However, no significant association was found between total flavonoid intake and NAFLD (OR 1.26, CI 0.96–1.67; P = 0.47). Subgroup analysis indicated a significant inverse association between total polyphenols and NAFLD in women (OR 0.64, CI 0.42–0.93; P = 0.001). Higher intake of total polyphenols, phenolic acid, and lignin was associated with reduced odds of NAFLD among adults in the Hoveyzeh cohort. This suggests that dietary patterns rich in these polyphenols may play a role in mitigating the risk of NAFLD. Further interventional and longitudinal studies are needed to validate these findings and explore potential preventive strategies involving polyphenol-rich diets.

Lianhua Qingwen exerts anti-liver cancer effects and synergistic efficacy with sorafenib through PI3K/AKT pathway: Integrating network pharmacology, molecular docking, and experimental validation

Liver cancer is one of the most lethal malignancies and sorafenib resistance is the main treatment obstacle for patients with advanced liver cancer. Developing drugs that sensitize liver cancer patients to sorafenib is of great importance. Lianhua Qingwen (LHQW), a sort of Traditional Chinese Medicine (TCM) approved by the Chinese Food and Drug Administration (CFDA), is reported to exert synergistic effects with oseltamivir against Influenza virus. However, whether LHQW could exhibit anti-liver cancer effects and enhance the efficacy of sorafenib against liver cancer have not been reported. In the present study, the potential anti-liver cancer effects of LHQW and its synergistic effects with sorafenib were investigated via applying network pharmacology, molecular docking, and in vitro experiments. An “ingredient-compound- target-liver cancer” network was constructed which included 12 ingredients, 164 compounds, and 402 targets. AKT1 was identified as the most hub gene and the PI3K/AKT pathway was revealed as the most enriched pathway. Subsequently, the molecular docking results showed that kaempferol, luteolin, and quercetin were screened as the top 3 compounds which showed the tightest binding to AKT1. Further, the in vitro experiments verified that LHQW significantly inhibited liver cancer cell proliferation and induced apoptosis. Western blot assays confirmed that LHQW could attenuate the PI3K/AKT pathway. Interestingly, LHQW showed a synergistic effect with sorafenib against liver cancer via reducing cell viability, inducing apoptosis, and down- regulating PI3K/AKT pathway. This study broadens the potential application of LHQW and provides insights for liver cancer treatment.

Influence of transcatheter arterial embolization on symptom distress and fatigue in liver cancer patients.

Hepatocellular carcinoma (HCC) is a prevalent malignancy, and transcatheter arterial embolization (TAE) has emerged as a pivotal therapeutic modality. However, TAE may induce symptom distress and fatigue, adversely affecting the quality of life of patients. To investigate symptom distress, fatigue, and associated factors in HCC patients undergoing TAE. We used a cross-sectional design and purposive sampling to enroll HCC patients who underwent TAE at our institution from January to December 2022. Questionnaires were utilized to collect data on symptom distress and fatigue scores from the first to the third day after TAE. Our study revealed a significant reduction in fatigue and symptom distress among patients after TAE. Pain, fatigue, insomnia, fever and abdominal distension were the most common symptoms troubling patients during the first 3 d post-TAE. Marital status, presence of family support, physical functional status, age, and symptom distress were identified as predictors of fatigue in patients. Healthcare professionals should educate HCC patients on symptom distress and fatigue, offering personalized relief strategies to lessen their psychological burden.