Disease Progression In Cancer Research Articles

Abstract C035: MAGEA6 Oncogene Upregulates MAPK and AMPK Signaling Pathways in Pancreatic Cancer Cells to Promote Survival under Nutrient Stress: Resistance to Glycolysis Inhibition and Increased Susceptibility to Glutamine Depletion

Abstract Introduction: Melanoma-associated antigens (MAGEs) are linked to aggressive disease progression and treatment resistance in many cancers, but their role in pancreatic cancer is not well understood. Our preliminary TCGA data analysis suggested that 10% of pancreatic tumors express MAGEA3/6 and potentially help pancreatic cancer cells survive and grow under nutrient stress. This study aims to uncover the molecular mechanisms of MAGEA3/6 function in pancreatic cancer cell metabolism and disease progression under nutrient-poor conditions. Methods: To understand the role of highly homologous genes MAGEA3 and MAGEA6 in pancreatic cancer, we expressed them in highly glycolytic MIA PaCa-2 pancreatic cancer cells. Cells were then exposed to cancer-related nutritional stressors, including glycolysis inhibition by 2-deoxy-D-glucose (2DG) treatment and glutamine depletion. We analyzed the effect of MAGEA6 expression on cell viability and cell metabolism by Alamar Blue viability assay (BioRad), Seahorse (Agilent), Phenotype MicroArray Mammalian analysis (Biolog), transmission electron microscopy (TEM), and RNA sequencing. To confirm our results, we performed loss-of- function studies in MAGEA3/6-positive cells, including PANC1. Results: We found that, compared to control GFP-expressing cells, MAGEA6-expressing MIA PaCa-2 cells were resistant to glycolysis inhibition with 2-DG. In contrast, they were more susceptible to glutamine depletion, suggesting the important role of MAGEA3/6 in metabolic phenotype and adaptations of pancreatic cancer cells. Further, we showed that MAGEA6-expressing cells exhibited increased ATP production and mitochondrial oxidative phosphorylation, especially under 2DG stress. After 48 hours of 2DG treatment, TEM images revealed significant differences in nuclear, mitochondrial, and ribosomal structures in MAGEA6-cells, further suggesting MAGEA6's role in metabolic adaptation. The Phenotype MicroArray assay demonstrated that α-D-Glucose is the primary nutrient source consumed by both GFP and MAGEA6-expressing cells among the 93 nutrients tested. Additionally, A6 cells utilize Pyruvic Acid as an alternative nutrient source more than GFP cells. To uncover molecular underpinning, we performed RNA sequencing and found that MAGEA6 expression affects transcriptome under glutamine depletion and 2DG treatment. Intriguingly, one of the major differentially regulated biological processes was associated with the upregulation of several signaling pathways, including MAPK and AMPK. Conclusion: Our findings suggest that in pancreatic cancer, MAGEA6 recruits stress and growth factor- dependent MAPK and AMPK pathways to overcome glycolysis inhibition, even in glutamine- depleted conditions, providing a growth advantage. This implies that patients with MAGEA6- positive tumors may benefit from combination therapy targeting metabolism and signaling pathways. Citation Format: Sima Tozandehjani, Barbara Breznik, Klementina Fon Tacer, Miloš Vittori, Juan Sebastian Solano, Sara Uhan. MAGEA6 Oncogene Upregulates MAPK and AMPK Signaling Pathways in Pancreatic Cancer Cells to Promote Survival under Nutrient Stress: Resistance to Glycolysis Inhibition and Increased Susceptibility to Glutamine Depletion [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C035.

Putative Dual Roles of Bone Morphogenetic Protein 8B (BMP8B) in Disease Progression of Gastric Cancer.

Increased expression of bone morphogenetic protein 8B (BMP8B) in bone marrow and primary tumors of patients with gastric cancer (GC) is associated with disease progression and poor prognosis. However, a reduced expression has also been seen in GCs due to histone acetylation. This study aimed to evaluate BMP8B transcript levels in a large GC cohort and its impact on cellular functions. BMP8B transcripts were determined in 319 gastric tumors and compared with 182 adjacent normal tissues using real time PCR, with a further analysis conducted in the TCGA database. Kaplan-Meier plotter analysis was performed to evaluate the correlation between BMP8B and prognosis of the disease. BMP8B knockdown model was employed to determine the effect of BMP8B on the function of GC cells (HGC27). BMP8B mRNA levels were significantly up-regulated in the GC tissues compared with adjacent normal tissues in both TCGA database and our own database from Beijing Cancer Hospital, and high BMP8B expression was associated with poor prognosis. BMP8B is most likely to be involved in the differentiation of GC. Poorly differentiated GC samples presented a significantly reduced BMP8B expression in relation to well-differentiated and moderately differentiated GC. BMP8B knockdown inhibited proliferation of GC cells, while promoted invasion and migration of cancer cells. BMP8B was reduced in GCs, whereas higher BMP8B expression was associated with poor prognosis. BMP8B knockdown inhibited proliferation of GC cells, and promoted invasion and migration. Our results suggest that BMP8B plays dual roles in GC.

Tumor-agnostic cancer therapy using antibodies targeting oncofetal chondroitin sulfate

Molecular similarities between embryonic and malignant cells can be exploited to target tumors through specific signatures absent in healthy adult tissues. One such embryonic signature tumors express is oncofetal chondroitin sulfate (ofCS), which supports disease progression and dissemination in cancer. Here, we report the identification and characterization of phage display-derived antibody fragments recognizing two distinct ofCS epitopes. These antibody fragments show binding affinity to ofCS in the low nanomolar range across a broad selection of solid tumor types in vitro and in vivo with minimal binding to normal, inflamed, or benign tumor tissues. Anti-ofCS antibody drug conjugates and bispecific immune cell engagers based on these targeting moieties disrupt tumor progression in animal models of human and murine cancers. Thus, anti-ofCS antibody fragments hold promise for the development of broadly effective therapeutic and diagnostic applications targeting human malignancies.

Neutrophil-to-lymphocyte ratio as a predictor of progression in patients with early-stage cervical cancer

Aims: The neutrophil-to-lymphocyte ratio (NLR) has shown promise as a prognostic marker in various cancers, but its role in early-stage cervical cancer is not well defined. This study evaluates the association between pre-treatment NLR and progression risk in patients with early-stage cervical cancer. Methods: This retrospective study included 220 patients with stage I and II cervical cancer treated from 2010 to 2024. Patients with prior treatment, infection at diagnosis, or hematological diseases were excluded. Pre-treatment NLR was calculated from blood counts taken within a week before treatment. Primary outcome was progression-free survival (PFS). Cox regression analyses identified prognostic factors. Results: The median follow-up was 46 months (range, 1-120). Disease progression occurred in 17.3% of patients, and 15% died. The 5-year overall survival and PFS rates were 84.8% (95% CI: 79.3-90.3) and 77.7% (95% CI: 71.4-84), respectively. Univariate analysis identified non-squamous cell carcinoma (non-SCC) histology, tumor size >4 cm, and elevated NLR as significant factors affecting PFS. Multivariate analysis confirmed non-SCC histology (HR: 3.2, p=0.002), tumor size >4 cm (HR: 2.3, p=0.007), and elevated NLR (HR: 1.1, p=0.041) as independent PFS risk factors. Higher NLR correlated with larger tumor size. Conclusions: Elevated pre-treatment NLR independently predicts disease progression in early-stage cervical cancer. Incorporating NLR into risk stratification could enhance prognostic assessments and guide personalized treatments. Larger prospective studies are needed for validation.

Intermediate-based virtual screening of c-Kit kinase inhibitors as potential anti-tumor agents via ab inito folding, molecular dynamics simulation, and molecular docking

Uncontrolled activation of c-Kit is closely related to the pathogenesis and progression of leukemia, gastrointestinal cancer, and other malignant diseases. Although there are several inhibitors available, due to the limitation of selectivity and the unfavorable side effects, designing and discovering highly selective inhibitors targeting c-Kit kinase, especially the gain of function mutation (for example c-Kit D816V), is still necessary. To identify novel c-Kit inhibitors, a metastable state-based virtual screening approach, which was successfully implemented in other kinase inhibitors, was employed in the current study. The results from our current study demonstrated the residues adjacent to the DFG motif within the activation loop could fold into short α-helices aside from the random coil, which was commonly found in the crystal structure. By expanding the conformation pool of the activation loop via PyRosetta-based ab initio folding protocol, we constructed a series of structural models of the c-Kit kinase intermediate between the inactive and active states. After evaluation of the thermal stability of the metastable state with molecular dynamics simulation, one structural model showed higher stability of α-helix, and the activation loop was retained. Considering the wild-type and D816V mutated KIT kinase shared similar metastable states during the kinase activation process, we developed a hypothesis that the identified intermediate might hold the potential to identify inhibitors targeting D816V mutations from the compound database. As expected, the intermediate structure showed higher selectivity to KIT D816V selective inhibitors, such as bezuclastinib, avapritinib, BLU-263, and elenestinib, than imatinib or masitinib. The virtual screening of the available KIT kinase inhibitor database further identified vorolanib, semaxanib, henatinib, and pexmetinib may possess potential inhibitory effects against wild type, as well as the mutated c-Kit kinase. The results from our current study not only proposed a novel structural model that could be used for the identification of selective c-Kit D816V inhibitors but also identified several potential inhibitors from available kinase inhibitors, which might shed new light on the design of new therapeutic approaches for c-Kit mutation-driven malignant diseases.

Implication of Capillary Morphogenesis Gene 2 (CMG2) in the Disease Progression and Peritoneal Metastasis of Pancreatic Cancer.

Capillary morphogenesis gene 2 (CMG2) mediates cell-matrix interactions to facilitate cell adhesion and migration. CMG2 has been implicated in the disease progression of breast cancer, prostate cancer and gastric cancer. The present study aims to determine the role of CMG2 in the disease progression and peritoneal metastasis of pancreatic cancer. Pancreatic tumour samples were collected from Peking University Cancer Hospital. CMG2 expression was determined using quantitative PCR. After the creation of knockdown and overexpression of CMG2 in pancreatic cancer cells, the effect of CMG2 on several cell functions and adhesion to the peritoneum was examined. Potential pathways regulated by CMG2 were found via proteomics analysis and drug tests. CMG2 was upregulated in pancreatic cancer tissues and associated with a poor prognosis. CMG2 was increased in metastatic lesions and those primary tumours with distant metastases. CMG2 promotes cell-cell, cell-matrix and cell-hyaluronic acid adhesion, which may be mediated by epidermal growth factor receptor (EGFR) and focal adhesion kinase (FAK) pathway activation.

Activating Transcription Factor 5; A Potential Prognostic Molecular Biomarker for Cervical Cancer (CC)

Background: Prognostic biomarkers with high sensitivity and specificity that accurately predict disease prognosis are crucial for influencing cancer patients' treatment and disease progression choices. This research attempts to determine ATF5's cervical cancer prognostic value and find a theoretical basis for cervical cancer treatment. Method: This study began with a survival analysis, then univariate and multivariate analyses using transcriptomics, methylation, and TCGA ATF5 clinical data. Second, ATF5's role in cervical cancer development was explored using GO, KEGG, and TIMER databases. We assessed ATF5's cervical cancer treatment potential using CMap, a drug development tool. Results: After conducting several analyses, we discovered that high levels of ATF5 mRNA expression and low levels of methylation were beneficial for patients with cervical cancer prognosis. An important finding is that ATF5 may promote apoptosis in cervical carcinoma cells. In addition, we assessed the therapeutic potential of four small molecules against cervical cancer. ATF 5 function as a tumor suppressor gene in cervical cancer has been demonstrated for the first time using numerous databases and bioinformatics techniques from multiple dimensions, which is a novel aspect of this research. Moreover, the finding that ATF5 is a biomarker that can contribute to the apoptosis of cervical cancer cells and predict a favorable prognosis for the disease was an additional innovation. In the future, ATF5 can be used as a therapeutic target and to develop anti-cancer medications.

Toward Smart Ultrasound Image Augmentation to Advance Tumor Treatment Monitoring: Exploring the Potential of Diffusion Generative Model

Abstract Medical imaging is a crucial tool in clinics to monitor tumor treatment progress. In practice, many imaging tools (such as magnetic resonance imaging (MRI) and computed tomography (CT) scans) are in general costly and may also expose patients to radiation, leading to potential side effects. Recent studies have demonstrated that ultrasound imaging, which is safe, low-cost, and easy to access, can monitor the drug delivery progress in solid tumors. However, the noisy nature of ultrasound images and the high-level uncertainty of cancer disease progression are still challenging in ultrasound-based tumor treatment monitoring. To overcome these barriers, this work presents a comparative study to explore the potential advantages of the emerging diffusion generative models against the commonly applied state-of-the-art generative models. Namely, the denoising diffusion models (DDMs), against the generative adversarial networks (GAN), and variational auto-encoders (VAE), are used for analyzing the ultrasound images through image augmentation. These models are evaluated based on their capacity to augment ultrasound images for exploring the potential variations of tumor treatment monitoring. The results across different cases indicate that the denoising diffusion implicit models (DDIM)/kernel inception distance (KID)-inception score (IS) model leveraged in this work outperforms the other models in the study in terms of similarity, diversity, and predictive accuracy. Therefore, further investigation of such diffusion generative models could be considered as they can potentially serve as a great predictive tool for ultrasound image-enabled tumor treatment monitoring in the future.

Discovery of Novel Imidazo[1,2-a]pyridine-Based HDAC6 Inhibitors as an Anticarcinogen with a Cardioprotective Effect.

Cardiotoxicity associated with chemotherapy has gradually become the major cause of death in cancer patients. The development of bifunctional drugs with both cardioprotective and antitumor effects has become the future direction. HDAC6 plays important roles in the progression, treatment, and prognosis of cancer and cardiovascular diseases, but bifunctional inhibitors have not been reported. Herein, structure-activity relationship studies driven by pharmacophore-based remodification and fragment-based design were performed to yield highly potent HDAC6 inhibitor I-c4 containing imidazo[1,2-a]pyridine. Importantly, I-c4 effectively suppressed the growth of MGC-803 xenografts in vitro and in vivo by inhibiting the deacetylation pathway without causing myocardial damage after long-term administration. Meanwhile, I-c4 could mitigate severe myocardial damage against H2O2 or myocardial ischemia/reperfusion in vitro and in vivo. Further studies revealed that the cardioprotective effect of I-c4 was associated with reduction of inflammatory cytokines. Taken together, I-c4 may represent a novel lead compound for further development of an anticarcinogen with a cardioprotective effect.

Phenotypic Plasticity and Cancer: A System Biology Perspective.

Epithelial-to-mesenchymal transition (EMT) is a major axis of phenotypic plasticity not only in diseased conditions such as cancer metastasis and fibrosis but also during normal development and wound healing. Yet-another important axis of plasticity with metastatic implications includes the cancer stem cell (CSCs) and non-CSC transitions. However, in both processes, epithelial (E) and mesenchymal (M) phenotypes are not merely binary states. Cancer cells acquire a spectrum of phenotypes with traits, properties, and markers of both E and M phenotypes, giving rise to intermediary hybrid (E/M) phenotypes. E/M cells play an important role in tumor initiation, metastasis, and disease progression in multiple cancers. Furthermore, the hybrid phenotypes also play a major role in causing therapeutic resistance in cancer. Here, we discuss how a systems biology perspective on the problem, which is implicit in the 'Team Medicine' approach outlined in the theme of this Special Issue of The Journal of Clinical Medicine and includes an interdisciplinary team of experts, is more likely to shed new light on EMT in cancer and help us to identify novel therapeutics and strategies to target phenotypic plasticity in cancer.

The Role of the PI3K/Akt/mTOR Axis in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies globally, representing a significant public health problem with a poor prognosis. The development of efficient therapeutic strategies for HNSCC prevention and treatment is urgently needed. The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved transduction network in eukaryotic cells that promotes cell survival, growth, and cycle progression. Dysfunction in components of this pathway, such as hyperactivity of PI3K, loss of PTEN function, and gain-of-function mutations in AKT, are well-known drivers of treatment resistance and disease progression in cancer. In this review, we discuss the major mutations and dysregulations in the PAM signaling pathway in HNSCC. We highlight the results of clinical trials involving inhibitors targeting the PAM signaling pathway as a strategy for treating HNSCC. Additionally, we examine the primary mechanisms of resistance to drugs targeting the PAM pathway and potential therapeutic strategies.

Comparative Analysis of Breast Cancer Metabolomes Highlights Fascin's Central Role in Regulating Key Pathways Related to Disease Progression.

Omics technologies provide useful tools for the identification of novel biomarkers in many diseases, including breast cancer, which is the most diagnosed cancer in women worldwide. We and others have reported a central role for the actin-bundling protein (fascin) in regulating breast cancer disease progression at different levels. However, whether fascin expression promotes metabolic molecules that could predict disease progression has not been fully elucidated. Here, fascin expression was manipulated via knockdown (fascinKD+NORF) and rescue (fascinKD+FORF) in the naturally fascin-positive (fascinpos+NORF) MDA-MB-231 breast cancer cells. Whether fascin dysregulates metabolic profiles that are associated with disease progression was assessed using untargeted metabolomics analyses via liquid chromatography-mass spectrometry. Overall, 12,226 metabolic features were detected in the tested cell pellets. Fascinpos+NORF cell pellets showed 2510 and 3804 significantly dysregulated metabolites compared to their fascinKD+NORF counterparts. Fascin rescue (fascinKD+FORF) revealed 2710 significantly dysregulated cellular metabolites compared to fascinKD+NORF counterparts. A total of 101 overlapped cellular metabolites between fascinKD+FORF and fascinpos+NORF were significantly dysregulated in the fascinKD+NORF cells. Analysis of the significantly dysregulated metabolites by fascin expression revealed their involvement in the metabolism of sphingolipid, phenylalanine, tyrosine, and tryptophan biosynthesis, and pantothenate and CoA biosynthesis, which are critical pathways for breast cancer progression. Our findings of fascin-mediated alteration of metabolic pathways could be used as putative poor prognostic biomarkers and highlight other underlying mechanisms of fascin contribution to breast cancer progression.

Clinical significance of circulating tumor cells in colorectal cancer with peritoneal metastases: a prospective cohort study using a novel method for monitoring treatment response, and assessing minimal residual disease.

The treatment for patients with colorectal cancer with metastases to the peritoneum is complex and may involve both surgery and chemotherapy. Circulating tumor cells (CTCs) have been poorly investigated in peritoneal metastatic colorectal cancer. The aim of the study is to examine the role of circulating tumor cells (CTCs) as a biomarker for monitoring disease progression, treatment response and residual disease using CellMate® - a new promising in vitro diagnostic platform technology. We prospectively followed clinical outcomes of 46 patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer with peritoneal metastases and examined whether CTCs were present the week of surgery. The CTC measurements were made with the CellMate® technology, which is a platform technology to detect CTCs based on the difference in biomechanical properties compared to blood resident cells. The study was registered online (ClinicalTrials.gov). CTCs were detected in 17 (37%) patients. The presence of CTCs was associated with shorter recurrence-free survival and overall survival after CRS and HIPEC. Both recurrence free survival (HR 4.00, 95%CI 1.15-13.9; P=0.029) and overall survival (HR 5.91; 95% CI 1.18-29.7; P=0.03) were significantly worse if CTCs were detected after neoadjuvant treatment. In the subgroup of patients with CTCs detected, adjuvant therapy tended to improve the prognosis while in CTC negative patients it did not. Pending a prospective multi-center trial to validate these findings, CTCs may in the future be used as a dynamic personalized biomarker for prognostication, predicting response to therapy, and for monitoring disease progression in colorectal cancer with metastases to the peritoneum.

Diamond-based quantum sensing of free radicals in migrating human breast cancer cells

Cell migration is a crucial parameter for disease progression in cancer. Reactive oxygen species (ROS) levels are involved in the regulation of the migration process, however, the exact role of free radical generation and where it occurs is unknown. Here we use a diamond-based quantum sensing technique to detect free radicals during cancer cell migration in real time with subcellular resolution. We investigated metastatic MDA-MB-231 human breast cancer cells and observed free radical formation after 16 h of starvation and 24 h of migration under low-serum conditions. Intracellular diamond dynamics were monitored at different migration points (0, 12, and 24 h), and cell morphology was evaluated. Additionally, the number of focal adhesions was analyzed as an indicator of the migratory potential of the cells. We further measured free radical generation under nicotinamide adenine dinucleotide phosphate hydrogen NADPH oxidases 2 (NOX2) inhibition by apocynin. We found that free radical levels decreased after 24 h treatment with 36 μg/mL apocynin while the levels of ROS and the migratory capacity of the cells increased. Our results evidence the complexity of the redox regulation in migrating cancer cells and offer a novel approach to specifically and locally interrogate pivotal players of the oxidative network behind metastatic success.

SAFETY ASSESSMENT OF A RANGE OF PLANT METABOLIC TOVES – ADVANCED GEROPROTECTORS IN VIVO RESEARCH

Background. Ageing is associated with progressive impairment of physical functions and increased risk of age-related chronic diseases. Polyphenols such as mangiferin, quercetin and trans-cinnamic acid are also used for the treatment and prevention of chronic diseases. Toxicological research was important in biomedical research, as some high-dose extracted polyphenols could contribute to the development and progression of cancer and other diseases. This study is aimed at assessing toxicological safety of previously isolated phenolic compounds from plants of the Siberian Federal District. Materials and methods. Rodents have been chosen as the model organism. The study of mutagenic and antimutagenic properties was carried out using a micronuclear test of bone marrow cell. Cytotoxicity in vitro was assessed using the MTT test. Results. Polyphenols studied at doses of 50.0 and 100.0 mg/kg are not mutagenic. Mangiferri and quercetin at a dose of 50.0 mg/kg do not have anti-thagenic effects. In this case, trans-cinnamic acid in the same concentration has antimutagenic effect. Mangiferin in concentrates from 4.2 to 16.7 ug/ml has a cytotoxic effect. Trans-cinnamic acid is not cytotoxic (at 2.1-33.3 ug/ml). Quercetin has a cytotoxic effect in concentrations of 0.21 and 1.67 ug/ml, and at concentrations of 3.33 ug/ml increases the viability of splenocytes, presumably due to antioxidant properties. Conclusion. Safety or low toxicity is a decisive advantage of the continued use of polyphenols as advanced heroic flow agents. Further study of biologically active substances (mangiferin, quercetin and trans-cinnamic acid) has been found to be ce-woody. The work was carried out by the state task on the topic «Development of biologically active additives consisting of metabolites of plant objects in vitro to protect the population from premature aging» (project FZSR-2024-0008) using the equipment of Center of Collective Use «Instrumental methods of analysis in the field of applied biotechnology» on the basis of KemSU.

Correlation Analysis of Genetic Mutations and Galectin Levels in Breast Cancer Patients.

Galectins are innate immune system regulators associated with disease progression in cancer. This paper aims to investigate the correlation between mutated cancer-critical genes and galectin levels in breast cancer patients to determine whether galectins and genetic profiles can be used as biomarkers for disease and potential therapy targets. Prisma Health Cancer Institute's Biorepository provided seventy-one breast cancer samples, including all four stages spanning the major molecular subtypes and histologies. Hotspot mutation statuses of cancer-critical genes were determined using multiplex PCR in tumor samples from the same patients by Precision Genetics and the University of South Carolina Functional Genomics Core Facility. The galectin-1, -3, and -9 levels in patients' sera were analyzed using Enzyme-linked Immunosorbent Assay (ELISA). An analysis was performed using JMP software to compare mean and median serum galectin levels between samples with and without specific cancer-critical genes, including pooled t-test, Wilcoxon Rank Sum Test, ANOVA, and Steel Dwass Test (α=0.05). Our analysis indicates that KIT mutations correlate with elevated serum levels of galectin-9 in patients with breast cancer. In patients with Luminal A subtype, FLT3 mutation correlates with lower serum galectin-1 and -9 levels and TP53 mutations correlate with higher serum galectin-3 levels. Patients with invasive ductal carcinoma had significantly higher serum galectin-3 levels than patients with ductal carcinoma in situ. Patients with both TP53 and PIK3CA mutations exhibit elevated serum galectin-3 levels, while patients with one or neither mutation show no significant difference in serum galectin-3 levels. In addition, metastatic breast cancer samples were more likely to have a KIT or PIK3CA mutation compared to primary breast cancer samples. The relationship between genetic mutations and galectin levels has the potential to identify appropriate candidates for combined therapy, targeting genetic mutations and galectins. Further understanding of the effect of genetic mutations and galectin levels on cancer progression and metastasis could aid in the search for biomarkers for breast cancer diagnosis, disease progression, and prognosis.

Prediction of peritoneal free cancer cells in gastric cancer patients by golden-angle radial sampling dynamic contrast-enhanced magnetic resonance imaging.

Peritoneal free cancer cells can negatively impact disease progression and patient outcomes in gastric cancer. This study aimed to investigate the feasibility of using golden-angle radial sampling dynamic contrast-enhanced magnetic resonance imaging (GRASP DCE-MRI) to predict the presence of peritoneal free cancer cells in gastric cancer patients. All enrolled patients were consecutively divided into analysis and validation groups. Preoperative magnetic resonance imaging (MRI) scans and perfusion were performed in patients with gastric cancer undergoing surgery, and peritoneal lavage specimens were collected for examination. Based on the peritoneal lavage cytology (PLC) results, patients were divided into negative and positive lavage fluid groups. The data collected included clinical and MR information. A nomogram prediction model was constructed to predict the positive rate of peritoneal lavage fluid, and the validity of the model was verified based on data from the verification group. There was no statistical difference between the proportion of PLC-positive cases predicted by GRASP DCE-MR and the actual PLC test. MR tumor stage, tumor thickness, and perfusion parameter Tofts-Ketty model volume transfer constant (Ktrans) were independent predictors of positive peritoneal lavage fluid. The nomogram model featured a concordance index (C-index) of 0.785 and 0.742 for the modeling and validation groups, respectively. GRASP DCE-MR could effectively predict peritoneal free cancer cells in gastric cancer patients. The nomogram model constructed using these predictors may help clinicians to better predict the risk of peritoneal free cancer cells being present in gastric cancer patients.

Use of Gynecologic Cancer Intergroup (GCIG) CA125 criteria to evaluate cell cycle checkpoint kinase 1 inhibitor (CHK1i) prexasertib response and disease progression (PD) in recurrent high-grade serous ovarian cancer (HGSOC).

e17536 Background: Data suggest discordance between serum biomarker CA125 and Response Evaluation Criteria in Solid Tumors (RECIST) response and/or PD in chemotherapies and PARP inhibitors. Here, we investigated the impact of CA125 on prognosis and its relationship with RECIST response/PD in HGSOC patients treated with a CHK1i, prexasertib. Methods: All relapsed HGSOC patients in this post-hoc analysis were treated with prexasertib at 105 mg/m2 IV every 14 days in a 28-day cycle until RECIST v1.1 PD, unacceptable toxicity, or consent withdrawal (NCT02203513). CA125 was assessed every cycle and CT scans obtained every two cycles. GCIG CA125 response was defined as >50% reduction confirmed after 28 days and PD as > 2X upper limit of normal (ULN) if baseline was normal or doubling of nadir if baseline was elevated. Patients with baseline CA125 < 2X ULN or nadir > 750 units/mL were not eligible for analysis. Clinical benefit rate (CBR; CR + PR + SD ≥ 6 months) was analyzed by Fisher’s exact test. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier curves and univariate (UV) and multivariate (MV) hazard ratios by Cox regression models. Positive predictive value (PPV) and negative predictive value (NPV) confidence intervals (CI) were estimated by the Wilson-Brown method. Results: Eighty-one patients received at least two cycles of prexasertib between January 2015 and November 2020, out of which 72 were evaluable by both RECIST and GCIG CA125 response criteria. CBR in the CA125 response (CA125-R) group (24/32; 75%) was significantly higher than the CA125 non-responder (CA125-N) group (12/40; 30%; p<0.001). CA125 response tended to occur prior to RECIST response (median: 28 days; IQR: 28, 30). PFS was improved in CA125-R at 8.0 months vs. CA125-N at 3.5 months (UV HR: 0.34, 95% CI: 0.21-0.56; MV HR: 0.35, 95% CI: 0.20-0.59). OS was improved in CA125-R at 19.8 months vs. CA125-N at 10.3 months (HR: 0.43, 95% CI: 0.26-0.71; MV HR: 0.45, 95% CI: 0.27-0.75). No significant differences in PFS or OS were observed between subgroups by BRCA mutation status, platinum-sensitivity, FIGO stage, baseline CA125 value, or previous PARP inhibitor therapy in MV analysis. Out of 70 patients evaluable by RECIST and CA125 PD criteria, 43 patients had CA125 PD and 24 of those had RECIST PD occur within one cycle of CA125 PD (PPV: 59%; 95% CI: 43-72). Of the 27 patients without a CA125 PD, 9 patients also did not have a RECIST PD (NPV: 33%; 95% CI: 19-52). Conclusions: GCIG CA125 response is an independent predictor of response to CHK1i in HGSOC prior to the first restaging scans and is associated with a higher CBR and improved PFS and OS. However, GCIG CA125 PD has poor PPV and NPV within a one cycle window, indicating that CA125 alone is not sufficient in monitoring for PD in HGSOC treated with CHK1i.

METRADS-P vs. RECIST/PCWG criteria to detect disease progression in metastatic castration-resistant prostate cancer (mCRPC).

5070 Background: Radiographic Progression-free survival (rPFS) derived from Computer Tomography (CT) and Bone Scan (BS) using Prostate Cancer Working Group (PCWG) criteria is utilized as an intermediate clinical endpoint for overall survival (OS) benefit in mCRPC. Whole Body MRI (WBMRI) is emerging as a potentially superior response biomarker, allowing a more accurate assessment of bone marrow and soft tissue disease. We have now compared the performance of previously reported WBMRI criteria (MET-RADS-P) with PCWG criteria as a response biomarker for mCRPC, and this with overall survival (OS). Methods: We retrospectively analysed imaging data from mCRPC patients that 1) discontinued therapy based on PCWG criteria; 2) had contemporaneous WBMRI, CT, and BS at time-points according to PCWG. Soft tissue lesions were classified according to RECIST1.1 both on CT and WBMRI; bone lesions were classified on BS using PCWG criteria as non-PD (non-progressive disease), PD-U (PD unknown) & PD (progressive disease) and on WBMRI using MET-RADS-P as non–PD (subclassified as partial response-PR & stable disease-SD) & PD, for each imaging time-point. We calculated % agreement between MET-RADS-P and PCWG across all time-points. Median PFS as per PCWG (rPFS) and METRADS-P (mPFS) and median OS according to METRADS-P response at 12 weeks was estimated by Kaplan Meier. Results: 100 cases (91 subjects received 100 lines of treatment, 100 baseline imaging & 216 follow-up imaging assessments). For soft tissue disease, RECIST 1.1 and WBMRI assessments were concordant at 201 of 216 time-points (93.1%); the discordance was related to superior detection of local disease and liver metastases on WBMRI. Bone metastases assessments showed agreement in 37.5% time-points, with details as follows (% over BS category): 1) Negative BS (13 time-points): WBMRI 69.2% negative, 15.4% PR, 15.4% as PD; 2) Non-PD BS (154 time-points): WBMRI non-PD 51% (34.4% PR, 17.5% SD), 48.1% PD; 3) PD-U BS (40 time-points): WBMRI PD 90%; Non-PD 10% (1pt FLARE & 3pt with subsequent concordant PD). At time of PD-U, 30 out of 40 pt (75%) discontinued treatment due to RECIST PD (24/40) & clinical progression (6/40). 4) PD confirmatory BS (9 time-points) : WBMRI 100%PD. Median rPFS by PCWG was 4.9 months (m) (95%CI: 3.8-5.7); the median mPFS by MET-RADS-P was 2.8 months (2.6-3.9), with overall progression rate of 70% and 94% respectively. Non-PD by WBMRI at 12-weeks associated with longer OS when compared with PD by MRI (median OS: 17.9m (14.2-22.6) vs 14.4m (9.6-17.0) (crude log-rank test 0.0059). Conclusions: Regarding soft-tissue disease, MET-RADS-P detects progression earlier than RECIST in 4.2% time-points, while for bone metastases it detects progression earlier than PCWG at 51.9% of timepoints. WBMRI can better classify BS non-PD patients in PR, SD and PD. Response evaluation based on WBMRI is a prognostic factor in mCRPC.

Hyaluronic Acid Interacting Molecules Mediated Crosstalk between Cancer Cells and Microenvironment from Primary Tumour to Distant Metastasis.

Hyaluronic acid (HA) is a prominent component of the extracellular matrix, and its interactions with HA-interacting molecules (HAIMs) play a critical role in cancer development and disease progression. This review explores the multifaceted role of HAIMs in the context of cancer, focusing on their influence on disease progression by dissecting relevant cellular and molecular mechanisms in tumour cells and the tumour microenvironment. Cancer progression can be profoundly affected by the interactions between HA and HAIMs. They modulate critical processes such as cell adhesion, migration, invasion, and proliferation. The TME serves as a dynamic platform in which HAIMs contribute to the formation of a unique niche. The resulting changes in HA composition profoundly influence the biophysical properties of the TME. These modifications in the TME, in conjunction with HAIMs, impact angiogenesis, immune cell recruitment, and immune evasion. Therefore, understanding the intricate interplay between HAIMs and HA within the cancer context is essential for developing novel therapeutic strategies. Targeting these interactions offers promising avenues for cancer treatment, as they hold the potential to disrupt critical aspects of disease progression and the TME. Further research in this field is imperative for advancing our knowledge and the treatment of cancer.