Treatment Of Colorectal Cancer Research Articles

Redefining Therapeutic Approaches in Colorectal Cancer: Targeting Molecular Pathways and Overcoming Resistance.

Colorectal cancer (CRC) arises through a combination of genetic and epigenetic alterations that affect key pathways involved in tumor growth and progression. This review examines the major molecular pathways driving CRC, including Chromosomal Instability (CIN), Microsatellite Instability (MSI), and the CpG Island Methylator Phenotype (CIMP). Key mutations in genes such as APC, KRAS, NRAS, BRAF, and TP53 activate signaling pathways like Wnt, EGFR, and PI3K/AKT, contributing to tumorigenesis and influencing responses to targeted therapies. Resistance mechanisms, including mutations that bypass drug action, remain challenging in CRC treatment. This review highlights the role of molecular profiling in guiding the use of targeted therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. Novel combination treatments are also discussed as strategies to improve outcomes and overcome resistance. Understanding these molecular mechanisms is critical to advancing personalized treatment approaches in CRC and improving patient prognosis.

Potential Utility of A Proliferation-Inducing Ligand (APRIL) in Colorectal Cancer.

APRIL (A proliferation-inducing ligand) is a member of the tumor necrosis factor superfamily that is overexpressed in a variety of malignant tumors, including colorectal cancer (CRC). Its key physiological roles include inducing the immunoglobulin switch and ensuring plasmocyte survival. In terms of pathological roles, APRIL antagonism has been identified as a key target in autoimmune diseases and immunoglobulin disorders. As previously demonstrated, several inflammatory processes occur at the site of neoplastic initial stages, and their local symptoms are difficult to detect, particularly in the early stages. That is why we chose to study the current literature on APRIL's role in the development of colorectal cancer. The main objective of our research was to investigate the role of APRIL in cancer initiation and its usefulness in the detection and therapy of CRC. Interestingly, the findings conducted so far show that the selected protein has a significant potential as a CRC biomarker and treatment target. Importantly, based on its concentration, it is possible to identify CRC patients, but whether the lesion has a benign or malignant nature, indicating the possibility of rapid detection of an ongoing disease process.

The impact of diet-induced obesity on 5 fluorouracil-induced tumor and liver immune cell cytotoxicity.

Obesity increases the risk for developing several cancers, including colorectal cancer (CRC), and is associated with liver perturbations, which likely impacts treatment tolerance. 5 fluorouracil (5FU) remains a first line treatment for CRC, but efficacy is hampered by interpatient variable responsiveness and off-target toxicities. The current study examined the impact of diet-induced obesity (DIO) on 5FU cytopenia and efficacy using two established CRC models: MC38 (C57BL/6) and C26 (CD2F1). DIO increased tumor size in both MC38 and C26. DIO reduced liver dihydropyrimidine dehydrogenase (dpyd) expression, the enzyme that catalyzes 5FU's catabolism to become inactive, in MC38 mice, but not in C26. 5FU remained efficacious against early MC38 and C26 tumor growth; however, 5FU-induced tumor and liver immune cell death was exacerbated following three cycles of 5FU with MC38. DIO caused dramatic changes to liver Kupffer cells (KCs), wherein there were increased prometastatic, immunosuppressive KCs in Obese Control and MC38. 5FU, however, depleted these KCs and increased inflammatory KCs in both Lean and Obese MC38. DIO yielded a milder obesity phenotype in CD2F1 mice, and 5FU-induced cytopenia was not different between Lean and Obese. DIO increased total liver KCs; however, C26 tumors increased liver KCs, which were normalized with 5FU treatment, irrespective of DIO. Although 5FU remained efficacious in both models of CRC and did not reduce survival, multiple cycles of 5FU monotherapy increased liver and tumor immune cell death in DIO mice. Altogether, obesity was not protective but rather exacerbated chemotherapy-induced cytotoxicity and promoted a prometastatic liver environment.NEW & NOTEWORTHY The current study aimed to examine the impact of obesity on tumorigenesis and 5FU safety and efficacy with two established murine models of colorectal cancer. Diet-induced obesity increased tumor burden in both models, and 5FU's antitumor efficacy remained and extended survival with both tumor models. Obese mice demonstrated increased 5FU-induced immune cell cytotoxicity following multiple cycles of 5FU with distinct changes to liver macrophages, suggesting an increased propensity for liver metastasis.

Green hydrothermal synthesis of gallic acid carbon dots: characterization and cytotoxic effects on colorectal cancer cell line

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths worldwide, necessitating the development of novel therapeutic approaches. Carbon dots (CDs) have emerged as promising nanoparticles for biomedical applications due to their unique properties. Gallic acid (GA), an anticancer agent, is effective against various tumor types. This study explores the potential of gallic acid-derived carbon dots (GA-CDs) as an innovative anticancer agent against HCT-116 CRC cells, focusing on apoptosis signaling pathways. GA-CDs were synthesized using a one-pot hydrothermal method. Characterization was conducted using transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy, and ultraviolet-visible (UV-vis) absorption spectroscopy. The cytotoxicity of GA and GA-CDs on HCT-116 cells was evaluated using the MTT assay at various concentrations over 24 and 48 h. Cellular uptake was assessed via fluorescence microscopy, and apoptosis was analyzed using acridine orange/propidium iodide (AO/PI) staining. Total RNA extraction followed by complementary DNA (cDNA) synthesis via reverse transcription-PCR was performed, and real time-PCR (Q-PCR) was conducted to examine the expression of apoptosis-related genes includingCaspase-3,Bax, andBcl-2. Characterization confirmed the successful synthesis of spherical GA-CDs. GA-CDs exhibited dose- and time-dependent cytotoxicity, with IC50 values of 88.55 μg ml-1for GA-CDs and 192.2 μg ml-1for GA after 24 h. Fluorescence microscopy confirmed the efficient uptake of GA-CDs by HCT-116 cells. AO/PI staining showed a significant increase in apoptotic cell numbers after treatment with GA-CDs. Q-PCR analysis revealed overexpression ofCaspase-3 andBaxgenes in GA-CD-treated cells, though no significant changes were observed in the expression ofBcl-2 or theBax/Bcl-2 ratio. GA-CDs demonstrated potent anticancer properties by inducing apoptosis and reducing cell viability in HCT-116 cells. These findings suggest the potential of GA-CDs as a novel therapeutic agent for CRC treatment, warranting further investigation into their mechanism of action andin vivoefficacy.

Increased potentiation of 5-fluorouracil induced thymidylate synthase inhibition by 5,10-methylenetetrahydrofolate (arfolitixorin) compared to leucovorin in patients with colorectal liver metastases; The Modelle-001 Trial

Background5-Fluorouracil (5-FU) is a cornerstone in treatment of colorectal cancer (CRC) and is usually combined with leucovorin (LV) to enhance the antitumour effect by increase thymidylate synthase (TS) inhibition, the key target enzyme for 5-FU. Arfolitixorin (Arfo) is an active form of the reduced folate, [6 R]-5,10-methylenetetrahydrofolate ([6 R]-MeTHF and in contrast to LV, does not need to be metabolized. The Modelle-001 was designed to explore whether a single intravenous bolus injection of Arfo as compared to LV, together with 5-FU increases the inhibition of TS, levels of folate concentrations and polyglutamylation in CRC liver metastases (CRLM) and liver parenchyma.Patients and methodsThirty patients with CRLM received either LV (60 mg/m2) or Arfo (30 mg/m2 or 120 mg/m2) in combination with 5-FU preoperatively. Levels of folates and and TS inhibition were measured.ResultsSignificantly higher MeTHF levels and higher TS inhibition were measured in the Arfo groups compared to LV60, and there was a difference in folate poly-glutamylation between the groups.ConclusionThe Modelle-001 Trial demonstrated significantly higher levels of MeTHF in metastases following Arfo compared to LV. This resulted in a greater increase TS inhibition in metastases although not statistically significant.

Combining in silico and in vitro approaches for understanding the mechanism of action of the galactomannan extracted from Cassia grandis seeds against colorectal cancer

This study aimed to investigate the antitumor activity of galactomannan extracted from Cassia grandis seeds (GCg) against colorectal cancer cells using both experimental and computational approaches. Galactomannan was extracted from C. grandis seeds and prepared into solutions with varying concentrations. The cytotoxicity of these solutions was tested on HT-29 and HCT-116 colorectal cancer cell lines using the MTT assay. Additionally, computational evaluations, including molecular docking and molecular dynamics simulations, were performed to explore the potential binding interactions of GCg with cyclin-dependent kinase 2 (CDK2). The experimental results demonstrated that GCg significantly inhibited the proliferation of HT-29 cells, especially at concentrations of 5 mg/mL. On the other hand, no concentration inhibited >30 % of HCT-116 cells. Computational analysis revealed that GCg could bind to the ATP-binding site of CDK2, promoting the inactive DFG-out conformation, similar to the known inhibitor K03861. This interaction suggests a mechanism through which GCg may exert its anticancer effects. GCg exhibits significant cytotoxic activity against HT-29 colorectal adenocarcinoma cells, likely through the inhibition of CDK2; however, its efficacy against HCT-116 cells is limited, possibly due to structural differences in the molecular targets. To the best of the authors' knowledge, no studies have explored the applications of GCg in cancers, particularly colorectal ones. Further studies are needed to explore the antimetastatic effects and potential clinical applications of GCg in colorectal cancer treatment.

Differences in the epidemiology and survival of patients with colorectal cancer between China and the United States: a large cross-sectional study.

Studying the epidemiological and management characteristics of colorectal cancer (CRC) between China and the US has important implications. The present cross-sectional study included patients from SEER and Southwest China Colorectal (SCC) databases. Incidence, treatment and survival information were compared between two countries.86859 patients in the SEER database and 5838 patients in the SCC database were included. The estimated incidence of CRC in the US was greater than that in China from 2006 to 2019. The most common tumor sites of CRC patients in China were the RSC (66.5%), RCC (20.2%) and LCC (13.3%), while those in the US were the RCC (44.4%), RSC (29.8%) and LCC (25.8%). Chinese CRC patients were more likely to be male (58.9% vs 52.4%, p < 0.001), have a greater stage II CRC rate (49.8% vs 27.8%, p < 0.001), younger age at diagnosis (median 64 vs 66years, p < 0.001). Radical surgery rates were lower in Chinese RCC (92.3% vs 93.9%, p < 0.001) and LCC (88.9% vs 92.0%, p < 0.001) patients. The adjuvant therapy rates were lower in Chinese CRC patients. The 5-year overall survival rates were 71.8% and 78.2% for Chinese and US CRC patients, respectively (p < 0.001).China is undergoing an increasing incidence of CRC. The treatment and mortality of CRC differ in China and US populations. China had a lower adjuvant therapy rate and a lower 5-year OS rate compared with the US.

Resection of Early Colorectal Neoplasms Using Endoscopic Submucosal Dissection: A Retrospective Multicenter Cohort Study.

Background: Endoscopic submucosal dissection (ESD) is a reliable method that can replace surgery in the treatment of early colorectal cancer under certain conditions. Aim: The aim of the study was to analyze factors influencing the ESD procedure in early colorectal cancer, with the intention of improving its effectiveness. Patients and Methods: We conducted a multicenter, retrospective cohort study on 214 patients who underwent ESD procedures for early colorectal cancer from January 2016 to October 2023. Results:En bloc resection was achieved in 197 (92.1%) of ESD procedures, R0 resection in 149 (69.6%), and curative resection in 54 (40.9%). The submucosal invasion was classified as level 1 (SM1) in 96 cases (45.3%), level 2 (SM2) in 61 cases (28.8%), and level 3 (SM3) in 36 cases (17%). R0 resection was achieved more often in the rectum-92 (81.4%), compared to the right-24 (64.9%) and left colon-33 (61.1%), p = 0.009. In rectal tumors, R0 resection was achieved in 51 (98.1%) SM1 invasion, 27 (73%) SM2 invasion, and 13 (65%) SM3 invasion (p < 0.001). Lateral and vertical resection margins were positive in 12 (7.7%) and 52 (25.2%) cases, respectively. Vertical resection margins were statistically more often positive in lesions located in the right colon-11 cases (28.9%) and left colon-21 cases (38.9%), than in rectum-20 cases (17.5%); p = 0.010. Complications were found in 32 (15%) cases of ESD procedure-perforation in 12 cases (5.6%) and delayed bleeding in four cases (1.9%). Procedures performed in the right colon were associated with a significantly higher risk of any complications (30%) and perforations (15%) than those performed in the rectum (10.3% and 2.6%) or the left colon (13.8% and 5.2%; p = 0.016; p = 0.015), respectively. Conclusions: ESD for early colon cancer is a viable strategy due to its effectiveness and low complication rate. The ESD technique performed in the rectum yields the best results; however, in the right colon, it still requires careful attention.

Prognostic Value of Baseline Skeletal Muscle Index in Colorectal Cancer Patients Treated with Fruquintinib: A multi-center real world analysis

BackgroundThe Skeletal Muscle Index (SMI) serves as an objective metric for assessing nutritional status in patients with malignant tumors. Research has found baseline nutritional status can influence both the efficacy and prognosis of targeted anti-tumor therapies, with growth factor tyrosine kinase inhibitors frequently inducing drug-related sarcopenia. Fruquintinib has received approval for the treatment of metastatic colorectal cancer. This study examines the prognostic significance of baseline SMI in patients with metastatic colorectal cancer undergoing treatment with fruquintinib. Additionally, the study investigates the incidence of SMI reduction following fruquintinib therapy to assess its impact on patient prognosis.MethodsA retrospective multicenter study was conducted to analyze patients with metastatic colorectal cancer who received fruquintinib treatment across eight medical centers in Eastern China. The muscle area at the third lumbar vertebra was assessed, and both baseline and post-treatment SMI values were calculated independently. The relationship between SMI and patient survival was subsequently examined.ResultsThe median progression-free survival (PFS) for the cohort of 105 patients was 4.2 months (95% CI, 3.7 to 4.9 months), while the median overall survival (OS) was 10.2 months (95% CI, 9.0 to 12.7 months). Notably, the baseline SMI prior to the initiation of fruquintinib therapy exhibited a significant correlation with OS (P = 0.0077). Multivariate analysis indicated that baseline SMI serves as an independent prognostic factor for OS (P = 0.005). Furthermore, after Propensity Score Matching (PSM) analysis, there was still a significant correlation between baseline SMI and OS. Among the patients, 28.87% developed sarcopenia following oral administration of fruquintinib. However, no statistically significant difference in OS was observed between the group with reduced SMI and the group without SMI reduction after treatment with fruquintinib.ConclusionThe baseline SMI was identified as an independent prognostic factor for OS and may influence the survival outcomes of patients with metastatic colorectal cancer undergoing treatment with fruquintinib. Despite the potential of fruquintinib to induce sarcopenia, no significant correlation was observed between changes in SMI following treatment and patient survival.

Erratum: Onvansertib in Combination With Chemotherapy and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial.

Erratum: Onvansertib in Combination With Chemotherapy and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial.

Multi-omics analysis reveals the role of the autophagy-related gene AGT in chemotherapy resistance in colorectal cancer and the therapeutic potential of its inhibitors.

Autophagy is a crucial mechanism for maintaining cellular homeostasis and responding to environmental stress, and it is closely linked to tumor drug resistance. Through multi-omics analysis, this study explores the expression patterns, functions, and potential role of the autophagy-related gene Angiotensinogen (AGT) in colorectal cancer (CRC), particularly in relation to chemotherapy resistance. This study first compared AGT expression between CRC and normal tissues using the GTEx and TCGA databases. Differences in expression were assessed using Wilcoxon Rank Sum Tests, and the prognostic impact of AGT was evaluated through univariate Cox survival analysis and meta-analysis. Functional enrichment was performed using the limma and fgsea packages. Drug sensitivity analysis was conducted based on the CTRP database, while immune infiltration was assessed using the CIBERSORT and ESTIMATE methods. Spatial transcriptomic characteristics were explored through 10x Visium technology and deconvolution analysis to investigate the correlation between AGT expression levels and tumor cell content.scRNA-seq data from CRC tissues were sourced from Tumor Immune Single Cell Hub (TISCH).Functional annotation was performed with Single-sample gene set enrichment analysis (SSGSEA), and pseudotime analysis using Monocle 2 mapped their developmental trajectories. The potential of AGT inhibitors in the treatment of CRC was analyzed using drug-target Mendelian randomization.Finally, Phenome-Wide Association Study (PheWAS) was conducted to evaluate genetic associations and potential side effects of AGT inhibitors. AGT expression was significantly higher in CRC tissues compared to normal tissues and was associated with shorter recurrence-free survival (RFS). Autophagy signaling pathways were markedly enriched in the high AGT expression group. AGT expression was positively correlated with resistance to chemotherapeutic agents such as gemcitabine, cisplatin, paclitaxel, and 5-fluorouracil. Spatial transcriptomic analysis revealed that AGT was predominantly expressed in malignant tumor regions. Single-cell analysis identified 21 distinct cell subpopulations across 13 major types. AGT expression was significantly higher in tumor samples, especially in the fibroblast C6 subpopulation. Tumor-related pathways were enriched in C1, C5, C6, and C8 subpopulations. Pseudotime analysis revealed that these subpopulations, particularly C6, were in terminal developmental stages.Drug-target Mendelian randomization analysis indicated a negative causal relationship between AGT inhibitors and the risk of both heart failure(ORdrug = 0.950, 95% CI, 0.912-0.990; P = 0.014) and CRC(ORdrug = 0.874, 95% CI: 0.792-0.964; P = 0.007).PheWAS analysis showed no genetic associations between AGT inhibitors and other traits, indicating its specificity and low risk of side effects. Elevated AGT expression in CRC is associated with resistance to chemotherapy, and its inhibition may offer a therapeutic avenue for the treatment of colorectal cancer.

Comprehensive Insights Into the Combinatorial Uses of Selected Phytochemicals in Colorectal Cancer Prevention and Treatment: Isothiocyanates, Quinones, Carotenoids, and Alkaloids.

Despite the advancement in cancer diagnosis and treatment, colorectal cancer remains the leading cause of cancer-related death worldwide. Given the high recurrence rate of colorectal cancer even after surgical resection, chemotherapy has been clinically used to improve the treatment outcomes of colorectal cancer. However, chemotherapy is well-known for its toxic side effects. Thus, phytochemicals have been widely studied in recent years as preventive and therapeutic agents for colorectal cancer owing to their relatively low toxicity. Moreover, combinatorial uses of phytochemicals with other natural compounds or with drugs may amplify the positive outcomes of colorectal cancer prevention and treatment by intervening in multiple signaling pathways and targets. This review summarized the combinatorial use of several well-studied groups of phytochemicals, that is, isothiocyanates, quinones, carotenoids, and alkaloids, in the prevention and treatment of colorectal cancer, and suggested it as a potential approach to improve the anticancer efficacy of single compounds and minimize the toxic side effects associated with conventional drugs. Notably, we generalized the invitro, invivo, and clinical experiments-based molecular mechanisms whereby the selected phytochemicals in combination with other compounds exerted anti-colorectal cancer effects by inhibiting cancer cell proliferation, cell apoptosis, cell invasion, and tumor growth. Overall, this review provides a reference and new perspective to propel further advancements in research and development of preventative and therapeutic strategies for colorectal cancer.

Mapping the relationship between alcohol use disorder and gut microbiota: a 20-year bibliometric study.

Alcohol use disorder (AUD) is a psychiatric disorder that is widespread worldwide. Alcohol use is a significant contributor to the global burden of death, disability and disease. Modulation of the gut microbiota is a promising approach to improve the efficacy and minimize the adverse effects of colorectal cancer treatment. The relationship between the presence of microbes and AUD has been widely validated. However, few studies have examined this relationship using bibliometric methods. Therefore, this study analyzes the research hotspots and trends in human gut microbiology and AUD over the last two decades from a bibliometric perspective. This study aims at provide new directions for basic and clinical research in this field. A comprehensive discussion of the relationship between the current state of research and trends in AUD and intestinal flora. We collected publications from the Web of Science Core Collection database from 2003 to 2023 according to established inclusion criteria. We analyzed countries, institutions, authors, and research contributions using CiteSpace, VOSviewer, and Scimago Graphics to visualize research trends in the field. A total of 2,102 publications were obtained, with a rapid increase in the number of publications since 2016. The United States and China are major contributors to the field and have established a network of partners in several countries. Five hundred ninety-five academic journals published articles on the topic. The author with the highest number of publications is Prof. Bernd Schnabl of the Department of Gastroenterology at the University of California, San Diego. In addition to "gut flora" and "AUD," high frequency words in the keyword co-occurrence network analysis included alcoholic liver disease, tryptophan metabolism, enterohepatic axis, and fecal microbial transplantation. The results of this study provide a bibliometric analysis and visualization of key research areas in the gut microbiota and AUD over the past 20 years. The results suggest that the role of the gut microbiota in AUD and its potential mechanisms, especially therapeutic targets, should be closely monitored and could become a hot topic in the field.

Abstract A033: Integrating spatial transcriptomics and second harmonic generation imaging to identify targets of supermere-associated Discoidin Domain Receptor 1 involved in collagen alignment

Abstract Immune checkpoint blockade has been shown to be an effective treatment for colorectal cancers (CRCs) highly infiltrated by CD8+ T cells. However, there is a paucity of CD8+ T-cell infiltration in the majority of CRCs. We previously identified the collagen-activated receptor Discoidin Domain Receptor 1 (DDR1) as a member of a four-gene signature associated with T-cell exclusion in CRC. The cleaved ectodomain (cECD) of DDR1 induces collagen alignment, leading to T-cell exclusion in a breast cancer model. We found that almost all DDR1 cECD is found in supermeres, a novel secreted nanoparticle identified by our lab, and that DDR1 cECD is required for supermere signaling in recipient cells. We hypothesized that supermere-associated DDR1 cECD signals to CRC stromal cells, leading to collagen alignment. To test this hypothesis, we developed a method to determine which genes are associated with collagen alignment and DDR1 expression. To do this, 30 μm thick CRC sections are imaged using a Nikon AX multiphoton microscope by second harmonic generation imaging, which permits label-free imaging of collagen fibers. Spatial heatmaps of the collagen alignment are generated from the resulting images. Spatial transcriptomics is performed on a serial tumor section using the Visium v2 platform and the gene expression matrix is integrated with the collagen alignment heatmap data. As proof-of-principle, two CRC tumors have been analyzed using this method. Highly aligned regions were found to be associated with expression of genes involved in extracellular matrix organization, keloidal collagen and specific fibroblast subtypes. Genes which may be regulated by DDR1 cECD and be involved in collagen alignment will be confirmed at the protein level by multiplexed immunofluorescence on serial sections and in vitro experiments. This method will provide a rich dataset to elucidate the roles of supermeres and DDR1 cECD in T-cell exclusion and collagen fiber alignment and may support the discovery of new strategies to overcome immune exclusion in CRC. Citation Format: Maxwell S. Hamilton, Oleg Tutanov, Harsimran Kaur, Alan J. Simmons, Clark Massick, Kasey Vickers, Ken S. Lau, Ambra Pozzi, Robert J. Coffey. Integrating spatial transcriptomics and second harmonic generation imaging to identify targets of supermere-associated Discoidin Domain Receptor 1 involved in collagen alignment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A033.

Discovery of a potent PARP1 PROTAC as a chemosensitizer for the treatment of colorectal cancer

Given the vulnerability of colorectal cancer (CRC) patients could not obtain a sustained benefit from chemotherapy, combination therapy is frequently employed as a treatment strategy. Targeting PARP1 blockade exhibit specific toxicity towards tumor cells with BRCA1 or BRCA2 mutations through synthetic lethality. This study focuses on developing a series of potent PROTACs targeting PARP1 in order to enhance the sensitivity of CRC cells with BRCA1 or BRCA2 mutations to chemotherapy. Compound C6, obtained based on precise structural optimization of the linker, has been shown to effectively degrade PARP1 with a DC50 value of 58.14 nM. Furthermore, C6 significantly increased the cytotoxic efficacy of SN-38, an active metabolite of Irinotecan, in BRCA-mutated CRC cells, achieving a favorable combination index (CI) of 0.487. In conclusion, this research underscores the potential benefits of employing a combination therapy that utilizes PAPRP1 degrader C6 alongside Irinotecan for CRC patients harboring BRCA mutations in CRC.

Delavinone elicits oxidative stress and triggers ferroptosis in colorectal cancer by inhibiting PKCδ-mediated phosphorylation of Nrf2

Ferroptosis is a potential therapeutic approach for colorectal cancer (CRC). Studies have shown that peimine and its analogs exhibit anti-cancer potential; however, the intricate relationship between ferroptosis and their efficacy in fighting CRC remains unclear. In this study, we attempted to assess the therapeutic impact of peimine and its analogs on CRC and unravel the underlying mechanisms. CRC cells and a DSS/AOM-induced CRC mouse model were employed for in vitro and in vivo experiments, molecular interactions and co-immunoprecipitation were used to identify target proteins. Among the compounds, delavinone significantly inhibited CRC cell proliferation and increased cellular lipid ROS levels, MDA accumulation, and GSH depletion; the ferroptosis inhibitors DFO and Fer-1 ameliorated delavinone-induced cell death. Mechanistically, delavinone impedes PKCδ-mediated Nrf2 phosphorylation by inhibiting the kinase activity of PKCδ, thereby decreasing Nrf2 nuclear translocation and downstream GSH synthesis-related gene expression. overexpression of GPX4 weakened the anticancer effect of delavinone, underscoring delavinone's inhibition of the PKCδ/Nrf2/GPX4 signaling axis and induction of ferroptosis in CRC cells. Consistent with in vitro findings, delavinone notably hindered AOM/DSS-induced colorectal carcinogenesis, exhibiting a pronounced pro-ferroptosis effect on CRC. This study delineates that delavinone exerts its anticancer activity by inducing ferroptosis through PKCδ inhibition, consequently reducing Nrf2 phosphorylation. These findings position delavinone as a promising candidate for CRC treatment.

Abstract B018: Multifaceted pro-metastatic role of IL-17 signaling in modulating the tumor microenvironment of colorectal cancer

Abstract Colorectal cancer (CRC) ranks second in mortality and advanced CRCs are resistant to current immunotherapies and prone to metastasis, which necessitates research into enhancing innate and adaptive anti-cancer immune responses. Chronic inflammation mediated by cytokines like IL6 and notably, IL17 activates the oncogenic pathways in cancer cells, promoting sporadic and inflammatory CRC. What is unknown, is the ability of cytokines to control tumor microenvironment (TME) via cell type specific mechanisms to increase cancer progression, metastasis and/or therapy resistance. Increased levels of IL17A in CRC portends poor prognosis indicating its potential involvement into metastasis. However, the role of IL17 signaling in TME in the process of CRC progression and metastasis remains enigmatic. We utilized different models of CRC progression and metastasis, as well as variety of genetic mice models and therapeutic interventions. First, using a model of colitis-associated cancer we found that “late” IL17A neutralization decreases tumor burden, possibly acting through regulation of ferroptosis, NK cells mediated cytotoxicity, as well as myeloid cells and chemokine network essential for the control of immunosuppressive TME. Next, models of CRC metastasis, including those based on MC38 cells and APTAK cancerous organoids, showed that IL17A neutralization reduces metastasis growth. Also, FACS analysis revealed that IL17A promotes the recruitment of tumor- associated macrophages and other key myeloid subsets into the metastatic liver environment. Further research, using mice with conditional knockout of IL17RC receptor in myeloid cells (Il17rc f/f -LysMCre) or hepatocytes (Il17rc f/f -AlbCre) also showed significance of IL17 signaling activation in CRC metastasis through two distinct mechanisms. Employing different techniques, from FACS, immunohistochemistry, to RNAseq and scRNAseq data analysis, we observed that local hepatic activation of IL17RC signaling recruits neutrophils and reduces infiltration of cytotoxic CD8+T and NK cells to the metastatic niche supporting tumor growth, while myeloid IL17RC signaling reshapes TME, including macrophages and neutrophils, enhancing CRC metastasis. Our research indicates that IL17 signaling plays a multifaceted pathogenic role in CRC progression by operating in at least several cell types, providing new insights into the basic biology of CRC metastasis and potentially illuminating the design and improvement of CRC treatment strategies. Citation Format: Katarzyna Chojnacka, Katrina Mae Reyes, Hana Tomizawa, Sergei Grivennikov. Multifaceted pro-metastatic role of IL-17 signaling in modulating the tumor microenvironment of colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B018.

Construction of a cell cycle-specific lncRNA-miRNA-mRNA network reveals novel key lncRNAs in colorectal cancer

Objective The current study aimed to determine the roles of pivotal and novel lncRNAs associated with the cell cycle in the occurrence and development of Colorectal cancer (CRC). Methods The TCGA-COAD project related to CRC was downloaded, and differential expression analysis was performed to identify differentially expressed lncRNAs, miRNAs, and mRNAs. A cell cycle-associated lncRNA-miRNA-mRNA regulatory network was constructed, and two novel lncRNAs were selected. Two subnetworks were constructed for selected lncRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were illustrated for the genes in each sub-network. qPCR analysis was used to validate the expression levels of the selected lncRNAs in CRC tissues compared to those adjacent normal tissues. Results The differential expression analysis identified 416 lncRNAs, 317 miRNAs, and 117 mRNAs. The ceRNA subnetwork genes were associated with different pathways, including cellular senescence, DNA replication, human T-cell leukemia virus 1 infection, and oocyte meiosis. The bioinformatic results based on the TCGA project indicated the dysregulation of two novel lncRNAs, MIR29B2CHG and HELLPAR, in CRC tissues compared to adjacent normal tissues. Moreover, qPCR confirmed the dysregulation of lncRNAs in the CRC tissues. ROC curves revealed that both selected lncRNAs had acceptable specificity and sensitivity as biomarkers. Conclusion In conclusion, novel cell cycle-associated lncRNAs have the potential to be understood as the underlying molecular mechanisms that influence CRC. Therefore, these lncRNAs can be considered as promising biomarkers for the diagnosis and treatment of CRC.

Safe implementation of minimally invasive surgery in a specialized colorectal cancer unit

IntroductionIn the past 30 years, minimally invasive surgery (MIS) has made remarkable progress and has become the standard of care in colorectal cancer treatment. The implementation of new techniques or platforms is, therefore, a challenge for surgical teams. This study aims to analyze the experience in the implementation of minimally invasive surgery in the colorectal unit in a specialized colorectal cancer center. We will report and compare the clinical outcomes of the patients submitted to the different surgical approaches, reflecting the importance of surgical training in the laparoscopic and robotic field for the reduction of surgical complications and improve short-term outcomes.MethodsThis study involved a retrospective analysis of data collected from a prospectively maintained database at the colorectal unit of Champalimaud Foundation between 2012 and 2023. Data were collected as part of routine clinical documentation and included variables on patient’s demographics, staging, short-term outcomes, and follow-up.ResultsA total of 661 patients treated at the Champalimaud Foundation between 2012 and 2023 were included, of which 389 (59%) had colon and 272 (41%) rectal cancer. Most of the patients underwent elective surgery, with a minimally invasive approach performed in 91% of cases. A complete resection (R0) was achieved in 95.1% (619) of the procedures with a pathology report staging 64.5% (409) of tumors as pT3–4. Eleven percent (70) of patients had complications classified as Clavien-Dindo (CD) ≥ 3.ConclusionThis study supports the safety of the implementation of minimally invasive surgery in colorectal cancer care, with improvement in postoperative outcomes and surgical quality, supporting the importance of surgical training and specialized teams.

Comparative Analysis of Laparoscopic Versus Open Surgery in Colorectal Cancer: An Eight-Year Single-Center Experience From Jordan.

Introduction The use of laparoscopic surgery has increased in the treatment of colorectal cancer (CRC). However, achieving oncological outcomes similar to those of open surgery remains challenging, particularly for CRC. In this comparative, retrospective study, we aim to investigate and compare the postoperative complications of open and laparoscopic CRC surgery in Jordan. Methods Using a retrospective study design, patients' records were obtained from the electronic hospital database of King Hussein Medical Center, Amman, Jordan, during the period between 2016 and 2024. Demographic data were collected for age and gender. Clinical data were collected for tumor site, tumor grade, body mass index, American Society of Anesthesiologists (ASA) score, lymph node ratio (LNR), postoperative complications such as ileus, anastomosis, stoma, renal complications, pain, wound infection, and death, and length of hospital stay. Results We included 857 CRC patients, with 437 (51.0%) undergoing laparoscopic resection and 420 (49%) undergoing open resection. The mean age was 58 years, with no age difference between the study groups. Most patients (507, 59%) were in good health based on the ASA score. The majority (671, 78%) had moderately differentiated tumors, with 320 (76%) in the open surgery group and 351 (80%) in the laparoscopy group. The mean LNR was 0.19, trending higher in the group that underwent open surgery (0.33 vs. 0.09, p = 0.065). The open surgery group had a significantly longer hospital stay (5.28 days) relative to the laparoscopic group (3.77 days, p < 0.001). Postoperative complications included wound infection (33, 3.9%), ileus (19, 2.2%), stoma (15, 1.8%), anastomosis (10, 1.2%), renal complications (9, 1.1%), and pain (6, 0.7%). The mortality rate was higher in the open surgery group (p = 0.035). Most patients (711, 83%) did not experience postoperative complications. Conclusion This is the first Jordanian study to compare long-term outcomes of CRC patients undergoing open versus laparoscopic surgical resection. Our findings suggested that the laparoscopic group had a shorter hospital stay, with no differences in postoperative complications rate between the study groups. Mortality rates were low overall but significantly higher in the open surgery group. These results suggest that laparoscopic resection may be superior for CRC surgery, though further multicenter studies are warranted to confirm our findings.