Colorectal Cancer Therapy Research Articles

Correlation of the KRAS gene’s copy number variation and the results of targeted therapy for colorectal cancer

BACKGROUND: to find predictive value of KRAS gene’s copy number variation (CNV_KRAS) to anti-EGFR therapy.PATIENTS AND METHODS: a prospective cohort single-center study included 150 patients, 103 patients with colorectal cancer (CRC) and wild-type RAS/BRAF, 39 patients with colorectal cancer with somatic mutations in the KRAS gene, as well as 8 non-oncological patients (as normal controls). CNV_KRAS was determined using digital droplet PCR.RESULTS: the clinically significant CNV_KRAS level of ≥ 9 copies established for a refusal of targeted anti-EGFR therapy. The incidence of clinically significant CNV_KRAS level in patients with wild-type RAS/BRAF was 17% (the first group of patients). Incidence of clinically significant CNV_KRAS level in patients with mutations in the KRAS gene was 3% (the second group of patients). At the I stage of CRC clinically significant CNV_KRAS was not detected in either the first or second group; at the stage II of CRC in the first group — in 14% of patients (3/22), and in the second group — not detected; at the stage III of CRC in the first group — in 21% of patients (8/39), and in the second group of patients — not detected; at the stage IV of CRC in the first group — in 17% (6/35) of patients, and in the second group of patients — in 5% (1/20). Tumor DNA was analyzed in 10 patients with the stage IV CRC from the first group who received anti-EGFR therapy to find out the clinically significant level of CNV_KRAS. Disease control was achieved in 7 out of 10 patients. The median CNV_KRAS score in the remaining three patients was higher than in the disease control group, 9.2 (9.05, 10.10) and 5.38 (4.77, 7.35) (p = 0.017).CONCLUSIONS: detection of CNV_KRAS level of ≥ 9 copies in a malignant colon tumor is a contraindication to targeted therapy. This phenomenon occurs significantly more often in patients without somatic mutations in the RAS genes (KRAS, NRAS) and BRAF, than in patients with point mutations in the KRAS gene (p = 0.02).

Efficacy and safety of PD-1 and PD-L1 inhibitors in advanced colorectal cancer: a meta-analysis of randomized controlled trials

BackgroundPD-1 and PD-L1 inhibitors have emerged as promising therapies for advanced colorectal cancer (CRC), but their efficacy and safety profiles require further evaluation. This meta-analysis aims to assess the efficacy and safety of PD-1/PD-L1 inhibitors in this patient population.MethodsA systematic review and meta-analysis were conducted following PRISMA guidelines, with data sourced from PubMed, Embase, CENTRAL, Web of Science, and CNKI up to August 3, 2024. Nine randomized controlled trials (RCTs) involving 1680 patients were included. The primary outcomes were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR), while safety was assessed through adverse events (AEs) and grade ≥ 3 AEs. Effect sizes were calculated using mean differences (MD) and risk ratios (RR) with 95% confidence intervals (CIs).ResultsOverall, the meta-analysis showed that PD-1/PD-L1 inhibitors did not significantly extend OS (MD = 0.86, 95% CI: -0.55, 2.27), but they significantly improved PFS (MD = 2.53, 95% CI: 0.92, 4.15). Additionally, PD-1/PD-L1 inhibitors did not significantly increase the ORR compared to controls (RR = 1.19, 95% CI: 0.99, 1.44). In terms of safety, PD-1/PD-L1 inhibitors did not significantly increase the incidence of overall AEs. Subgroup analysis further indicated that PD-1 inhibitors significantly improved OS (MD = 1.24, 95% CI: 0.20, 2.29) and PFS (MD = 6.27, 95% CI: 0.56, 11.97), while PD-L1 inhibitors did not have a significant impact on these outcomes. Additionally, PD-L1 inhibitors were associated with a higher risk of grade ≥ 3 AEs (RR = 1.29, 95% CI: 1.07, 1.57), a risk not observed with PD-1 inhibitors.ConclusionPD-1 inhibitors significantly improve PFS and OS in advanced CRC, making them a preferable option over PD-L1 inhibitors, which show limited efficacy and a higher risk of severe AEs. These findings support prioritizing PD-1 inhibitors in clinical practice for this patient group, while caution is warranted with PD-L1 inhibitors due to their safety concerns.Trial registrationPROSPERO (CRD42024611696).

High Carbonyl Graphene Oxide Suppresses Colorectal Cancer Cell Proliferation and Migration by Inducing Ferroptosis via the System Xc−/GSH/GPX4 Axis

Background/Objectives: Colorectal cancer (CRC) is characterized by a high rate of both incidence and mortality, and its treatment outcomes are often affected by recurrence and drug resistance. Ferroptosis, an iron-dependent programmed cell death mechanism triggered by lipid peroxidation, has recently gained attention as a potential therapeutic target. Graphene oxide (GO), known for its oxygen-containing functional groups, biocompatibility, and potential for functionalization, holds promise in cancer treatment. However, its role in ferroptosis induction in CRC remains underexplored. The objective of this study was to investigate the effects of High Carbonyl Graphene Oxide (HC-GO) on ferroptosis in CRC and elucidate the underlying mechanisms. Methods: In vitro assays were conducted to evaluate the impact of HC-GO on CRC cell proliferation, mitochondrial function, iron accumulation, lipid peroxidation, and reactive oxygen species (ROS) production. The ferroptosis inhibitor Fer-1 was used to confirm the role of ferroptosis in HC-GO’s anti-tumor effects. In vivo, the anti-tumor activity of HC-GO was assessed in a CRC xenograft model, with organ toxicity evaluated. Results: HC-GO significantly inhibited CRC cell proliferation, induced mitochondrial damage, and enhanced iron accumulation, lipid peroxidation, and ROS production. It also downregulated the ferroptosis-inhibiting proteins GPX4 and SLC7A11, which were reversed by Fer-1, confirming the involvement of ferroptosis in HC-GO’s anti-cancer effects. In vivo, HC-GO significantly suppressed tumor growth without noticeable toxicity to vital organs. Conclusions: HC-GO triggered ferroptosis in CRC cells by suppressing the System Xc−/GSH/GPX4 pathway, providing a novel therapeutic strategy for CRC treatment. These findings suggest HC-GO as a promising nanomedicine for clinical application, warranting further investigation to explore its potential in CRC therapy.

Therapeutic potential of Xihuang Pill in colorectal cancer: Metabolomic and microbiome-driven approaches.

The Xihuang Pill (XHP), a venerated traditional Chinese medicine, has demonstrated significant anti-cancer capabilities. Despite its proven efficacy, the scarcity of comprehensive pharmacological studies limits the widespread application of XHP. This research endeavor seeks to demystify the therapeutic underpinnings of XHP, particularly in the realm of colorectal cancer (CRC) therapy. In this study, mice harboring CT26 tumors were divided into four groups, each administered with either XHP monotherapy, 5-fluorouracil (5-FU), or a combination of both. The tumor growth trajectory was closely monitored to evaluate the effectiveness of these anti-neoplastic interventions. Advanced techniques, including 16S-rDNA gene sequencing and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), were harnessed to scrutinize the gut microbiota and serum metabolite profiles. Immunohistochemical assays were employed to gauge the expression levels of CD4, CD8, and Foxp3, thereby providing insights into the dynamics of tumor-infiltrating lymphocytes within the tumor microenvironment. Our findings indicate that XHP effectively suppresses the initiation and progression of colorectal tumors. The combinatorial therapy of XHP with 5-FU exhibited an enhanced inhibitory effect on tumor growth. Metabolic profiling revealed that XHP induced notable metabolic shifts, particularly impacting pathways such as steroid hormone synthesis, arachidonic acid metabolism, purine biosynthesis, and renin secretion. Notably, 17α-ethinyl estradiol and α-ergocryptine were identified as serum metabolites with the most substantial increase following XHP administration. Analysis of the gut microbiome suggested that XHP promoted the expansion of specific bacterial taxa, including Lachnospiraceae_NK4A136_group, Clostridiales, Desulfovibrionaceae, and Anaerotignum_sp., while suppressing the proliferation of others such as Ligilactobacilus, Lactobacillus_taiwanensis, and Candidatus_saccharimonas. Immunohistochemical staining indicated an upregulation of CD4 and CD8 post-XHP treatment. This study delineates a potential mechanism by which XHP inhibits CRC tumorigenesis through modulating the gut microbiota, serum metabolites, and reshaping the tumor immune microenvironment in a murine CRC model. These findings contribute to a more profound understanding and potentially broaden the clinical utility of XHP in oncology.

Chitosan and hyaluronic acid in colorectal cancer therapy: A review on EMT regulation, metastasis, and overcoming drug resistance.

Up to 90% of cancer-related fatalities could be attributed to metastasis. Therefore, understanding the mechanisms that facilitate tumor cell metastasis is beneficial for improving patient survival and results. EMT is considered the main process involved in the invasion and spread of CRC. Essential molecular components like Wnt, TGF-β, and PI3K/Akt play a role in controlling EMT in CRC, frequently triggered by various factors such as Snail, Twist, and ZEB1. These factors affect not only the spread of CRC but also determine the reaction to chemotherapy. The influence of non-coding RNAs, especially miRNAs and lncRNAs, on the regulation of EMT is clear in CRC. Exosomes, involved in cell-to-cell communication, can affect the TME and metastasis of CRC. Pharmacological substances and nanoparticles demonstrate promise as efficient modulators of EMT in CRC. Chitosan and HA are two major carbohydrate polymers with considerable potential in inhibiting CRC. Chitosan and HA can be employed to modify nanoparticles to enhance cargo transport for reducing CRC. Additionally, chitosan and HA-modified nanocarriers, which can be utilized as potential approaches in suppressing EMT and reversing drug resistance in CRC, can inhibit EMT and chemoresistance, crucial components in tumorigenesis.

Long-Term Effects on Gonadal Function After Treatment of Colorectal Cancer: A Systematic Review and Meta-Analysis.

The incidence of colorectal cancer (CRC) is increasing in the population under 50 years of age, with more than 10% of cases occurring in young adults. Fertility preservation counseling has therefore received increased attention in this younger patient population. The treatment of CRC is often based on multimodal therapies, including surgery, radiotherapy, chemotherapy, and, more recently, immunotherapy, which makes it difficult to estimate the expected effect of treatment on fertility. We, therefore, systematically analyzed the published literature on the gonadotoxic effects of CRC treatments to better advise patients on the risk of infertility and the need for fertility preservation measures. This systematic review and meta-analysis are part of the FertiTOX project, which aims to reduce the data gap regarding the gonadotoxicity of oncological therapies. The aim of this review and meta-analysis is to evaluate the potential impact of CRC therapies on gonadal function to allow more accurate counseling regarding the risk of clinically relevant gonadotoxicity and the need for fertility preservation measures before oncological treatment. A systematic literature search was conducted in Medline, Embase, the Cochrane database of systematic reviews, and CENTRAL in March 2024. A total of 22 out of 4420 studies were included in the review. Outcomes were defined as clinically relevant gonadotoxicity, indicated by elevated follicle-stimulating hormone (FSH) and/or undetectable anti-Müllerian hormone (AMH) levels and/or the need for hormone replacement therapy in women and azoo-/oligozoospermia and/or low inhibin B levels in men. Studies with fewer than nine patients were excluded from the meta-analysis. The qualitative analysis included 22 studies with 1634 subjects (775 women, 859 men). Treatment consisted of active surveillance after surgery (37.7%), chemotherapy (12.7%), radiation (0.2%), or radiochemotherapy (53.9%). In 0.5%, the therapy was not clearly described. The meta-analysis included ten studies and showed an overall prevalence of clinically relevant gonadotoxicity of 23% (95% CI: 13-37%). In women, the prevalence was 27% (95% CI: 11-54%), and in men, 18% (95% CI: 13-26%). A subanalysis by type of CRC was only possible for rectal cancer, with a prevalence of relevant gonadotoxicity of 39% (95% CI: 20-64%). In patients undergoing chemotherapy exclusively, the prevalence was 4% (95% CI: 2-10%). In those receiving only radiotherapy, the prevalence was 23% (95% CI: 10-44%); in contrast, it reached 68% (95% CI: 40-87%) in patients who received radiochemotherapy. This first meta-analysis of the clinically relevant gonadotoxicity of CRC therapies provides a basis for counseling on the risk of infertility and the need for fertility preservation measures. Despite the low prevalence of gonadotoxicity in cases receiving chemotherapy alone, fertility preservation is still recommended due to the uncertainty of subsequent therapy and the lack of large longitudinal data on individual treatment effects. Further prospective studies are needed to investigate the impact of CRC treatment on gonadal function and estimate the effect of new treatment modalities, such as immunotherapies.

EGFR-targeting polydopamine nanoparticles co-loaded with 5-fluorouracil, irinotecan, and leucovorin to potentially enhance metastatic colorectal cancer therapy

Despite all prevention programs, many cases of colorectal cancer (CRC) are diagnosed when they have already metastasized. Herein, chemotherapy is required, and combination of 5-fluorouracil, irinotecan, and leucovorin (FOLFIRI) is one of the first-line treatments chosen. However, it is so toxic that compromises patient outcomes. Thus, with the aim of improving FOLFIRI pharmacokinetics while reducing its side effects, the three compounds that make it up were simultaneously absorbed in this work into polydopamine nanoparticles (PDA NPs), also loaded with an antibody to target CRC cells overexpressing the epithermal growth factor receptor (EGFR). All adsorptions, which were successfully executed without toxic solvents, were electrostatic in nature according to the calorimetry results obtained. Otherwise, based on the experiments done, 5-flurouracil, irinotecan, and leucovorin release from PDA NPs followed a burst-like pattern, which was possibly mediated by Fickian diffusion mechanisms. Finally, the assays performed with two EGFR-overexpressing CRC cell lines showed that the uptake of the nanosystem was rapid, and that its therapeutic effect was very significant. It managed to greatly reduce the viability of these cells to 22–30% after 72 h of incubation. Furthermore, when tumor spheroids were developed and treated with PDA NPs loaded with FOLFIRI and the anti-EGFR antibody (FOLFIRI-CTX@PDA NPs), these demonstrated to continue to have very marked therapeutic activity. In addition, FOLFIRI-CTX@PDA NPs affected to a lesser extent the survival rate of stromal cells, with which viability experiments were also done. Therefore, the novel developed PDA nanocarrier could be a promising strategy to enhance metastatic CRC therapy hereafter.

Probiotic nanovesicles encapsulating baicalin: a strategy to overcome colorectal cancer.

Escherichia coli Nissle 1917 (EcN) is a unique probiotic utilized to treat inflammatory bowel disease and irritable bowel syndrome. Outer membrane vesicles (OMVs) from EcN can not only deliver pro-biotic anti-inflammatory molecules to cancer cells to exert anti-rectal cancer effects, but also deliver therapeutic drugs, genes, and other "cargoes" encapsulated in the vesicles to specific cells, making them an ideal vehicle for drug delivery. In this study, we successfully isolated OMVs of probiotic origin and obtained BCN-OMVs by encapsulating baicalin (BCN) in EcN-OMVs. Fluorescence microscopy showed that both fluorescently labeled EcN-OMVs and BCN-OMVs were able to enter HT-29 cells. The results of CCK-8, plate cloning, flow cytometry, and western blotting indicated that the vitality and proliferation of HT-29 cells were sensibly inhibited after treatment with BCN-OMVs. Additionally, apoptosis-related proteins and proteins involved in the NF-κB pathway were also expressed differently. The results above suggest that EcN-OMVs, serving as a bio-nanocarrier of BCN, can effectively address the limitations of BCN, such as poor water solubility and low bioavailability. They also play a significant anti-tumor role by enhancing cancer cell apoptosis, showing promising potential in targeted therapy for colorectal cancer (CRC).

Sustained Endocytosis Inhibition via Locally-Injected Drug-Eluting Hydrogel Improves ADCC-Mediated Antibody Therapy in Colorectal Cancer.

The epidermal growth factor receptor (EGFR) is a validated therapeutic target for RAS/RAF wild-type colorectal cancer (CRC). However, monoclonal antibody-based anti-EGFR therapies such as cetuximab have limited effectiveness. Herein, it is identified that EGFR internalization is associated with poor treatment response and prognosis in patients with CRC, based on a retrospective analysis of patients treated with cetuximab. It is further demonstrated that the endocytosis inhibitor prochlorperazine (PCZ) can move EGFR, which is hidden inside the cell, to the cell surface to improve therapeutic antibody binding. Thus, a thermosensitive hydrogel co-loaded with cetuximab and PCZ (Gel@Cmab/PCZ) is constructed for sustained inhibition of endocytosis and effective cetuximab delivery. Peritumoral injection of Gel@Cmab/PCZ shows strong antitumor efficacy in subcutaneous and orthotopic CRC tumor models and completely abrogated liver metastasis when combined with chemotherapy. In a humanized patient-derived xenograft model, a single injection of Gel@Cmab/PCZ with one-third of theconventional cetuximab dose achieved 91% tumor growth inhibition, which promoted NK cell infiltration into tumor tissues and their antibody-dependent cell-mediated cytotoxicity effect. This study represents a novel strategy to boost the monoclonal antibody-mediated anti-tumor response in CRC.

Thymoquinone Pectin Beads Produced via Electrospray: Enhancing Oral Targeted Delivery for Colorectal Cancer Therapy.

Background/Objectives: Thymoquinone (TQ) exhibits diverse biological activities, but its poor solubility and bioavailability limit its cancer efficacy, requiring innovative solutions. This study explores the development of an oral delivery system targeting colon cancer based on TQ pectin beads (TQ-PBs) produced through an adjustable electrospray technique. This study hypothesised that adjusting bead diameter through the electrospray technique enables precise control over water absorption and erosion rates, thereby achieving a controlled release profile for encapsulated TQ, which enhances targeted delivery to the colon. Methods: TQ-PBs were synthesised and optimised using an electrospray technique based on the ionic gelation method. The prepared beads were characterised based on particle size, sphericity, encapsulation efficiency (EE), water uptake, erosion, surface morphology, molecular interactions, and texture. The cumulative TQ release studies, an accelerated stability test, and cytotoxicity evaluation against the colon cancer HT-29 cell line were also assessed. Results: The optimised TQ-PB formulation demonstrated an average bead size of 2.05 ± 0.14 mm, a sphericity of 0.96 ± 0.05, and an EE of 90.32 ± 1.04%. The water uptake was 287.55 ± 10.14% in simulated gastric fluid (SGF), 462.15 ± 12.73% in simulated intestinal fluid (SIF), and 772.41 ± 13.03% in simulated colonic fluid (SCF), with an erosion rate of 45.23 ± 5.22%. TQ release was minimal in SGF (8.13 ± 1.94% after 2 h), controlled in SIF (29.35 ± 3.65% after 4 h), and accelerated in SCF (94.43 ± 2.4% after 3 h). Stability studies over one month showed a size reduction of 17.50% and a 6.59% decrease in TQ content. Cytotoxicity assessments revealed significant anticancer activity of TQ-PB, with an IC50 of 80.59 ± 2.2 μg/mL. Conclusions: These findings underscore the potential of TQ-PB as an effective oral drug delivery system for targeted colorectal cancer therapy.

Preferential activation of type I interferon-mediated antitumor inflammatory signaling by CuS/MnO2/diAMP nanoparticles enhances anti-PD-1 therapy for sporadic colorectal cancer

Converting the “cold” tumor microenvironment (TME) to a “hot” milieu has become the prevailing approach for enhancing the response of immune-excluded/immunosuppressed colorectal cancer (CRC) patients to immune checkpoint blockade (ICB) therapy. During this process, inflammation accompanied by different kinds of chemokines/cytokines inevitably occurs. However, some activated inflammatory signals exhibit protumor potency. Therefore, strategies that preferentially activate antitumor inflammatory signaling rather than tumor-promoting signaling need to be developed. Herein, we constructed a STING agonist-loaded CuS/MnO2 bimetallic nanosystem, termed diAMP-BCM. BCM with an optimized Cu/Mn ratio efficiently promoted the activation of proinflammatory signaling, and in combination with the STING agonist diAMP, diAMP-BCM controllably activated tumoricidal inflammatory signaling in APCs. DiAMP-BCM can efficiently generate ROS and promote the activation of STING, which induces the apoptosis of cancer cells and promotes the recruitment of monocytes while facilitating the polarization of macrophages and maturation of DCs. MC38 and CT26 CRC models were established to evaluate the in vivo antitumor effects of diAMP-BCM. Combined with ICB therapy, diAMP-BCM enables the rebuilding of tumor milieus with efficient tumor growth inhibition and alleviation of T-cell exhaustion, particularly in distal tumors, in sporadic colorectal cancer therapy. This study established a nanoplatform to promote the preferential activation of antitumor inflammatory signaling, rebuild the T-cell repertoire and alleviate T-cell exhaustion to enhance cancer ICB immunotherapy.Graphical

INNV-06. ADULT GLIOBLASTOMA WITH MISMATCH REPAIR DEFICIENCY FORMS A DISTINCT HIGH-RISK MOLECULAR SUBGROUP FOR WHICH TREATMENT WITH IPILIMUMAB-NIVOLUMAB SHOWS SURVIVAL ADVANTAGE

Abstract Glioblastoma is the most frequent and malignant primary brain tumor. Although the survival is generally dismal for glioblastoma patients, risk stratification and the identification of high-risk subgroups is important for prompt and aggressive management. The G1-G7 molecular subgroup classification based on the MAPK pathway activation has offered for the first time a non-redundant, all-inclusive classification of adult glioblastoma. Five patients from the large, 220-patient prospective cohort showed germline mutations in mismatch repair (MMR) genes and significantly worse median survival (3.25 months post-surgery) than those from other subgroups or from the rest of the cohort adjusted for age. These tumors were assigned to a new subgroup, G3/MMR, a spin-off from the major G3/NF1 subgroup, as they generally show genomic alterations leading to RAS activation. An integrated clinical, histological, immunohistochemical and molecular analysis of the G3/MMR tumors showed distinct characteristics as compared to other glioblastomas, including those with iatrogenic high tumor mutation burden (TMB), warranting a separate subgroup. Among these, prior history of cancer, midline location or multifocality, presence of multinucleated giant cells, positive p53 and MMR immunohistochemistry, and specific molecular characteristics, including high TMB, alert to this high-risk G3/MMR subgroup. High TMB constitutes the criterium for treatment with immune checkpoint inhibitors in solid cancers. The FDA-approved first-line therapy for advanced non-small cell lung cancer and high-TMB colorectal cancer is with the dual ipilimumab-nivolumab regimen. One of the five G3/MMR subgroup patients received the dual ipilimumab-nivolumab regimen and survived much longer than the rest of the G3/MMR patients, setting a proof-of-principle example for the treatment of these very aggressive G3/MMR glioblastomas.

Comparison of efficacy and safety of regorafenib and anti-EGFR targeted therapy in metastatic colorectal cancer: A retrospective study

Aim. To compare the efficacy of regorafenib and the combination of chemotherapy (CT) with anti-EGFR (cetuximab/panitumumab) in the third-line treatment of metastatic colorectal cancer (mCRC). Materials and methods. A retrospective analysis of a prospective database of patients with mCRC from two clinics in the Russian Federation was conducted. Overall survival was considered the primary efficacy criterion. Additional criteria were progression-free survival (PFS), objective effect (OE), and incidence of toxicity. No statistical hypothesis was assumed. Statistical analysis was performed using SPSS (IBM SPPS Statistics v. 20). Results. The database identified 51 patients with morphologically confirmed left-sided mCRC with wild-type RAS and BRAF genes who received more than two lines of antitumor drug therapy from 2010 to 2021, one of which included anti-EGFR antibodies in the third and subsequent lines of treatment. Thirty patients who received regorafenib in the third line and 21 patients who received CT in combination with anti-EGFR in the third line were selected, of which 7 patients had a history of anti-EGFR use, and 14 patients received anti-EGFR for the first time. The median overall survival from the third line initiation date in the CT group in combination with anti-EGFR was numerically higher (21 months, CI 9.0–32.9 months) than in the regorafenib group (10 months, CI 2.4–17.5 months); p=0.1 by log-rank test (Mantel–Cox test); p=0.2 by Breslow–Wilcoxon test; p=0.3 (Tarone–Ware test). PFS was also higher in the anti-EGFR CT group (6 months, CI 3.8–8.2 months) than in the regorafenib group (3 months, CI 1.2–4.7 months); p=0.05 according to Breslow–Wilcoxon test. OE of third-line therapy was reported in 57.1% (n=12) of patients in the CT with anti-EGFR group and significantly less often in the regorafenib group – 10.3% (n=3) of patients (p=0.001). The toxicity of drug therapy of all grades in the regorafenib group was reported in 86.2% (n=25) of patients, while in the CT anti-EGFR group, it was significantly less common – in 52.4% (n=11) of patients (p=0.01). Conclusion. Compared with regorafenib, combining CT with anti-EGFR agents in the third-line treatment of patients with left-sided mCRC with wild-type RAS and BRAF genes is associated with better PFS and the frequency of OE with significantly less toxicity.

A Necessary Role for Cyclin D2 Induction During Colon Cancer Progression Mediated by L1.

The cell adhesion molecule L1CAM (L1), mainly known for its function in brain cells, is a Wnt/β-catenin signaling target gene in colorectal cancer (CRC) cells, where it promotes invasion and liver metastasis. We interrogated which genes are expressed at increased levels in human CRC tissue and induced in CRC cell lines overexpressing L1. We found increased cyclin D2 levels in CRC tissue and LS 174T and HCT 116 human CRC cells overexpressing L1. Increased cyclin D2 in CRC cells was associated with higher proliferation rates, faster motility, tumorigenesis, and liver metastasis. The suppression of cyclin D2 expression by shRNA to cyclin D2 blocked the increase in these cellular properties of L1-expressing cells. The overexpression of cyclin D2 in the absence of L1 also conferred tumorigenic properties similar to L1 expression. The pathways involved in the elevation of cyclin D2 by L1 include NF-κB, Akt, and β-catenin signaling but not the Erk pathway. We found that in a significant percentage of human CRC tissue samples, cyclin D2 is expressed at high levels in the nuclei of cancer cells. At the same time, the adjacent normal mucosa was negative for cyclin D2 staining. The results suggest that the increased cyclin D2 expression by L1 is required to induce proliferative, motile tumor development in CRC tissue and can serve as a diagnostic marker and a target for CRC therapy.

5-Fluorouracil/curcumin loaded silk fibroin hydrogel for the adjuvant therapy in colorectal cancer

This study employed silk fibroin (SF) as a carrier material to encapsulate curcumin (CUR) and 5-fluorouracil (5-FU), forming a highly effective drug-loaded hydrogel. The process involved mixing SF solution containing 5-FU with curcumin solution dissolved in acetone (AC), leading to the formation of composite drug-loaded nanospheres with particle sizes ranging from 77.87 nm to 299.22 nm, demonstrated enhanced permeability and retention (EPR) effects, enabling passive targeting of solid tumors. After the formation of the nanospheres, they were dispersed into a solution containing SF and polyethylene glycol (PEG). Following gelation and PEG removal, a SF hydrogel loaded with 5-FU and CUR (5-FU/CUR@SF hydrogel) was obtained. Results indicated that the 5-FU/CUR@SF hydrogel exhibited excellent drug release properties, with 5-FU and CUR achieving sustained release of 59.66 ± 3.76 % and 47.94 ± 5.03 %, respectively, over a 400-h of sustainable releasing period. Human colorectal cancer cell line (HT-29) and normal human colon epithelial cell line (NCM-460) were cultured with the 5-FU/CUR@SF hydrogel, resulting an apoptosis rate of only 17.38 ± 1.98 % for NCM-460 cells, whereas the apoptosis rate for HT-29 cells significantly increased to 72.31 ± 2.18 %, and its cell viability dropped to 59.77 ± 0.55 %. These findings suggest that the 5-FU/CUR@SF hydrogel exhibits low cytotoxicity toward normal NCM-460 cells, while exerting significant and sustained inhibitory effects on HT-29 cancer cells. In conclusion, the SF-based drug-loaded composite hydrogel holds great potential as a novel adjuvant therapeutic strategy for the treatment of CRC.

Folic-acid-targeted drug delivery system implementing Angelica gigas polysaccharide: A potential strategy for colorectal cancer treatment.

The study focuses on the development of folate-targeted conjugates utilizing Angelica gigas polysaccharide (F2) as a drug carrier for colorectal cancer therapy. We synthesized F2-C-5-FU conjugates by linking carboxymethyl-5-fluorouracil (C-5-FU) with folic acid (FA) through ester bonding. The drug release behavior of F2-C-5-FU-FA was pH-dependent, favoring release under alkaline conditions. After 96 h in phosphate buffer (pH 7.4), the conjugate exhibited a cumulative release of 54.7 %, which was higher compared to other pH environments. In vitro, F2-C-5-FU-FA showed enhanced cytotoxicity and increased cellular uptake in folate receptor-positive HCT-116 cells compared to A549 cells. The conjugate also induced G2/M cell cycle arrest and modulated the BAX/BCL-2 mRNA expression ratio through the MAPK and NF-κB signaling pathways. In vivo, F2-C-5-FU-FA increased tumor fluorescence intensity, prolonged drug circulation, and reduced organ toxicity to non-target organs. The treatment promoted cancer cell apoptosis by inhibiting the expression of apoptosis-related proteins. Overall, F2-C-5-FU-FA conjugates demonstrate potential as an effective drug delivery system for targeted colorectal cancer therapy.

Percutaneous hepatic artery infusion chemotherapy with oxaliplatin and fluoropyrimidines in treatment-resistant colorectal cancer patients with unresectable liver metastases: a retrospective cohort study

BackgroundSubsequent lines of therapy for chemotherapy-resistant metastatic colorectal cancer (CRC) have shown limited efficacy. Herein, we retrospectively investigated the efficacy and safety of hepatic artery infusion chemotherapy (HAIC) using oxaliplatin plus 5-FU/FUDR in patients with unresectable colorectal liver metastases (CRLM) who progressed following standard chemotherapy regimens. MethodsFrom March 2017 to April 2023, CRC patients with unresectable CRLM who progressed following standard chemotherapy and subsequently received HAIC oxaliplatin plus 5-FU/FUDR were evaluated. Objective response rate (ORR), disease control rate (DCR), median depth of tumor response (DpR), no evidence of disease (NED) rate, progression-free survival (PFS), overall survival (OS), and safety were assessed. ResultsA total of 21 patients who progressed after a median of two (range: 1–4) lines of standard systemic chemotherapy were included. The ORR and DCR were 28.6 % and 95.2 %, respectively, with six patients reaching partial response. Additionally, the median DpR was 10.6 %, and seven patients underwent successful conversion surgery. Stratification further revealed that patients with liver-limited metastases had a significantly better PFS compared to patients with concurrent hepatic and extrahepatic metastases (P = 0.0003). ConclusionHAIC oxaliplatin plus 5-FU/FUDR is a robust regimen for treatment-resistant CRC patients with unresectable CRLM, especially in those with liver-limited disease.

Multifunctional PAMAM Dendrimers Carrying SAHA, 5‐FU, and a Therapeutic Gene for Targeted Co‐Delivery Toward Colorectal Cancer Cells

ABSTRACTA promising approach to treat colorectal cancer (CRC) involves combining chemotherapy, epigenetics, and gene therapy to combat drug resistance. Multifunctional nanocarriers have emerged as a valuable tool for targeted CRC therapy. By delivering multiple treatments directly to cancer cells, these nanocarriers offer the potential for improved outcomes and reduced side effects. PAMAM‐based dendrimers were functionalized with a unique combination of folic acid, 5‐FU, SAHA, and plasmid DNA pCIneoGFP for targeted delivery to CRC cells. Biophysical characterizations of therapeutic loaded dendrimers and their complexes with pCIneoGFP were performed by: dynamic light scattering, fluorescence spectroscopy, and gel electrophoresis. Further, cellular analyses of dendriplexes demonstrated high transfection efficiency and anticancer activity on HCT 116 and HT‐29 cell lines. We have successfully developed a multifunctional nanocarrier platform based on PAMAM dendrimers, offering a promising tool for targeted combination therapy of CRC.

Application of Nanoparticles in the Diagnosis and Treatment of Colorectal Cancer.

Colorectal cancer is a common malignant tumor with high morbidity and mortality rates, imposing a huge burden on both patients and the healthcare system. Traditional treatments such as surgery, chemotherapy and radiotherapy have limitations, so finding more effective diagnostic and therapeutic tools is critical to improving the survival and quality of life of colorectal cancer patients. While current tumor targeting research mainly focuses on exploring the function and mechanism of molecular targets and screening for excellent drug targets, it is crucial to test the efficacy and mechanism of tumor cell therapy that targets these molecular targets. Selecting the appropriate drug carrier is a key step in effectively targeting tumor cells. In recent years, nanoparticles have gained significant interest as gene carriers in the field of colorectal cancer diagnosis and treatment due to their low toxicity and high protective properties. Nanoparticles, synthesized from natural or polymeric materials, are NM-sized particles that offer advantages such as low toxicity, slow release, and protection of target genes during delivery. By modifying nanoparticles, they can be targeted towards specific cells for efficient and safe targeting of tumor cells. Numerous studies have demonstrated the safety, efficiency, and specificity of nanoparticles in targeting tumor cells, making them a promising gene carrier for experimental and clinical studies. This paper aims to review the current application of nanoparticles in colorectal cancer diagnosis and treatment to provide insights for targeted therapy for colorectal cancer while also highlighting future prospects for nanoparticle development.

Hybrid Biosilica Nanoparticles for in-vivo Targeted Inhibition of Colorectal Cancer Growth and Label-Free Imaging.

Metastasis-initiating cells are key players in progression, resistance, and relapse of colorectal cancer (CRC), by leveraging the regulatory relationship between Transforming Growth Factor-beta (TGF-β) signaling and anti-L1 cell adhesion molecule (L1CAM). This study introduces a novel strategy for CRC targeted therapy and imaging based on the use of a hybrid nanosystem made of gold nanoparticles-covered porous biosilica further modified with the (L1CAM) antibody. The nanosystem intracellularly delivers galunisertib (LY), a TGF-β inhibitor, aiming to inhibit epithelial-mesenchymal transition (EMT), a process pivotal for metastasis. Anti-L1CAM antibody-functionalized nanoparticles (NPs) target tumor-initiating cells expressing L1CAM, inhibiting cancer growth. The number of antibody molecules conjugated to the single NP is precisely quantified, revealing a high surface coverage that facilitates the tumor targeting. The therapeutic efficacy of the nanosystem is investigated in organoid-like cultures of CRC cells and in vivo mouse models, showing a significant reduction in tumor growth. The spatial distribution of NPs within CRC tumors from mice is investigated using a label-free optical approach based on Raman micro-spectroscopy. This research highlights the multifunctional capabilities of engineered biosilica NPs, which offer new insights in targeted CRC therapy and imaging, improving patient outcomes and paving the way for personalized therapies.