Treatment Of Advanced Colorectal Cancer Research Articles

Efficacy and safety of anlotinib as a later-line treatment for advanced colorectal cancer.

194 Background: Colorectal cancer (CRC) is increasingly prevalent in China, with rising incidence and mortality rates. Often, early-stage CRC presents with no symptoms, leading to most patients being diagnosed at an advanced stage, where prognosis is poor. First- and second-line treatments for advanced CRC typically include chemotherapy combined with cetuximab or bevacizumab. However, third-line therapies such as regorafenib, furosemide, and TAS102 have shown limited efficacy. Anlotinib, a multi-targeted tyrosine kinase inhibitor (TKI), has demonstrated improved progression-free survival (PFS) in refractory metastatic CRC (mCRC) in a phase III trial (NCT02332499), showing both efficacy and manageable toxicity. This report provides updated results from extended follow-up. Methods: This study enrolled 73 patients with advanced colorectal cancer who had undergone at least two prior standard treatments and were treated with oral anlotinib hydrochloride (8-12 mg daily, days 1-14 of a 21-day cycle) between November 2021 and March 2024 at Tangdu Hospital. Patients were treated until disease progression or intolerable adverse events. Efficacy was assessed using RECIST version 1.1, and adverse reactions were evaluated using CTCAE version 5.0. The primary endpoints were PFS, disease control rate (DCR), and adverse events (AEs), while secondary endpoints included overall survival (OS). Results: Of the 73 patients included, 38 had an ECOG performance status (PS) of 0-1, and 35 had a PS of 2. Clinical staging identified 18 patients with stage IIIB/IIIC and 55 with stage IV disease. Patients received anlotinib doses of 8 mg (n=11), 10 mg (n=44), or 12 mg (n=18), with 48 patients also receiving chemotherapy and 25 receiving anlotinib alone. The median PFS was 4.0 months (95% CI: 3.4-4.6), and the median OS was 7.0 months (95% CI: 5.7-8.3). Subgroup analysis indicated that patients under 60 years of age, those without liver metastases, and those with ECOG PS 0-1 derived greater benefit from anlotinib. The most common treatment-related adverse event was hypertension (19.2%). Other notable adverse events included elevated AST (11.0%), proteinuria (6.8%), and jaundice (6.8%). Most adverse reactions were grade 1-2, although 1 patient experienced grade ≥3 gastrointestinal bleeding. Conclusions: Anlotinib showed promising efficacy and a favorable safety profile as a later-line treatment for advanced colorectal cancer. These findings suggest that anlotinib may be a viable clinical option for advanced CRC, though larger-scale clinical trials are necessary to confirm these results and further define its role in treatment.

Bevacizumab plus mFOLFOX6/FOLFIRI sequential bevacizumab plus capecitabine maintenance in RAS-mutated advanced colorectal cancer: A real-world study of first-line/second-line conversion therapy.

77 B ackground: Currently, the standard first-line/second-line treatment for advanced colorectal cancer with RAS mutations is chemotherapy combined with bevacizumab. Patients with colorectal cancer confirmed maintenance therapy can effectively improve progression-free survival, improve patient quality of life. Therefore, this study aims to evaluate the efficacy and safety of bevacizumab combined with mFOLFOX6/FOLFIRI sequential bevacizumab combined with capecitabine as first-line/second-line conversion therapy for RAS-mutated advanced colorectal cancer. M ethods: This is an open-label, single-center study in previously untreated patients with RAS mutant mCRC. Eligible patients received first-line chemotherapy of bevacizumab (5mg/m 2 ) combined with mFOLFOX6/FOLFIRI for 12 cycles randomly, during which the efficacy was assessed every 4 cycles, then followed by bevacizumab(7.5mg/m 2 ) in combination with capecitabine maintenance therapy which assessed every 2 cycles until disease progression, and then switched to the second-line therapy FOLFIRI/mFOLFOX6 combined with bevacizumab which was assessed every 4 cycles until disease progression or intolerable toxicity. Imaging studies were performed to assess treatment efficacy according to RECIST1.1 criteria, and the primary endpoint was progression-free survival (PFS), including first-line PFS and second-line PFS after progression, and the secondary endpoints included disease response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. R esults: This study recruited 78 subjects from January 2021 to May 2024. As of September 10, 2024, a total of 70 subjects were analyzable for the first-line treatment, of which 6 subjects met the surgical criteria after treatment and achieved NED status; 45 patients reached the first-line PFS endpoint, with a median PFS (mPFS) of 249 days (95% CI: 204.4-293.6), an ORR of 38.6%, and a DCR of 95.7% . Twenty patients entered the first-line maintenance therapy, with a mPFS of 358 days (95% CI: 53.8-662.2). For the second-line treatment, a total of 43 subjects were analyzable, of which 35 patients reached the second-line PFS endpoint, with a second-line mPFS of 171 days (95% CI: 89.8-252.1). 41 subjects underwent at least one efficacy evaluation, with ORR of 14.6% and DCR of 75.6%. The most common grade 3 treatment-related adverse events were neutropenia, leukopenia, anemia, hypertension, diarrhea, and thrombocytopenia. There were no treatment-related deaths. No new adverse events occurred during the entire combination treatment period. C onclusions: This real world study has demonstrated good tolerability and encouraging clinical efficacy, especially with potential implications for treatment planning and management strategies for advanced colorectal cancer with RAS mutations. Clinical trial information: ChiCTR2100042553 .

Adaptive Plasticity Tumor Cells Modulate MAPK-Targeting Therapy Response in Colorectal Cancer.

MAPK pathway inhibitors (MAPKi) are increasingly used in the treatment of advanced colorectal cancer, but often produce short-lived responses in patients. Although acquired resistance by de novo mutations in tumors have been found to reduce response in some patients, additional mechanisms underlying the limited response durability of MAPK targeting therapy remain unknown. Here, we denote new contributory tumor biology and provide insight on the impact of tumor plasticity on therapy response. Analysis of MAPKi treated patients revealed activation of stemness programs and increased ASCL2 expression, which are associated with poor outcomes. Greater ASCL2 with MAPKi treatment was also seen in patient-derived CRC models, independent of driver mutations. We find ASCL2 denotes a distinct cell population, arising from phenotypic plasticity, with a proliferative, stem-like phenotype, and decreased sensitivity to MAPKi therapy, which were named adaptive plasticity tumor (APT) cells. MAPK pathway suppression induces the APT phenotype in cells, resulting in APT cell enrichment in tumors and limiting therapy response in preclinical and clinical data. APT cell depletion improved MAPKi treatment efficacy and extended MAPKi response durability in mice. These findings uncover a cellular program that mitigates the impact of MAPKi therapies and highlights the importance of addressing tumor plasticity to improve clinical outcomes.

Minimally invasive multivisceral resection in rectal cancer: Preparation or Precipitation?

Rectal cancer is a malignant neoplasm that constitutes a significant public health challenge due to its high incidence and associated mortality. In this editorial, we comment on the article by Chan et al. In recent years, there has been progress in the development of new treatments for initial and metastatic rectal cancer due to introduction of techniques of innovative and minimally-invasive surgery (MIS) such as laparoscopy and robotic surgery. However, only a few studies have analyzed the feasibility, safety, and results of MIS in relation to open surgery, thereby highlighting the promising and superior results of MIS in functional and oncological terms. The findings were corroborated by the comparative study of Chan et al which evaluated the feasibility and safety of minimally invasive multivisceral resection (miMVR). A comparison of postoperative outcomes between open MVR and miMVR showed that miMVR presented less blood loss, fewer postoperative complications, and less morbidity. This editorial article is focused specifically on analysis of the characteristics of new minimally-invasive surgical techniques in rectal cancer, particularly in advanced stages. The importance of future research is emphasized by progress in knowledge, training, and clinical practice in the application of these surgical procedures for the treatment of advanced colorectal cancer.

Raddeanin A Inhibits Colorectal Cancer Growth and Ameliorates Oxaliplatin Resistance Through the WNT/β-Catenin Signaling Pathway.

Background: Chemotherapy based on oxaliplatin (OXA) is the first-line treatment for advanced colorectal cancer (CRC), and acquired resistance to OXA is the main reason for clinical treatment failure in CRC. Methods: To search for compounds that can reverse OXA resistance, we screened a small molecule inhibitor drug library and identified a drug, Raddeanin A (RA), that enhanced the anticancer effect of OXA. Using human CRC cell lines, CRC organoid models, and invivo subcutaneous tumorigenic studies, we determined that RA inhibits the proliferation of CRC cells by promoting apoptosis and inducing cell cycle arrest. Results: We constructed OXA-resistant CRC cell lines and demonstrated that RA enhances the sensitivity of these cells to OXA. Further experiments showed that the mechanism by which RA enhanced the anticancer effects of OXA in CRC was by inhibiting the activation of the WNT/β-catenin signaling pathway. Conclusions: Because RA has been shown to be biocompatible in animal models, there is a possibility that RA could be developed as a sensitizer for resistant cancer cells or as a novel lead compound to enhance the therapeutic efficacy of OXA in resistant CRCs.

Characterizing m6A modification factors and their interactions in colorectal cancer: implications for tumor subtypes and clinical outcomes

BackgroundThe study aims to comprehensively combine colorectal cancer data cohorts in order to analyze the effects of various DNA methylation-coding genes on colorectal cancer patients. The annual incidence and mortality of colorectal cancer are very high, and there are no effective treatments for advanced colorectal cancer. DNA methylation is a method widely used to regulate epigenetics in the molecular mechanism study of tumors.MethodThree single-cell cohorts GSE166555, GSE146771, and EMTAB8107, and five transcriptome cohorts GSE17536, GSE39582, GSE72970, and TCGA-CRC (TCGA-COAD and TCGA-READ) were applied in this study. 2 erasers (ALKBH5 and FTO), There are 7 writers (METTL3, METTL14, WTAP, VIRMA, RBM15, RBM15B, and ZC3H13) and 11 readers (YTHDC1, IGF2BP1, IGF2BP2, IGF2BP3, YTHDF1, YTHDF3, YTHDC2, and HNRNPA2B1, YTHDF2, HNRNPC and RBMX), a total of 20 M6A regulators, were used as the basis of the dataset in this study and were applied to the construction of molecular typing and prognostic models. Drugs that are differentially sensitive in methylation-regulated gene-related prognostic models were identified using the ConsensusClusterPlus package, which was also used to identify distinct methylation regulatory expression patterns in colorectal cancer and to model the relationship between tissue gene expression profiles and drug IC50 values. Finally, TISCH2 assessed which immune cells were significantly expressed with M6A scores. The immunosuppression of M6A methylation is spatially explained.ResultsThis study used data from 583 CRC patients in the TCGA-CRC cohort. Firstly, the mutation frequency and CNV variation frequency of 20 m6A modification-related factors were analyzed, and the corresponding histogram and heat map were drawn. The study next analyzed the expression variations between mutant and wild forms of the VIRMA gene and explored differences in the expression of these variables in tumor and normal tissues. In addition, the samples were divided into different subgroups by molecular clustering method based on m6A modification, and each subgroup’s expression and clinicopathological characteristics were analyzed. Finally, we compared prognostic differences, tumor microenvironment (TME) characteristics, immune cell infiltration, and gene function enrichment among different subpopulations. We also developed a colorectal cancer m6A-associated gene signature and validated its prognostic effects across multiple cohorts. Finally, using single-cell RNA sequencing data, we confirmed that tumor cells show elevated expression of m6A-related gene signatures.DiscussionThis study explored the mutation frequency, expression differences, interactions, molecular clustering, prognostic effect, and association with tumor characteristics of m6A modification-related factors in CRC and validated them at the single-cell level. These results clarify the association between m6A alteration and colorectal cancer (CRC) and offer important insights into the molecular recognition and management of cancer.

AKR1C1 interacts with STAT3 to increase intracellular glutathione and confers resistance to oxaliplatin in colorectal cancer

Oxaliplatin (OXA), a platinum-based chemotherapeutic agent, remains a mainstay in first-line treatments for advanced colorectal cancer (CRC). However, the eventual development of OXA resistance represents a significant clinical challenge. In the present study, we demonstrate that the aldo-keto reductase 1C1 (AKR1C1) is overexpressed in CRC cells upon acquisition of OXA resistance, evident in OXA-resistant CRC cell lines. We employed genetic silencing and pharmacological inhibition strategies to establish that suppression of AKR1C1 restores OXA sensitivity. Mechanistically, AKR1C1 interacts with and activates the transcription factor STAT3, which upregulates the glutamate transporter EAAT3, thereby elevating intracellular glutathione levels and conferring OXA resistance. Alantolactone, a potent natural product inhibitor of AKR1C1, effectively reverses this chemoresistance, restricting the growth of OXA-resistant CRC cells both in vitro and in vivo. Our findings uncover a critical AKR1C1-dependent mechanism behind OXA resistance and propose a promising combinatorial therapeutic strategy to overcome this resistance in CRC.

Application of ARHGAP8 in Predicting the Efficacy of Neoadjuvant Chemotherapy for Locally Advanced Mid-Low Rectal Cancer

Objective To analyze the sensitivity of ARHGAP8 in predicting the efficacy of neoadjuvant chemotherapy in the patients with locally advanced mid-low colorectal cancer and provide accurate evidence for the treatment of advanced colorectal cancer. Methods The differentially expressed gene ARHGAP8 was screened out by bioinformatics analysis.Cancer tissue and rectal tissue of 68 patients with primary rectal cancer were selected.The rectal cancer tissue samples and the rectal tissue samples were collected for clinical validation of ARHGAP8 expression by quantitative real-time PCR,Western blotting,and immunohistochemistry.The clinical and pathological features such as gender,age,tumor stage,differentiation degree,and pathological type of the patients were collected for functional validation.Forty-four patients with locally advanced mid-low rectal cancer who received neoadjuvant chemotherapy were selected for immunohistochemical examination of ARHGAP8 expression.The expression level of ARHGAP8 was compared between before and after chemotherapy and among different efficacy groups. Results The bioinformatics analysis revealed differences in the expression level of ARHGAP8 between the cancer tissue and rectal tissue (P<0.001).The expression level of ARHGAP8 was correlated with tumor stage (P=0.024),lymph node metastasis (P=0.007),and age (P=0.005).Quantitative real-time PCR results showed that the mRNA level of ARHGAP8 in the cancer tissue was higher than that in the rectal tissue (P<0.001).Western blotting and immunohistochemistry results demonstrated that the protein level of ARHGAP8 in the cancer tissue was higher than that in the rectal tissue (P=0.011).The expression of ARHGAP8 was correlated with tumor size (P=0.010) and pathological stage (P=0.005),while it showed no significant association with tumor differentiation degree,lymph node metastasis,liver metastasis,Ki-67,or microsatellite instability expression level.The 44 patients receiving neoadjuvant chemotherapy included 13,8,8,and 15 patients of tumor regression grades 0,1,2,and 3,respectively.Among them,65.91% (29/44) patients showed responses to the treatment.After neoadjuvant chemotherapy,the expression of ARHGAP8 in the cancer tissue was down-regulated in the patients who responded to the chemotherapy (P<0.001).The response rate in the patients with low protein level of ARHGAP8 was 92.86%,which was higher than that (53.33%) in the patients with high protein level of ARHGAP8 (P=0.033). Conclusion ARHGAP8 is highly expressed in the rectal cancer tissue.The patients with locally advanced mid-low rectal cancer and low ARHGAP8 expression are more sensitive to neoadjuvant chemotherapy with the XELOX protocol.ARHGAP8 can serve as a potential biomarker for the occurrence and development of rectal cancer and an important index for evaluating the efficacy of neoadjuvant chemotherapy with the XELOX protocol in the patients with locally advanced mid-low rectal cancer.

Identification of ASMTL-AS1 and LINC02604 lncRNAs as novel biomarkers for diagnosis of colorectal cancer

PurposeColorectal cancer is one of the major leading causes of death worldwide, and available treatments for advanced colorectal cancer are not successful. Therefore, early detection of colorectal cancer is essential to improve patient survival, and biomarkers are potential tools to achieve this goal. Considering the key role of lncRNAs in cancers, the aim of this study is to identify lncRNAs involved in colorectal cancer as new potential prognosis biomarkers for CRC.MethodsIn this observational study, gene expression data obtained from the TCGA database were analyzed, Identification of differentially expressed mRNAs, miRNAs, and lncRNAs was performed, and ceRNA network was drawn. Also, survival analysis of patients was performed in order to identify potential biomarkers related to the diagnosis and prognosis of colon cancer. After confirming the results using the GSE39582 dataset, the expression of target lncRNAs in colorectal tumor tissues was also investigated to confirm the bioinformatic data.ResultsAnalysis of the TCGA data showed that the expression of three lncRNAs—SNHG7, ASMTL-AS1, and LINC02604—that had the highest interaction with other miRNAs and mRNAs identified based on the ceRNA network was increased in colorectal cancer. Also, based on the ceRNA network, three microRNAs, hsa-let-7d-5p, hsa-mir-92a-3p, and hsa-mir-423-5p, and eight mRNAs, including CPA4, MSI2, RRM2, IGF2BP1, ONECUT2, HMGA1, SOX4, and SRM, were associated with all three mentioned lncRNAs, the expression of microRNAs was decreased and the expression of mRNAs was increased. By enrichment analysis, it was found that the target lncRNAs are involved in the processes of cell proliferation, apoptosis, and metastasis, indicating their importance in the development and malignancy of colorectal cancer. Furthermore, Kaplan–Meier analysis showed a significant increase in mortality in patients with higher expression levels of these lncRNAs. Analysis of the GSE39582 dataset, and real-time RT-PCR analysis, confirmed our bioinformatic results. Also, ROC analysis showed that SNHG7 was a relatively good promising biomarker (AUC = 0.73, p value = 0.02), while ASMTL-AS1 (AUC = 0.92, p value < 0.0001) and LINC02604 (AUC = 1.00, p value < 0.0001) emerged as excellent diagnostic biomarkers in colorectal cancer.ConclusionIt seems that increased expression of lncRNAs ASMTL-AS1 and LINC02604 can serve as molecular biomarkers for CRC, possibly through the sponge hsa-let-7d-5p, hsa-mir-92a-3p, and hsa-mir-423 5p, which increases target mRNAs, which are effective in the carcinogenesis process.

Subacute inferior vena cava occlusion after treatment for advanced colorectal cancer: presentation and management

Thrombosis of the inferior vena cava is an uncommon condition and may not be recognized until the affected patient develops severe symptoms. It is associated with a higher risk of complications than other locations of deep venous thrombosis. Here we present a case of a 72-year-old man with bilateral occlusion of the external iliac veins and inferior vena cava. Keywords: Inferior vena cava, thrombosis, managemen

An optimal combination of four active components in Huangqin decoction for the synergistic sensitization of irinotecan against colorectal cancer

BackgroundIrinotecan (CPT-11) is a first-line treatment for advanced colorectal cancer (CRC). Four components (baicalin, baicalein, wogonin, and glycyrrhizic acid) derived from Huangqin Decoction (HQD) have been proven to enhance the anticancer activity of CPT-11 in our previous study.ObjectiveThis study aimed to determine the optimal combination of the four components for sensitizing CPT-11 as well as to explore the underlying mechanism.MethodsThe orthogonal design method was applied to obtain candidate combinations (Cmb1-9) of the four components. The influence of different combinations on the anticancer effect of CPT-11 was first evaluated in vitro by cell viability, wound healing ability, cloning formation, apoptosis, and cell cycle arrest. Then, a CRC xenograft mice model was constructed to evaluate the anticancer effect of the optimal combination in vivo. Potential mechanisms of the optimal combination exerting a sensitization effect combined with CPT-11 against CRC were analyzed by targeted metabolomics.ResultsIn vitro experiments determined that Cmb8 comprised of baicalin, baicalein, wogonin, and glycyrrhizic acid at the concentrations of 17 μM, 47 μM, 46.5 μM and 9.8 μM respectively was the most effective combination. Importantly, the cell viability assay showed that Cmb8 exhibited synergistic anticancer activity in combination with CPT-11. In in vivo experiments, this combination (15 mg/kg of baicalin, 24 mg/kg of baicalein, 24 mg/kg of wogonin, and 15 mg/kg of glycyrrhizic acid) also showed a synergistic anticancer effect. Meanwhile, inflammatory factors and pathological examination of the colon showed that Cmb8 could alleviate the gastrointestinal damage induced by CPT-11. Metabolic profiling of the tumors suggested that the synergistic anticancer effect of Cmb8 might be related to the regulation of fatty acid metabolism.ConclusionThe optimal combination of four components derived from HQD for the synergistic sensitization of CPT-11 against CRC was identified.

Discovery of the Next-Generation Platinum-Based Anticancer Agents for Combating Oxaliplatin-Induced Drug Resistance.

Oxaliplatin-based chemotherapy has proven to be one of the most effective treatments for advanced or metastatic colorectal cancer. However, increasing clinical resistance to oxaliplatin poses unprecedented challenges for both patients and clinicians. Despite extensive efforts to combat this issue, to date, no new molecules have been discovered that can successfully replace oxaliplatin. With the aim of developing a new generation of Pt(II)-based anticancer agents in response to the challenges of oxaliplatin-induced drug resistance, we performed a systematic screening of new Pt(II)-complexes with a quantitative structure-activity relationship (QSAR) study based on their antiresistance activity against oxaliplatin-resistant colon cancer cells. The results revealed that both the structure and chirality of the chelating ligand had a significant impact on the antiresistance properties of the Pt(II)-complexes. Our study culminated in the identification of chiral R-binaphthyldiamine-ligated Pt(II)-malonatoglycoconjugates that can completely counteract oxaliplatin resistance with excellent in vitro and in vivo potency.

To investigate the clinical efficacy of recombinant human endostatin combined with FOLFOX4 in the treatment of advanced colorectal cancer.

To investigate the clinical efficacy of recombinant human endostatin combined with FOLFOX4 in the treatment of advanced colorectal cancer.

The effect of HER2-targeted inhibitors as second-line or later-line regimens in the treatment of HER2-positive advanced colorectal cancer: A systematic review and meta-analysis.

e15542 Background: To systematically evaluate and meta-analyze the efficacy and safety of Human Epidermal Growth Factor Receptor-2 Inhibitor (HER2 Inhibitor) as a second-line or later-line antitumor regimen in the treatment of HER2-positive advanced colorectal cancer and provides a new method to treat metastatic colorectal cancer who failed with first-line treatment. Methods: Literature focusing on the use of HER2-targeted inhibitors in the treatment of HER2-positive mCRC was downloaded from Pubmed, Web of Science, EMBASE and Google Scholar databases from January 1, 2019 to October 31, 2022, and the final included articles were determined by screening and relevant data were extracted, including Objective Response Rate (ORR), disease control rate (DCR), Progression-Free-Survival (PFS), Overall Survival (OS), and Serious Adverse Events (SAEs) (Grade 3/4 adverse events). Binary variables were compared using 95% confidence intervals (CI) and odds ratios (OR); for continuous variables, heterogeneity was checked using Cochran's Q Test (p values and I²) and Weighted mean difference (WMD) and 95% CI. P &lt; 0.05 or I² &gt; 50% denote statistical significance, and results were combined using a random-effects model. The efficacy and safety of adding HER2-targeted inhibitors in treating HER2-positive mCRC were further discussed using the above methods. Results: The systematic review and meta-analysis included 17 studies with a total of 267 patients, with an overall DCR of 57% (95% CI: 43%-70%), an ORR of 29% (95% CI: 21%-37%), a median OS of 13.11 months (95% CI: 10.57-15.64), a median PFS of 4.40 months (95% CI: 3.64-5.15), and SAEs of 20% (95% CI: 0.11-0.29). The efficacy of the second-line and later-line treatment was significantly better than that of the well-known EPIC study, ML18147 study, CONCUR study and FRESCO-2 study. Conclusions: Systematic review and meta-analysis show that HER2-targeted inhibitors as second-line or later-line regimens demonstrate ideal antitumor efficacy and safety in HER2-positive mCRC, which is better than the standard regimen without anti-HER2 therapy. Specifically, the new ADC drug (A antibody-drug Conjugate, ADC) should be able to improve the treatment effect of these patients more effectively. Therefore, HER2-targeted inhibitors can effectively improve the efficacy of second-line and later-line therapy for HER2-positive mCRC. Furthermore, it is still worth exploring its therapeutic effects application as first-line therapy, which is expected to offer new strategies for the clinical diagnosis and treatment of HER2-positive advanced colorectal cancer.

Efficacy and safety of chidamide in combination with serplulimab and standard third-line treatments in advanced colorectal cancer: A single arm, exploratory phase 2 trial.

TPS3637 Background: The efficacy of third line and subsequent treatments for advanced colorectal cancer (mCRC) is suboptimal, and the available drug options are limited. Approximately 95% of mCRC patients belong to the type of satellite stability (MSS), which often shows poor response to single immunotherapy. Previous clinical trials have preliminarily demonstrated that the potential application of combining anti-angiogenesis drugs with immune checkpoint inhibitors (ICIs) in mCRC. Chidamide is an isoform selective inhibitor of histone deacetylase (HDAC). Studies have shown its synergistic effect with PD-1 monoclonal antibody in anti-tumor activity. Therefore, we aim to conduct further investigations centered on the combination of Chidamide+Serplulimab+standard third-line treatments in mCRC. Methods: This prospective, open-label, single-arm, exploratory multi-center clinical trial has been planned to enroll 30 patients with advanced CRC who have progressed after two lines of standard therapies. The key inclusion criteria are: pathologically confirmed colorectal malignancy; age ≥18 years, regardless of gender; estimated survival ≥3 months; ECOG score 0-1; at least one measurable lesion according to iRECIST criteria; requiring third-line or beyond treatment and no prior treatment with PD1 monoclonal antibody, regorafenib/fruquintinib or TAS-102±bevacizumab; adequate major organ function; and signed informed consent and good compliance, agreeing to cooperate with survival follow-up. Enrolled patients receive Chidamide (20mg twice a week), Serplulimab (3mg/kg on day 1 every two weeks), and standard third-line treatments (TAS-102 35mg/m² twice daily on days 1-5 and 8-12 of a 28-day cycle ± bevacizumab 5mg/kg on day 1 every two weeks or regorafenib 120mg daily or fruquintinib 5mg daily for three weeks followed by one week off ).The primary endpoints are safety and objective response rate (ORR) determined by investigators. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate(DCR), PFS rate at 6 months and 12 months, OS rate at 6 months and 12 months, DCR, quality of life score(QoL), and nutritional score PG-SGA. As of February 2024, eight patients have been enrolled in the study. Trial registration number: ChiCTR2300077213. Clinical trial information: ChiCTR2300077213.

Single-center retrospective analysis of second-line treatment with regorafenib in patients with advanced colorectal cancer among the COVID-19 pandemic.

e15552 Background: Regorafenib targets multiple tyrosine kinases that has been approved for the third-line treatment in metastatic colorectal cancer (mCRC) patients in China. Here, We retrospectively analyzed the efficacy and safety of regorafenib alone or combined with chemotherapy/immunotherapy in the second-line treatment for those who cannot visit hospital for their chemotherapies because of the COVID-19 pandemic. Methods: Individual patient data from Peking University Third Hospital were analyzed retrospectively from January 2020 to September 2023. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS) and safety. Results: The median age of 31 patients was 65 years, the median PFS was 6 months (1–21 months), and the median OS was 20 months (3–38 months). PFS tended to be prolonged with regorafenib plus capecitabine or immunotherapy in 12 subjects versus regorafenib alone in 19 subjects (8 months vs. 4 months, P = 0.306), with no statistical difference, and so did OS (27 months vs. 15 months, P = 0.899).The analysis of PFS (2.5 months vs. 7 months vs. 4 months, P = 0.164) and OS (13 months vs. 28 months vs. 20 months, p = 0.417) in patients with liver, lung, or abdominal/peritoneal metastases at the initiation of treatment demonstrated poor survival prognosis in patients with liver metastasis. Multivariate analysis showed that regorafenib combined with capecitabine or immunotherapy (wald = 5.766, p = 0.016) and non-liver metastasis (wald = 4.223, p = 0.040) were independent prognostic factors for PFS in the second-line treatment. Adverse drug reactions (ADRs) mainly included hand-foot skin reactions (HFSRs), fatigue, hypertension, and proteinuria, due to which 3 subjects discontinued the treatment. The incidence of Grade 3/4 ADRs was 19.3%, 16.9%, 12.9%, and 9.6%, respectively. Conclusions: Regorafenib alone or combined with chemotherapy/immunotherapy is safe and feasible in the second-line treatment for advanced colorectal cancer, and therefore further prospective studies can be conducted to explore combination therapies.

Updated efficacy and safety results from the phase Ib/II study of surufatinib combined with camrelizumab and chemotherapy in patients with advanced colorectal cancer.

e15547 Background: Preclinical and clinical data have demonstrated the synergistic anti-tumor effects of surufatinib, a novel VEGFR1-3, FGFR and CSF-1R inhibitor, in combination with immune checkpoint inhibitors (ICIs)/chemotherapy. A phase Ib/II, open-label study (NCT04929652) was conducted to evaluate the efficacy and safety of surufatinib plus camrelizumab (anti-PD-1), irinotecan and GM-CSF as second-line treatment in advanced colorectal cancer (CRC). In the phase Ib part, this combination showed favorable safety and efficacy profile, which was presented at ASCO 2023 in poster format (#255). Here, we reported the updated results from the phase Ib and phase II dose escalation part together. Methods: In the phase Ib, pts with CRC received surufatinib at 250mg once daily (QD) as starting dose, in combination with fixed dose of camrelizumab (200 mg, d1), irinotecan (200 mg/m2, d1) and GM-CSF (5ug/kg, d2-d7), every 3 weeks (Q3W). It had been reported in phase Ib that surufatinib 300 mg QD was defined as the recommended phase 2 dose (RP2D). In phase II dose expansion part, a further 36 pts were treated with the same regimen. The primary endpoint of phase II was ORR as per RECIST 1.1. Secondary endpoints included PFS, DCR, OS and safety. Results: As of Jan 18, 2024, 30 CRC pts (median age 57) were enrolled in the study with 12 pts in the phase Ib part and 18 pts in the phase II part. 70% were male and 23% had ECOG PS 1. 24/30 (80%) pts were positive for KRAS, NRAS or BRAF mutations. Among the 30 efficacy evaluable pts, the ORR was 30.0% (95% CI 14.7–49.4; 9 PR) and DCR was 93.3% (95% CI 77.9–99.2; 28 PR+SD). Pts with RAS/BRAF mutations were more likely to achieve better responses (9 PR in 24 pts, ORR-37.5%). After a median follow-up time of 11.1 months, the median PFS was 6.34 months (95% CI 4.57-9.23) and median OS was not mature. The most common grade 1-2 treatment related adverse events (TRAEs) (≥35%) were diarrhea (70%), fatigue (40%), anemia (36.7%), proteinuria (36.7%) and nausea (36.7%). Eleven pts experienced at least one grade 3 or 4 TRAEs. Grade 3 or 4 TRAEs occurred in &gt; 1 pt included diarrhea (n = 3, 10%) and neutrophil count decreased (n = 2, 6.7%). Conclusions: Surufatinib plus camrelizumab, irinotecan and GM-CSF demonstrated promising anti-tumor activity in pts with advanced CRC, with a manageable safety profile. Expansion enrollment is ongoing and updated information will be presented. Clinical trial information: NCT04929652 .

Preclinical development of ATR04-484, an auxotrophic strain of Staphylococcus epidermidis, for the topical treatment of epidermal growth factor receptor (EGFR) inhibitor-induced dermal toxicity.

e24074 Background: Agents targeting the EGFR-mediated signaling pathway are commonly used for the treatment of advanced lung, pancreatic, colorectal, and head and neck cancers. Significant dermal toxicities, which occur in up to 90% of patients treated with EGFR inhibitors (EGFRis) and other therapies inhibiting downstream signaling pathways, may be disruptive to a patient’s quality of life and adherence to therapy. Inhibition of the EGFR pathway may suppress host defenses and lead to opportunistic pathogenic colonization or infection. EGFRi-induced dermal toxicity is associated with elevated levels of Staphylococcus aureus and IL-36γ. ATR04-484 is a topical ointment containing S. epidermidis strain SE484, isolated from a healthy human volunteer that was selected for its ability to inhibit S. aureus and IL-36γ . Methods: Reconstructed human epidermis (RHE) and ex vivo pig skin were used to measure the effect of ATR04-484 on S. aureus in therapeutic and prophylactic settings with S. aureus added prior to or after ATR04-484, respectively. To evaluate the anti-inflammatory effects of ATR04-484, IL-36γ levels were measured on untreated RHE and RHE treated with erlotinib alone or in combination with ATR04-484. 104 colony-forming units (CFU) of methicillin-resistant (MRSA) or methicillin-sensitive (MSSA) S. aureus were used. Toxicology was assessed by measuring cell viability in three in vitro toxicology assays: the eye irritant potential was tested on 3D reconstituted human cornea-like epithelium (RhCE), the skin irritant potential of the strain in the ointment was assessed on 3D RHE, and the skin corrosive potential was evaluated on RHE. Results: ATR04-484 comparably inhibited growth of both MRSA and MSSA in therapeutic and prophylactic settings. In a therapeutic setting, ATR04-484 inhibited MRSA growth by 1 log (90%) compared to untreated MRSA in both RHE and pig skin. In a prophylactic setting, ATR04-484 inhibited MRSA growth by approximately 5 logs on RHE and 2 logs on pig skin. Additionally, application of ATR04-484 reduced IL-36γ to a level comparable to untreated RHE. The effect was dose-dependent; application of 109CFU/cm2 of ATR04-484 showed more potent IL-36γ reduction compared to 108 CFU/cm2. The three toxicology assays indicate that ATR04-484 does not cause irritation or corrosion. Conclusions: In these preclinical studies, ATR-04-484 showed a promising preclinical profile for the treatment of EGFRi-induced dermal toxicity by significantly reducing S. aureus growth, completely ameliorating IL-36γ levels, and showing no safety concerns.

Fisetin and/or capecitabine causes changes in apoptosis pathways in capecitabine-resistant colorectal cancer cell lines

Capecitabine is recommended as one of the first-line chemotherapy treatments for advanced or metastatic colorectal cancer. Researches have been conducted on capecitabine’s impact on the viability of human colon cancer cells and its potential to induce apoptosis. However, even in cases initially responsive to treatment, the development of acquired resistance significantly limits its efficacy. Challenges still exist in effectively treating patients with chemotherapy, and developing new cytotoxic drugs is hindered by drug resistance. Fisetin alters the cell cycle, inducing apoptosis, inhibiting cancer cell proliferation, and enhancing the therapeutic effectiveness of chemotherapy drugs. This work aims to create a plan for reversing capecitabine resistance. For this purpose, the role of capecitabine and/or fisetin combinations in cell proliferation and apoptosis has been determined in both wild-type and capecitabine-resistant HT29 cells (CR/HT29). We developed capecitabine-resistant cell line from wild-type HT29 cells. This study demonstrated the effects of capecitabine, fisetin, and their combinations on both resistant and wild-type cells through experiments including cell survival skills, cell proliferation, wound healing, colony formation, hoechst staining, and western blot analysis. We established capecitabine-resistant cell lines. P-gp expression increased in CR/HT29 cells. Capecitabine effects on a CR/HT29 cells less than wild-type HT29 cells. The combination of fisetin and capecitabine in cell proliferation caused greater reductions in wild-type HT29 cells than in capecitabine-resistant cells. Fisetin has also additive effects on the apoptotic pathway in CR/HT29 cells. This study provides new perspectives on the combination of capecitabine and/or flavonoid treatment in resistant cells.Graphical abstract

LncRNA GAS6-AS1 contributes to 5-fluorouracil resistance in colorectal cancer by facilitating the binding of PCBP1 with MCM3

5-Fluorouracil (5-FU) resistance has always been a formidable obstacle in the adjuvant treatment of advanced colorectal cancer (CRC). In recent years, long non-coding RNAs have emerged as key regulators in various pathophysiological processes including 5-FU resistance. TRG is a postoperative pathological score of the chemotherapy effectiveness for CRC, of which TRG 0–1 is classified as chemotherapy sensitivity and TRG 3 as chemotherapy resistance. Here, RNA-seq combined with weighted gene correlation network analysis confirmed the close association of GAS6-AS1 with TRG. GAS6-AS1 expression was positively correlated with advanced clinicopathological features and poor prognosis in CRC. GAS6-AS1 increased the 50% inhibiting concentration of 5-FU, enhanced cell proliferation and accelerated G1/S transition, both with and without 5-FU, both in vitro and in vivo. Mechanistically, GAS6-AS1 enhanced the stability of MCM3 mRNA by recruiting PCBP1, consequently increasing MCM3 expression. Furthermore, PCBP1 and MCM3 counteracted the effects of GAS6-AS1 on 5-FU resistance. Notably, the PDX model indicated that combining chemotherapeutic drugs with GAS6-AS1 knockdown yielded superior outcomes in vivo. Together, our findings elucidate that GAS6-AS1 directly binds to PCBP1, enhancing MCM3 expression and thereby promoting 5-FU resistance. GAS6-AS1 may serve as a robust biomarker and potential therapeutic target for combination therapy in CRC.