Treatment Of Advanced Colorectal Cancer Research Articles

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.

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 < 0.05 or I² > 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.

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 > 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.

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.

Abstract 1728: Senescent cancer-associated fibroblast drives colorectal cancer progression in a METTL1-dependent manner

Abstract Background: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. More comprehensive studies of key molecular alterations were urgent. Cancer-associated fibroblasts (CAFs) exhibit the senescence-associated secretory phenotype (SASP) which contributes to the progression of cancer through the transcriptomic reprogramming at their senescent states. N7-methylguanosine (m7G), one of the most common RNA modifications, is catalyzed by Methyltransferase-like 1 (METTL1) in human RNA. We therefore investigated the role of METTL1-mediated transcriptomic reprogramming in the crosstalk between senescent CAFs (s-CAFs) and cancer cells. Methods: The SA-β-gal staining and immunofluorescence assays were conducted to characterize the senescent cells. The transwell, wound scratch and organoids assays were preformed to test the abilities of viability, migration and invasion. The concentrations of cytokines and chemokines were determined by Luminex liquid suspension chip. The methylated RNA immunoprecipitation and dot blot assays were performed to characterize the RNA m7G levels in the transcriptome. Results: Through the activation of mTOR signaling, the expression of P16 gene was significantly up-regulated in s-CAFs which was treated by H2O2, accompanied by an increased proportion of SA-β-gal+ cells and altered expression level of METTL1 protein. Luminex liquid suspension chip analysis revealed a significant increase in SASP cytokines such as TNF-α and PDGF-BB in the conditioned media of s-CAFs. Co-culturing CRC cell and organoids with s-CAFs resulted in down-regulation of METTL1 expression and significantly enhanced its invasion and migration abilities, while organoids exhibited increased activity and proliferated more rapidly. TNF-α and PDGF-BB down-regulated the METTL1 expression in CRC cell, while inhibitors targeting TNF-α and PDGF-BB rescued this trend. Interestingly, the regulatory effect on METTL1 of CRC cell by s-CAFs which treated by rapamycin was disappeared. These results indicated that METTL1 modulates RNA m7G modifications influenced by SASP cytokines for promoting CRC metastasis flow. Conclusions: In summary, our findings illustrated that METTL1 plays a role in relaying tumor-promoting signals from s-CAFs in response to SASP cytokines. This ultimately contributes to the tumor-promoting signal flow from s-CAFs. This highlights the importance of understanding the molecular mechanisms underlying the communication between different cell types in the tumor microenvironment. In addition, it also provides a novel strategy for clinical treatment in advanced CRC. Keywords: METTL1, Epigenetic regulation, Senescent CAFs, Tumor microenvironment Citation Format: Jingrong Weng, Xiaolin Wang, Xiaoxia Liu, Yanxin Luo, Huichuan Yu. Senescent cancer-associated fibroblast drives colorectal cancer progression in a METTL1-dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1728.

CircHAS2 activates CCNE2 to promote cell proliferation and sensitizes the response of colorectal cancer to anlotinib

BackgroundTyrosine kinase inhibitors (TKIs) are crucial in the targeted treatment of advanced colorectal cancer (CRC). Anlotinib, a multi-target TKI, has previously been demonstrated to offer therapeutic benefits in previous studies. Circular RNAs (circRNAs) have been implicated in CRC progression and their unique structural stability serves as promising biomarkers. The detailed molecular mechanisms and specific biomarkers related to circRNAs in the era of targeted therapies, however, remain obscure.MethodsThe whole transcriptome RNA sequencing and function experiments were conducted to identify candidate anlotinib-regulated circRNAs, whose mechanism was confirmed by molecular biology experiments. CircHAS2 was profiled in a library of patient-derived CRC organoids (n = 22) and patient-derived CRC tumors in mice. Furthermore, a prospective phase II clinical study of 14 advanced CRC patients with anlotinib-based therapy was commenced to verify drug sensitivity (ClinicalTrials.gov identifier: NCT05262335).ResultsAnlotinib inhibits tumor growth in vitro and in vivo by downregulating circHAS2. CircHAS2 modulates CCNE2 activation by acting as a sponge for miR-1244, and binding to USP10 to facilitate p53 nuclear export as well as degradation. In parallel, circHAS2 serves as a potent biomarker predictive of anlotinib sensitivity, both in patient-derived organoids and xenograft models. Moreover, the efficacy of anlotinib inclusion into the treatment regimen yields meaningful clinical responses in patients with high levels of circHAS2. Our findings offer a promising targeted strategy for approximately 52.9% of advanced CRC patients who have high circHAS2 levels.ConclusionsCircHAS2 promotes cell proliferation via the miR-1244/CCNE2 and USP10/p53/CCNE2 bidirectional axes. Patient-derived organoids and xenograft models are employed to validate the sensitivity to anlotinib. Furthermore, our preliminary Phase II clinical study, involving advanced CRC patients treated with anlotinib, confirmed circHAS2 as a potential sensitivity marker.

Is Older Age an Independent Prognostic Factor of Survival in Metastatic Colorectal Cancer?

Plain Language SummaryOlder patients with advanced CRC constitute a heterogeneous population, including patients with excellent health status and others with multiple comorbidities, functional dependence, or limited life expectancy. Furthermore, the definition of an “elderly” or “older” patient is not widely accepted and may vary between studies, although 75 years may be an appropriate cut-off point, as confirmed in our study. At present, there are few prospective and randomized studies focused on the progression and treatment of advanced colorectal cancer in elderly patients, so understanding the factors that influence its clinical course is a difficult challenge. In this retrospective real-world study, we analyze the influence of advanced age on the survival of patients with advanced colorectal cancer. The analysis of eighteen characteristics that were grouped in three subcategories: characteristic related to the patient (age, sex, comorbidities, polypharmacy, ECOG, and nutritional status [albumin levels at diagnosis]), to the tumor (stage at diagnosis, tumor side, molecular profile, tumor burden [CEA levels at diagnosis], location and number of metastasis), and to the treatment administrated (systemic treatment for advanced disease, chemotherapy schedule and number of lines, severe adverse events and dose reductions, and surgery of liver metastasis) showed that older age at diagnosis is not an independent prognostic factor of overall survival in patients with metastatic colorectal cancer. However, tumor burden, nutritional status, systemic treatment of advanced disease, or surgery of liver metastases are independent predictors of survival.

Controversial role of γδ T cells in colorectal cancer.

Colorectal cancer (CRC) is the third most frequent type of cancer, and the second leading cause of cancer-related deaths worldwide. Current treatments for patients with CRC do not substantially improve the survival and quality of life of patients with advanced CRC, thus necessitating the development of new treatment strategies. The emergence of immunotherapy has revitalized the field, showing great potential in advanced CRC treatment. Owing to the ability of tumor cells to evade the immune system through major histocompatibility complex shedding and heterogeneous and low antigen spreading, only a few patients respond to immunotherapy. γδ T cells have heterogeneous structures and functions, and their key roles in immune regulation, tumor immunosurveillance, and specific primary immune responses have increasingly been recognized. γδ T cells recognize and kill CRC cells efficiently, thus inhibiting tumor progress through various mechanisms. However, γδ T cells can potentially promote tumor development and metastasis. Thus, given this dual role in prognosis, these cells can act as either a "friend" or "foe" of CRC. In this review, we explore the characteristics of γδ T cells and their functions in CRC, highlighting their application in immunotherapy.

Study on prediction of early adverse events by CapeOX therapy in patients with colorectal cancer.

CapeOX is a regimen used as postoperative adjuvant chemotherapy for the treatment of advanced recurrent colorectal cancer. If early adverse events occur, treatment may not progress as planned and further dose reduction may be necessary. In this study, we investigated whether pre-treatment medical records could be used to predict adverse events in order to prevent adverse events caused by CapeOX treatment. The 178 patients were classified into two groups (97 in the adverse event positive group and 81 in the adverse event-negative group) based on withdrawal or postponement of four or fewer courses. In univariate analysis, age, height, weight, body surface area (BSA), creatinine clearance, muscle mass, and lean body mass were associated with early adverse events (P<0.05). The area under the receiver operating characteristic curve obtained by Stepwise logistic regression analysis using the Akaike information criterion method was 0.832. For nested k-fold cross validation, the accuracy rates of the support vector machine, random forest, and logistic regression algorithms were 0.71, 0.70, and 0.75, respectively. The results of the present study suggest that a logistic regression prediction model may be useful in predicting early adverse events caused by CapeOX therapy in patients with colorectal cancer. J. Med. Invest. 71 : 141-147, February, 2024.

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer

Immune checkpoint inhibitors (ICIs) have limited activity in microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer. Recent findings suggest the efficacy of ICIs may be modulated by the presence of liver metastases (LM). To investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer. In this secondary analysis of the Canadian Cancer Trials Group CO26 (CCTG CO.26) randomized clinical trial, patients with treatment-refractory colorectal cancer were randomized in a 2:1 fashion to durvalumab plus tremelimumab or best supportive care alone between August 10, 2016, and June 15, 2017. The primary end point was overall survival (OS) with 80% power and 2-sided α = .10. The median follow-up was 15.2 (0.2-22.0) months. In this post hoc analysis performed from February 11 to 14, 2022, subgroups were defined based on the presence or absence of LM and study treatments. Durvalumab plus tremelimumab or best supportive care. Hazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. Plasma tumor mutation burden at study entry was determined using a circulating tumor DNA assay. The primary end point of the study was OS, defined as the time from randomization to death due to any cause; secondary end points included progression-free survival (PFS) and disease control rate (DCR). Of 180 patients enrolled (median age, 65 [IQR, 36-87] years; 121 [67.2%] men; 19 [10.6%] Asian, 151 [83.9%] White, and 10 [5.6%] other race or ethnicity), LM were present in 127 (70.6%). For patients with LM, there was a higher proportion of male patients (94 of 127 [74.0%] vs 27 of 53 [50.9%]; P = .005), and the time from initial cancer diagnosis to study entry was shorter (median, 40 [range, 8-153] vs 56 [range, 14-181] months; P = .001). Plasma tumor mutation burden was significantly higher in patients with LM. Patients without LM had significantly improved PFS with durvalumab plus tremelimumab (HR, 0.54 [90% CI, 0.35-0.96]; P = .08; P = .02 for interaction). Disease control rate was 49% (90% CI, 36%-62%) in patients without LM treated with durvalumab plus tremelimumab, compared with 14% (90% CI, 6%-38%) in those with LM (odds ratio, 5.70 [90% CI, 1.46-22.25]; P = .03). On multivariable analysis, patients without LM had significantly improved OS and PFS compared with patients with LM. In this secondary analysis of the CCTG CO.26 study, the presence of LM was associated with worse outcomes for patients with advanced colorectal cancer. Patients without LM had improved PFS and higher DCR with durvalumab plus tremelimumab. Liver metastases may be associated with poor outcomes of ICI treatment in advanced colorectal cancer and should be considered in the design and interpretation of future clinical studies evaluating this therapy.

ZNF746 plays cardinal roles on colorectal cancer (CRC) cell invasion and migration and regulates mitochondrial dynamics and morphological changes of CRC cells-Role of combined melatonin and 5-FU regimen.

The underlying mechanism of colorectal cells developing into cancer cells has been extensively investigated, yet is still not fully delineated, resulting in the treatment of advanced colorectal cancer (CRC) remains regrettably an unmet need. Zinc Finger Protein 746/Parkin-interacting substrate (ZNF746/PARIS) has previously been identified to play a fundamental role on bladder cancer cell proliferation and metastasis that were effectively inhibited by melatonin (Mel). In this study, we utilized ex vivo/in vivo studies to verify whether the ZNF746 signaling was also crucial in CRC growth/invasion/migration. Tissue-bank specimens showed that the protein expression of ZNF746 was significantly increased in CRC than that of healthy colorectal tissues (p < 0.001). Additionally, in vitro study demonstrated that excessive expression of ZNF746 significantly inhibited mitochondrial activity via (1) interfering with the dynamic balance of mitochondrial fusion/fission and (2) inhibiting the protein expression of MFN1/MFN2/PGC1a (all p < 0.001). Furthermore, we identified that inhibition of ZNF746 protein expression significantly reduced the resistance of CRC cell lines to the anticancer drug of 5-FU (p < 0.001), whereas overexpression of ZNF746 significantly augmented resistance of CRC cells to 5-FU (all p < 0.001). Finally, using the cell culture method, we found that combined Mel and 5-FU was superior to merely one on promoting the CRC cell apoptosis (p < 0.001). Our results confirmed that ZNF746 signaling played a cardinal role of CRC cell proliferation/survival and combined Mel and 5-FU treatment attenuated the resistance of CRC cells to the drug mainly through suppressing this signaling.

Anti-PD-1/PD-L1 therapy for colorectal cancer: Clinical implications and future considerations

Colorectal cancer (CRC) is the third most prevalent cancer in the world. The PD-1/PD-L1 pathway plays a crucial role in modulating immune response to cancer, and PD-L1 expression has been observed in tumor and immune cells within the tumor microenvironment of CRC. Thus, immunotherapy drugs, specifically checkpoint inhibitors, have been developed to target the PD-1/PD-L1 signaling pathway, thereby inhibiting the interaction between PD-1 and PD-L1 and restoring T-cell function in cancer cells. However, the emergence of resistance mechanisms can reduce the efficacy of these treatments. To counter this, monoclonal antibodies (mAbs) have been used to improve the efficacy of CRC treatments. mAbs such as nivolumab and pembrolizumab are currently approved for CRC treatment. These antibodies impede immune checkpoint receptors, including PD-1/PD-L1, and their combination therapy shows promise in the treatment of advanced CRC. This review presents a concise overview of the use of the PD-1/PD-L1 blockade as a therapeutic strategy for CRC using monoclonal antibodies and combination therapies. Additionally, this article outlines the function of PD-1/PD-L1 as an immune response suppressor in the CRC microenvironment as well as the potential advantages of administering inflammatory agents for CRC treatment. Finally, this review analyzes the outcomes of clinical trials to examine the challenges of anti-PD-1/PD-L1 therapeutic resistance.

Randomised, placebo-controlled, phase 3 trial of the effect of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) on colorectal cancer recurrence and survival after surgery for resectable liver metastases: EPA for Metastasis Trial 2 (EMT2) study protocol

IntroductionThere remains an unmet need for safe and cost-effective adjunctive treatment of advanced colorectal cancer (CRC). The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and has anti-inflammatory...

TGF-β in correlation with tumor progression, immunosuppression and targeted therapy in colorectal cancer.

Colorectal cancer (CRC) is a complex malignancy responsible for the second-highest cancer deaths worldwide. TGF-β maintains normal cellular homeostasis by inhibiting the cell cycle and inducing apoptosis, but its elevated level is correlated with colorectal cancer progression, as TGF-β is a master regulator of the epithelial-to-mesenchymal transition, a critical step of metastasis. Tumors, including CRC, use elevated TGF-β levels to avoid immune surveillance by modulating immune cell differentiation, proliferation, and effector function. Presently, the treatment of advanced CRC is mainly based on chemotherapy, with multiple adverse effects. Thus, there is a need to develop alternate tactics because CRC continue to be mostly resistant to the present therapeutic regimen. TGF-β blockade has emerged as a promising therapeutic target in cancer therapy. Blocking TGF-β with phytochemicals and other molecules, such as antisense oligonucleotides, monoclonal antibodies, and bifunctional traps, alone or in combination, may be a safer and more effective way to treat CRC. Furthermore, combination immunotherapy comprising TGF-β blockers and immune checkpoint inhibitors is gaining popularity because both molecules work synergistically to suppress the immune system. Here, we summarize the current understanding of TGF-β as a therapeutic target for managing CRC and its context-dependent tumor-promoting or tumor-suppressing nature.

623P VIC regimen (vemurafenib/irinotecan/cetuximab) versus bevacizumab plus chemotherapy as first-line treatment for BRAF V600E-mutated advanced colorectal cancer

623P VIC regimen (vemurafenib/irinotecan/cetuximab) versus bevacizumab plus chemotherapy as first-line treatment for BRAF V600E-mutated advanced colorectal cancer

Matrix stiffness triggers lipid metabolic crosstalk between tumor and stromal cells to mediate bevacizumab resistance in colorectal cancer liver metastases.

Bevacizumab is an anti-vascular endothelial growth factor (VEGF) monoclonal antibody that plays an important role in the combination treatment of advanced colorectal cancer (CRC). However, resistance remains a major hurdle limiting bevacizumab efficacy, highlighting the importance of identifying mechanism of anti-angiogenic therapy resistance. Here, we investigated biophysical properties of the extracellular matrix (ECM) related to metabolic processes and acquired resistance to bevacizumab. Evaluation of paired pre- and post-treatment samples of liver metastases from 20 CRC patients treated with combination bevacizumab therapy, including 10 responders and 10 non-responders, indicated that ECM deposition in liver metastases and a highly activated fatty acid oxidation (FAO) pathway were elevated in non-responders after anti-angiogenic therapy compared to responders. In mouse models of liver metastatic CRC, anti-VEGF increased ECM deposition and FAO in CRC cells, and treatment with the FAO inhibitor etomoxir enhanced the efficacy of antiangiogenic therapy. Hepatic stellate cells (HSCs) were essential for matrix stiffness-mediated FAO in colon cancer cells. Matrix stiffness activated lipolysis in HSCs via the focal adhesion kinase (FAK)/yes-associated protein (YAP) pathway, and free fatty acids secreted by HSCs were absorbed as metabolic substrates and activated FAO in colon cancer cells. Suppressing HSC lipolysis using FAK and YAP inhibition enhanced the efficacy of anti-VEGF therapy. Together, these results indicate that bevacizumab-induced ECM remodeling triggers lipid metabolic crosstalk between colon cancer cells and HSCs. This metabolic mechanism of bevacizumab resistance mediated by the physical tumor microenvironment represents a potential therapeutic target for reversing drug resistance.