Colorectal Cancer Therapy Research Articles

Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer.

Metastatic colorectal cancer remains a deadly malignancy and is the third leading cause of cancer-related death. The mainstay of treatment for metastatic colorectal cancer is chemotherapy, but unfortunately, even with recent progress, overall survival is still poor. Colorectal cancer is a heterogeneous disease, and the underlying genetic differences among tumors can define the behavior and prognosis of the disease. Given the limitations of cytotoxic chemotherapy, research has focused on developing targeted therapy based on molecular subtyping. Since the early 2000s, multiple targeted therapies have demonstrated efficacy in treating metastatic colorectal cancer and have received FDA approval. The epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and DNA mismatch repair pathways have demonstrated promising results for targeted therapies. As new gene mutations and proteins involved in the oncogenesis of metastatic colorectal cancer are identified, new targets will continue to emerge. We herein provide a summary of the updated literature regarding targeted therapies for patients with mCRC.

Gut Microbiome Mediates Ferroptosis Resistance for Colorectal Cancer Development.

Colorectal cancer is a prevalent cancer type in the United States, affecting both genders and influenced by genetics and environmental factors. The role of the gut microbiome in colorectal cancer development and therapy response is a burgeoning field of study. A recent study uncovered that trans-3-indoleacrylic acid (IDA), a microbial metabolite from P. anaerobius, promotes colorectal cancer by inhibiting ferroptosis, a type of nonapoptotic cell death driven by unrestricted lipid peroxidation and subsequent membrane damage. IDA activates aryl hydrocarbon receptor (AHR), a nuclear transcription factor, leading to the expression of aldehyde dehydrogenase 1 family member A3 (ALDH1A3). ALDH1A3, known for aldehyde detoxification, also contributes to ferroptosis resistance by generating reduced nicotinamide adenine dinucleotide (NADH), critical for the synthesis of reduced coenzyme Q10 (COQH10), by apoptosis-inducing factor mitochondria-associated 2 (AIFM2, also known as FSP1). Knocking out AHR, AIFM2, or ALDH1A3 reverses the inhibitory effect of IDA on ferroptosis and IDA-mediated tumor growth. Significantly, P. anaerobius is enriched in patients with colorectal cancer, and supplementing IDA or P. anaerobius accelerates colorectal cancer progression in spontaneous or orthotopic mouse models. Taken together, these findings suggest that targeting P. anaerobius-mediated ferroptosis resistance emerges as a promising strategy to combat colorectal cancer development.

Establish a novel tumor budding-related signature to predict prognosis and guide clinical therapy in colorectal cancer

Tumor budding is a long-established independent adverse prognostic marker for colorectal cancer (CRC), yet assessment of tumor budding was not reproducible. Therefore, development of precise diagnostic approaches to tumor budding is in demand. In this study, we first performed bioinformatic analysis in our single-center CRC patients’ cohort (n = 84) and identified tumor budding-associated hub genes using the weighted gene co-expression network analysis (WGCNA). A machine learning methodology was used to identify hub genes and construct a prognostic signature. Nomogram model was used to identified hub genes score for tumor budding, and the receiver operating characteristic (ROC) curve and calibration plot indicated high accuracy and stability of hub gene score for predicted the prognosis of CRC. The association between budding-associated hub genes and score and prognosis of CRC were further verified in TCGA CRC cohort (n = 342). Then gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were applied to explore the signaling pathways related to the tumor budding and validated by immunohistochemistry (IHC) of our clinical samples. Subsequently, immune infiltration analysis demonstrated that there was a high correlation between hub genes score and M2-like macrophages infiltrated in tumor tissue. In addition, somatic mutation and chemotherapeutic response prediction were analyzed based on the risk signature. In summary, we established a tumor budding diagnostic molecular model, which can improve tumor budding assessment and provides a promising novel molecular marker for immunotherapy and prognosis of CRC.

A biomimetic nanocarrier facilitates glucose consumption and reactive oxide species accumulation in enzyme therapy for colorectal cancer

Glucose oxidase (GOx)-based enzyme therapeutics are potential alternatives for colorectal cancer (CRC) treatment via glucose consumption and accumulation of hydrogen peroxide (H2O2). Given that H2O2 can be eliminated by cytoprotective autophagy, autophagy inhibitors that can interrupt autolysosome-induced H2O2 elimination are promising combination drugs of GOx. Here, we developed a multifunctional biomimetic nanocarrier for effective co-delivery of an autophagy inhibitor-chloroquine phosphate (CQP) and GOx to exert their synergistic effect by irreversibly upregulating intracellular reactive oxygen species (ROS) levels. Poly (D, l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) were used to encapsulate both GOx and CQP using a W/O/W multi-emulsion method. Calcium phosphate (CaP) was used to “fix” CQP to GOx in the internal water phase, where it served as a pH-sensitive unit to facilitate intracellular drug release. Folic acid-modified red blood cell membranes (FR) were used to camouflage the GOx/CQP/CaP encapsulated PLGA NPs (referred to as PLGA/GCC@FR). In an AOM/DSS-induced CRC mouse model, PLGA/GCC@FR exhibited improved antitumor effects, in which the number of tumor nodes were only a quarter of that in the free drug combination group. The enhanced therapeutic effects of PLGA/GCC@FR were attributed to the prolonged tumor retention which was verified by both dynamic in vivo imaging and drug biodistribution. This multifunctional biomimetic nanocarrier facilitated combined enzyme therapeutics by depleting glucose and augmenting intracellular ROS levels in tumor cells, which exerted a synergistic inhibitory effect on tumor growth. Therefore, this study proposed a novel strategy for the enhancement of combined enzyme therapeutics, which provided a promising method for effective CRC treatment.

Transcription Silencing and CpGs Hypermethylation as Therapeutic Gene Editing in Clinical Colorectal Adenocarcinoma Repression.

Colorectal cancer is the most common cancer in oncopathology, with an increasing incidence among the elderly during the last decade. Various genetic and environmental factors play important roles in the emergence of colorectal adenocarcinoma. Non-coding RNAs, approximately 20-22 nucleotides, are transcribed irregularly in many cancer cells and play a critical role in many metabolic pathways in clinical cancer cases. DNA methylation is a critical epigenetic alteration that controls gene expression. In the current study, transcriptional silencing and CpG hypermethylation were developed as a therapeutic gene editing strategy for the clinical repression of colorectal adenocarcinoma. A human colorectal adenocarcinoma cell line (Caco2) and a normal lung fibroblast cell line (Wi38) were utilized as the paradigms in this research to examine the effect of mir155 molecule transfection and CpGs-island (CGI) methylation. Cell counting was achieved using six-well and 24-well plates before transfection using a hemocytometer. The two cell lines were transfected with the mir155 agomir and antagomir molecules. The transfection efficiency, cell viability, cell IC50, and target gene expression were measured, and CGIs-methylation was achieved by bisulfate conversion. The outcomes revealed the downregulation of oncogenes (AKT1 and VCAM1 genes as cancer-associated genes) and the upregulation of tumor suppressor genes (TSGs, Tp53 and KEAP1). In addition, CpG-islands methylation showed significant blocking of the oncogene promoter regions, and the switch on of TSG promoter regions was continuous. miRNA-CGI-methylation led to the regression of Caco2 cell proliferation, suggesting the potential use of RNA silencing and DNA methylation in targeted gene therapy for colorectal cancer.

KLF15 transcriptionally activates LINC00689 to inhibit colorectal cancer development

Colorectal cancer is a grievous health concern, we have proved long non-coding RNA LINC00689 is considered as a potential diagnosis biomarker for colorectal cancer, and it is necessary to further investigate its upstream and downstream mechanisms. Here, we show that KLF15, a transcription factor, exhibits the reduced expression in colorectal cancer. KLF15 suppresses the proliferative and metastatic capacities of colorectal cancer cells both in vitro and in vivo by transcriptionally activating LINC00689. Subsequently, LINC00689 recruits PTBP1 protein to enhance the stability of LATS2 mRNA in the cytoplasm. This stabilization causes the suppression of the YAP1/β-catenin pathway and its target downstream genes. Our findings highlight a regulatory network involving KLF15, LINC00689, PTBP1, LATS2, and the YAP1/β-catenin pathway in colorectal cancer, shedding light on potential therapeutic targets for colorectal cancer therapy.

Collagen I-induced VCAN/ERK signaling and PARP1/ZEB1-mediated metastasis facilitate OSBPL2 defect to promote colorectal cancer progression

The global burden of colorectal cancer (CRC) has rapidly increased in recent years. Dysregulated cholesterol homeostasis facilitated by extracellular matrix (ECM) remodeling transforms the tumor microenvironment. Collagen I, a major with ECM component is highly expressed in colorectal tumors with infiltrative growth. Although oxysterol binding protein (OSBP)-related proteins accommodate tumorigenesis, OSBPL2, which is usually involved in deafness, is not associated with CRC progression. Therefore, we aimed to investigate the pathological function of OSBPL2 and identify the molecular link between ECM-Collagen I and OSBPL2 in CRC to facilitate the development of new treatments for CRC. OSBPL2 predicted a favorable prognosis in stage IV CRC and substantially repressed Collagen I-induced focal adhesion, migration, and invasion. The reduction of OSBPL2 activated ERK signaling through the VCAN/AREG/EREG axis during CRC growth, while relying on PARP1 via ZEB1 in CRC metastasis. OSBPL2 defect supported colorectal tumor growth and metastasis, which were suppressed by the ERK and PARP1 inhibitors SCH772984 and AG14361, respectively. Overall, our findings revealed that the Collagen I-induced loss of OSBPL2 aggravates CRC progression through VCAN-mediated ERK signaling and the PARP1/ZEB1 axis. This demonstrates that SCH772984 and AG14361 are reciprocally connective therapies for OSBPL2Low CRC, which could contribute to further development of targeted CRC treatment.

Targeted Nanoparticles: the Smart Way for the Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is a widespread cancer that starts in the digestive tract. It is the third most common cause of cancer deaths around the world. The World Health Organization (WHO) estimates an expected death toll of over 1 million cases annually. The limited therapeutic options as well as the drawbacks of the existing therapies necessitate the development of non-classic treatment approaches. Nanotechnology has led the evolution of valuable drug delivery systems thanks to their ability to control drug release and precisely target a wide variety of cancers. This has also been extended to the treatment of CRC. Herein, we shed light on the pertinent research that has been performed on the potential applications of nanoparticles in the treatment of CRC. The various types of nanoparticles in addition to their properties, applications, targeting approaches, merits, and demerits are discussed. Furthermore, innovative therapies for CRC, including gene therapies and immunotherapies, are also highlighted. Eventually, the research gaps, the clinical potential of such delivery systems, and a future outlook on their development are inspired.

Photodynamic Therapy as a Desirable Approach in the Treatment of Colorectal Cancer, with Special Focus on Photodynamic Nanotherapeutics in Immunotherapy.

Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide; however, there is not a convincing treatment for this disease. Limitations of conventional CRC therapies force scientists to develop novel treatment concepts for both primary care alongside adjuvant therapy. Photodynamic therapy (PDT) has been introduced as a promising therapeutic procedure for CRC mediated through theranostic principle in which special dyes, photosensitizers (PSs), are excited by near-infrared (NIR) and visible light. Recent studies showed that PDT has synergistic effects in combination with chemotherapy or immunotherapy in the treatment of CRC patients. Of note, nanoformulation of PS or immunotherapeutic agents could augment the PDT effectiveness. In this review, we summarize PDT application in CRC management with a special focus on the nanoparticles-based delivery system from the perspective of targeting deeper CRC and increased PDT efficiency, which could provide a desirable approach for clinical translation.

Prognostic value of circulating tumor DNA following local therapy in colorectal cancer with liver metastases.

26 Background: Local therapies have the potential to cure a portion of patients with colorectal cancer with liver-only metastatic disease (CRLM). Peri-operative chemotherapy has not been shown to improve overall survival when added to local therapy in CRLM. Circulating-tumor DNA (ct-DNA) may have potential to help guide management decisions following local therapy. Methods: We conducted a retrospective analysis of health records of CRLM patients who had tumor-informed ct-DNA (Signatera) measurement following curative-intent local therapy prior to August 30th, 2023. Disease-free survival (DFS) was defined as the time from ct-DNA test until radiographic evidence of disease. Descriptive characteristics of the cohort, ct-DNA results and their impact on adjuvant therapy decisions were recorded. Survival analysis was carried out using R software v4.3.1 with survival and survminer packages. The Kaplan–Meier method was used to estimate the survival distribution. Log-rank test was used for comparison. A multivariable Cox proportional hazards model was used to assess prognostic factors associated with DFS ( coxph). Results: 27 patients with CRLM underwent local therapy followed by ct-DNA collection. The median age was 61 years, 67% were male, and 85% were White. Molecular characteristics: KRAS 31%, NRAS/BRAF 0%, microsatellite instability 4%. The median time from initial diagnosis to treatment of liver disease was 21.0 months. 63% of patients received less than 6 months of systemic therapy prior to local therapy. ct-DNA was checked prior to definitive therapy in 12 cases and was positive in 5 cases (detection rate of 42%). Liver-directed therapy involved: resection (n=15), ablation (6), radiation (2) or a combination (4). The median follow-up time from liver-directed therapy was 13.2 months. Post-local therapy chemotherapy was initiated prior to recurrence in 59% of cases. ct-DNA results contributed to immediate post-management decisions in 15% of cases. There were 14 radiographic recurrences (11 to liver only, 3 to other sites). Positive ct-DNA on initial testing following local therapy was associated with poorer DFS in univariate analysis and was the only prognostic factor identified on multivariable analysis. Conclusions: ct-DNA positivity following local therapy for CRLM is associated with earlier recurrence. Baseline testing before local therapy may be important for interpretation of testing results post-local therapy, given frequent missed disease detection. Additional clinical trial data is needed to explore ct-DNA-guided treatment decisions in CRLM. [Table: see text]

Amivantamab monotherapy in relapsed/refractory metastatic colorectal cancer: OrigAMI-1, an open-label, phase 1b/2 study.

135 Background: Amivantamab (ami), an EGFR-MET bispecific antibody with immune cell-directing activity, has shown preclinical activity in colorectal cancer (CRC) models. MET amplification is implicated in driving resistance to anti-EGFR therapies in metastatic CRC (mCRC). We hypothesize that dual, co-inhibition of EGFR and MET with ami could improve outcomes in relapsed/refractory mCRC. Methods: OrigAMI-1 (NCT05379595) is assessing the safety and efficacy of ami as monotherapy in patients (pts) with refractory mCRC in 3 separate cohorts (Table). Eligible pts were wild-type for KRAS, NRAS, BRAF, and EGFR ectodomain by ctDNA testing, without ERBB2/ HER2 amplification. Cohorts A and B included pts with left-sided mCRC without/with prior exposure to anti-EGFR monoclonal antibodies, respectively, and cohort C included pts with right-sided mCRC. Safety population included all pts receiving the recommended phase 2 dose (RP2D; 1050 mg [1400 mg, ≥80kg]). Investigator-assessed response per RECIST v1.1 is reported for evaluable pts with post-baseline disease assessment(s) or who discontinued for any reason. Ami plus FOLFOX or FOLFIRI is being explored in additional cohorts. Results: As of September 4, 2023, 93 pts were treated at RP2D; 89 were response evaluable (median follow-up: 4.4 mo). Median age was 60 years, 66% were male, and median prior lines of therapy were 2, with 94% receiving prior bevacizumab and 69% prior anti-EGFR therapy. Best timepoint responses were: Cohort A: 7/17, 41.2%; Cohort B: 13/54, 24.1%; Cohort C: 1/18, 5.6%. Disease control rates (DCR) were 88.2%, 72.2%, and 77.8% for Cohorts A, B, and C, respectively. Median duration of response (mDoR) for confirmed responders was 7.5 and 7.4 mo for Cohorts A and B, respectively. Treatment is ongoing for the responder in Cohort C. 10/13 responders (77%) remain on treatment. Preliminary biomarker data suggest ami may be active in alterations associated with anti-EGFR antibody resistance (eg, EML4-ALK fusion, PTEN). The most frequent treatment-emergent adverse events were rash (84%) and infusion-related reactions (53%). No new safety signals were observed. Updated results will be presented at the meeting. Conclusions: Ami monotherapy demonstrated promising, durable antitumor activity in refractory mCRC, including pts treated with prior anti-EGFR therapy and pts with right-sided disease. The safety profile of ami in mCRC is manageable and consistent with prior NSCLC experience. Clinical trial information: NCT05379595 . [Table: see text]

Combination of hSTC810 and capecitabine therapy in metastatic colorectal cancer with resistance or intolerance to oxaliplatin and irinotecan-based chemotherapy: A single arm, phase 1b/2, multicenter study.

TPS223 Background: hSTC810 is a humanized anti-BTN1A1 monoclonal antibody of the IgG4 isotype that binds to human BTN1A1 and blocks the interaction between BTN1A1 and its ligands. Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint protein that exhibits an expression pattern mutually exclusive to that of PD-1/PD-L1. BTN1A1 has been shown to inhibit anti-CD3-induced cytokine production and T-cell proliferation and also inhibit anti-CD3-induced p38 mitogen-activated protein kinase (MAPK), cAMP response element-binding protein (CREB) and target of rapamycin (TOR) phosphorylation in human T-cells. Mouse studies demonstrated that an anti-BTN1A1 antibody exhibited antitumor activity both as a single agent and in combination with anti-PD-1/PD-L1 or radiation therapy. In the first in human phase 1 study, investigating the safety and efficacy of hSTC810 in solid tumors, hSTC810 showed acceptable safety profile and the disease control rate (DCR) was 39.3%, which indicates its potential efficacy. Methods: This multi-center, open label phase 1b/2 study evaluates the safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of hSTC810 combined with capecitabine in patients with metastasis/recurrent colorectal cancer. The trial is enrolling adults who are (1) histologically or cytologically confirmed colorectal adenocarcinoma (2) resistant or intolerant to oxaliplatin and irinotecan-based chemotherapy (3) adequate hematologic, hepatic, renal function (4) measurable or non-measurable disease by RECIST 1.1 (5) ECOG PS 0~2 (6) resolved acute effects of any prior therapy. Treatment will continue until disease progression or unacceptable toxicity, whichever occurs first. The primary endpoint of phase 1b is to determine dose-limiting toxicity (DLT), and recommended phase 2 dose (RP2D) of hSTC810 combined with capecitabine, each in 21-day cycles. Phase 1 comprises 3 escalation arms, and if the initial dose is deemed unsafe, 2 deescalation arms will be initiated. Once the RP2D is determined, the Phase 2 will enroll up to 39 patients. The primary endpoint of phase 2 is progression free survival (PFS); secondary endpoints include objective response rate, overall survival, disease control rate, duration of response and quality of life. The study began in Q4 2023 and is recruiting patients. AEs are assessed according to CTCAE v5. Tumor response is determined according to RECIST 1.1 criteria. An exploratory study is underway to investigate the impact of hSTC810 on the tumor microenvironment and cytokines, utilizing both tissue biopsies and blood sampling. Clinical trial information: NCT05990543 .

Real-world data of TAS-102 therapy in refractory metastatic colorectal cancer (mCRC): The experience of the University Hospital of Montreal (CHUM).

137 Background: Colorectal cancer poses a substantial healthcare burden due to its elevated rates of diagnosis and mortality. Managing refractory metastatic cases remains a challenge in our practice due to the paucity of therapeutic options. Treatment with Trifluridine-Tipiracil (TAS-102) prolonged overall survival among patients (pts) with mCRC. This study investigates the efficacy of TAS-102 therapy in this patient population and explores various prognostic factors influencing clinical outcomes. Methods: We retrospectively reviewed the data of 53 patients with refractory mCRC treated with at least 1 cycle of TAS-102 at CHUM between March 2018 and January 2023. Multivariate and univariate analyses were employed to evaluate the impact of age, number of prior treatments, presence of KRAS mutation, gender, tumor origin, and Eastern Cooperative Oncology Group (ECOG) performance status on progression-free survival (PFS) and overall survival (OS). Survival analysis was conducted using the Kaplan-Meier method, and Cox regression analysis assessed prognostic factors. Results: The median age was 61 years (23-82), and 27 pts (50.9%) were females. Twenty-two pts (41.5%) had their primary tumor located in the left colon, 17 pts (32.1%) had right-sided tumors, and 14 pts (26.4%) with rectal tumors. 52% of pts received TAS-102 after 2 lines of therapy and 43% beyond third line. The performance status was: ECOG 0/1 in 46 pts (86.8%), and ECOG 2 in 7 pts (13.2%). In our refractory mCRC pts, median PFS was 3 months and median OS 7 months. Univariate analysis demonstrated no significant differences in PFS or OS based on patient sex, KRAS mutation status, tumor sidedness, or the number of prior treatments. In univariate and multivariate analysis ECOG 0/1 pts compared to ECOG 2 pts had a significant improvement in both PFS (HR = 0.33; p = 0.0511) and OS (HR = 0.21; p = 0.0086). Conclusions: In our real-world experience, clinical outcomes were comparable to the findings from the RECOURSE trial, suggesting improved PFS and OS with TAS-102 in heavily pre-treated mCRC patients. ECOG performance status remains a significant prognostic factor and underscores its importance in treatment decisions for this patient population.

Subgroup analyses of the phase 3 CAIRO3 trial: Association of number and total volume of metastases on survival in patients with metastatic colorectal cancer based on a deep-learning automatic segmentation model.

130 Background: Maintenance treatment with capecitabine and bevacizumab after capecitabine, oxaliplatin, and bevacizumab therapy in metastatic colorectal cancer (mCRC) is shown to be effective with observation as an acceptable alternative. Metastatic burden might aid in shared decision-making and the aim of this exploratory analysis is to assess the prognostic and predictive value of number and total volume of metastases in mCRC patients included in the CAIRO3 study. Methods: Patients in the CAIRO3 study with liver and/or lung metastases were included. Every individual liver and lung metastasis was counted and volumes were assessed using deep-learning automatic segmentation software (SAS analytical platform and Philips IntelliSpace). Lymph node metastases were counted manually. Each scan was supervised by a dedicated radiologist. Kaplan-Meier analyses were used to estimate progression-free survival (PFS) and overall survival (OS) using log-rank testing for statistical comparison. Hazard ratios (HR) were estimated using Cox regression models. Results: A total of 156 patients were included with 154 OS events, in which 8198 metastases were identified: 5179 were liver metastases, 2835 lung metastases, and 184 lymph node metastases. Patients had a mean age of 63 years and 67% were male. At randomization, the median number of metastases was 9 and mean total metastatic volume was 116 cm3. Median OS for patients with ≤10 versus >10 metastases was 22.0 months (95%CI: 19.3-29.3) and 14.3 months (95% CI: 11.6-20.9, p-value <0.01), with similar differences for low/high tumor volume. In multivariable analysis number and total volume were independent prognostic markers for PFS and OS, respectively, after adjustment for age, sex, WHO performance score, treatment arm, serum lactate dehydrogenase (LDH) level, site of primary tumor, time to metastases, and treatment response. Benefit of maintenance therapy was most pronounced in patients with ≤10 compared to >10 metastases with a PFS HR of 0.24 (0.12-0.46) compared to 0.52 (0.28-0.96) and OS HR of 0.75 (0.42-1.34) compared to 1.17 (0.66-2.08), demonstrating potential predictive value. Conclusions: Metastatic burden is associated with a poor prognosis in patients with mCRC. Furthermore, patients with limited metastatic disease (1-10 metastases) benefit most from maintenance treatment and this could potentially be a predictive biomarker. [Table: see text]

Effect of Hospital Cancer Designation on use of Multimodal Therapy and Survival of Metastatic Colorectal Cancer: A State-Wide Analysis.

Stage IV colorectal cancer (CRC) often requires multidisciplinary approach. However, multimodal treatment options (receipt of >1 type of treatment) may not be uniformly delivered across health systems. We characterized the association between center-level cancer center designation and receipt of multimodal treatment and survival. The Texas Cancer Registry was used to identify patients diagnosed with stage IV CRC from 2004-2017. We identified those who received care at either: a National Cancer Institute-designated (NCI-D), an American College of Surgeons-Commission on Cancer-designated (ACS-D), or an undesignated facility. We used multivariable logistic regression and Cox regression for analysis to assess receipt of one or more treatment modality and 5-year overall survival. Of 19,355 patients with stage IV CRC, 2955 (15%) received care at an NCI-D facility and 5871 (30%) received multimodal therapy. Both NCI-D (odds ratio [OR] 1.64; 95% confidence interval [CI] 1.49-1.81) and ACS-D (OR 1.37; 95% CI 1.27-1.48) were associated with increased likelihood of multimodal therapy compared with undesignated centers. NCI-D also was associated with significantly improved survival (hazard ratio [HR] 0.74; 95% CI 0.70-0.78), although ACS-D was associated with a modest improvement in survival (HR 0.95; 95% CI 0.92-0.99). Receipt of multimodal therapy was strongly associated with improved survival (HR 0.61; 95% CI 0.59-0.63). In patients with stage IV CRC, treatment at ACS-D and NCI-D facilities was associated with increased use of multimodality therapy and improved survival. However, only a small proportion of patients have access to these specialized centers, highlighting a need for expanded access to multimodal therapies at other centers.

Initial efficacy evaluation of fruquintinib plus capecitabine versus capecitabine as maintenance treatment for metastatic colorectal cancer (mCRC): A randomized, controlled, phase Ib/II study.

119 Background: The standard first-line therapy followed by maintenance treatment is an optional approach to balance the efficacy and toxicity for mCRC. Fruquintinib (Fru), a highly specific inhibitor of VEGFR1/2/3, has demonstrated favorable safety and efficacy outcomes in the treatment of mCRC. In this study, we present findings from an investigation into the comparative efficacy and safety of Fru in combination with capecitabine (Cap) versus Cap as a maintenance therapy for patients (pts) with mCRC. Methods: Pts with histologically confirmed mCRC who achieved disease control (including CR/PR and SD) after at least six cycles of first-line standard chemotherapy were included in the study. During phase Ib, pts received Fru (4 mg p.o. qd, 3 weeks on/1 week off, q4w]) plus Cap (850 mg/m2, p.o. bid, d1-7 and d15-21, q4w). In phase II, pts were randomized in a 1:1 ratio to receive either Fru (RP2D, 3mg, 3 weeks on/1 week off) plus Cap or Cap alone. The primary outcome was progression-free survival (PFS). Results: By Sep 10, 2023, a total of 34 pts were enrolled in the study, and 26 pts were considered evaluable for efficacy. During Fru plus Cap (n=14) and Cap (n=12), the median age was 61.5 (39-78) and 57.5 (32-75) years. The main primary tumor side was left (64.3% / 66.7%) and approximately half of the pts harbored a RAS mutation (50.0% / 58.3%). Most pts had previously received bevacizumab therapy (57.1% /58.3%) or cetuximab (35.7% /25.0%), respectively. The mPFS was significantly improved in Fru plus Cap vs Cap (9.1 vs 3.8 months, HR: 0.289, 95% CI 0.083 to 1.01, p=0.039). Consistently, ORR (21.4% vs 0%) and DCR (92.9% vs 66.7%) were improved with Fru plus Cap. Grades 3 and 4 treatment-emergent adverse events (TEAEs) were hypertension (11.1%), oral mucositis (5.6%), voice alteration (5.6%), small intestinal obstruction (5.6%), acrodynia (5.6%) and blood bilirubin increased (5.6%) in Fru plus Cap, and diarrhea (6.3%), oral mucositis (6.3%) and acrodynia (6.3%) in Cap therapy. Conclusions: The findings suggest that Fruquintinib plus Capecitabine can be considered as a first-line maintenance therapy for metastatic colorectal cancer, as it demonstrated a promising improvement in mPFS by 5.3 months while maintaining a controlled level of safety. Clinical trial information: NCT05451719 .

Serum angiopoietin-like protein 2 level in patients who received bevacizumab-containing chemotherapy for metastatic colorectal cancer.

209 Background: Anti-angiogenic agents are important for treating patients with advanced colorectal adenocarcinoma, however, their efficacy is not long-lasting and survival benefits are modest. Reliable biomarkers and novel targets for angiogenesis are still required in this era. Angiopoietin-like protein 2 (AGLP-2) is an emerging biomarker for angiogenesis in cardiovascular disease, but its role in the oncology area is yet to be elucidated. Methods: Serum samples from patients with advanced colorectal carcinoma treated with bevacizumab-containing chemotherapy were retrospectively studied. Blood samples at baseline and at disease progression of the first line systemic therapy were selected. Serum angiopoietin-like protein 2 (AGLP-2) concentrations were measured using ELISA kit, serial changes, and the relationship with progression-free survival and overall survival on the systemic therapy were statistically analyzed. Results: 68 patients were enrolled. Their median age was 66 years old (range, 38-82), and 14 (20.6%) patients had metastatic lesions at 3 or 4 organs. The median serum AGLP-2 levels at baseline and at disease progression (PD) were 41,618 pg/ml (95% confidence interval (CI) 34,560-40,713), and 49,706 pg/ml (95% CI 39,853-49,017), respectively. There was a tendency of difference between AGLP-2 levels at baseline and at PD ( p=0.057). Patients whose baseline serum AGLP-2 levels with 40,000 pg/ml or above showed relatively shorter overall survival (median 31.4 months with 95% CI, 14.4-38.6) compared with patients with serum AGLP-2 level below 40,000 pg/ml at baseline (median 38.6 months with 95% CI, 23.6-127.3), but not statistically significant ( p=0.0946). There was no survival difference observed according to serum AGLP-2 levels at disease progression on the first line bevacizumab-containing chemotherapy. Conclusions: Serum angiopoietin-like protein-2 has potential as a new target for novel anti-angiogenic therapy in metastatic colorectal cancer.

Front-line use of FOLFOXIRI plus bevacizumab and subsequent therapies in metastatic colorectal cancer (mCRC).

45 Background: Emerging data shows that the higher incidence of mCRC in younger patients (pts) is accompanied by more aggressive front-line treatment with chemotherapies, such as FOLFOXIRI+bevacizumab (triplet+bev). We explored the use of triplet+bev and subsequent therapies in a representative sample of community practices in the USA. Methods: This was a retrospective study using the nationwide de-identified Flatiron Health Electronic Health Record-derived database from January 1, 2013, to February 28, 2023. The use of triplet+bev and subsequent treatments were analyzed in pts with newly diagnosed mCRC (≥18 years [yrs] of age) by oncologist-defined, rule-based line of treatment (LOT) and age (18–49, 50–64, and ≥65 yrs). Results: Of 24,285 eligible pts, 14%, 37%, and 49% were 18–49, 50–64, and ≥65 yrs at treatment initiation, respectively (Table). Triplet+bev use in any LOT was the most prevalent in the youngest age group (18–49 yrs) at 7% (Table). Two-thirds (67%) received triplet+bev in first line (1L) and 23% in second line (2L), 57% were male, and 34% had a KRAS mutation (23% missing). From 2013 to 2022, triplet+bev use in newly treated pts increased; this trend was more pronounced in pts 18–49 yrs (Table). Among pts not censored before the end of the respective LOT, median duration of 1L and 2L triplet+bev was 25.1 and 21.6 weeks, respectively (Table). For non-censored pts with and without a KRAS mutation, respectively, median duration of triplet+bev was 26.1 vs 23.5 weeks in 1L and 21.6 vs 16.5 weeks in 2L. Most frequently used new agents after 1L triplet+bev included anti-EGFR (panitumumab or cetuximab; 19%), TAS-102 (12%), regorafenib (10%), and capecitabine (3%). Most frequently used new agents after 2L triplet+bev were TAS-102 (21%), anti-EGFR (17%), regorafenib (15%), and pembrolizumab (8%). Conclusions: Our study shows that the use of triplet+bev has increased in pts with mCRC over time, particularly in those <50 yrs. Most frequent subsequent therapies across all pts following 1L and 2L triplet+bev included TAS-102, anti-EGFR, and regorafenib. Future research is needed to identify the optimal treatment strategies after triplet+bev. [Table: see text]

Exosome-Transmitted miR-224-5p Promotes Colorectal Cancer Cell Proliferation via Targeting ULK2 in p53-Dependent Manner

ObjectiveTo investigate the role and molecular mechanism of exosomal miR-224-5p in colorectal cancer (CRC). MethodsThe miR-224-5p expression in CRC patient tissues and cell-derived exosomes was measured by laser capture microdissection and qRT-PCR, respectively. Dual-luciferase reporter gene assay was used to determine the target gene of miR-224-5p. The protein expressions of p53 and unc-51 like kinase 2 (ULK2) in CRC cells were detected by western blot. Flow cytometry was used to detect cell cycle and apoptosis. Cell proliferation was measured by CCK8 and EdU assay. ResultsThe miR-224-5p expression was upregulated in CRC tissues and increased progressively with the rise of CRC stage. CRC cells secreted extracellular miR-224-5p mainly in an exosome-dependent manner, and then miR-224-5p could be transferred to surrounding tumor cells to regulate cell proliferation in the form of autocrine or paracrine. Moreover, ULK2 was characterized as a direct target of miR-224-5p and was downregulated in CRC tissues. Interestingly, ULK2 inhibited CRC cell proliferation in a p53-dependent manner. Furthermore, exosome-derived miR-224-5p partially reversed the proliferation regulation of ULK2 on CRC cells. ConclusionOur findings demonstrate that exosome-transmitted miR-224-5p promotes p53-dependent cell proliferation by targeting ULK2 in CRC, which may offer promising targets for CRC prevention and therapy.

Enhancing tumor-specific recognition of programmable synthetic bacterial consortium for precision therapy of colorectal cancer

Probiotics hold promise as a potential therapy for colorectal cancer (CRC), but encounter obstacles related to tumor specificity, drug penetration, and dosage adjustability. In this study, genetic circuits based on the E. coli Nissle 1917 (EcN) chassis were developed to sense indicators of tumor microenvironment and control the expression of therapeutic payloads. Integration of XOR gate amplify gene switch into EcN biosensors resulted in a 1.8-2.3-fold increase in signal output, as confirmed by mathematical model fitting. Co-culturing programmable EcNs with CRC cells demonstrated a significant reduction in cellular viability ranging from 30% to 50%. This approach was further validated in a mouse subcutaneous tumor model, revealing 47%-52% inhibition of tumor growth upon administration of therapeutic strains. Additionally, in a mouse tumorigenesis model induced by AOM and DSS, the use of synthetic bacterial consortium (SynCon) equipped with multiple sensing modules led to approximately 1.2-fold increased colon length and 2.4-fold decreased polyp count. Gut microbiota analysis suggested that SynCon maintained the abundance of butyrate-producing bacteria Lactobacillaceae NK4A136, whereas reducing the level of gut inflammation-related bacteria Bacteroides. Taken together, engineered EcNs confer the advantage of specific recognition of CRC, while SynCon serves to augment the synergistic effect of this approach.