Treatment Of Colorectal Cancer Research Articles

Initial Assessment of Resectability of Colorectal Cancer Liver Metastases Versus Clinical Outcome

BackgroundSurgery improves long-term survival for resectable, liver-only metastatic colorectal cancer (mCRC). With no consensus definition of “resectable” disease, decisions regarding resectability are reliant on the expertise and judgement of the treating clinician working in consultation with a multidisciplinary team (MDT). This study examines the clinical outcome versus initial assessment of resectability in an Australian population with mCRC. Patients and MethodsPatients with liver-only mCRC diagnosed January 2009 to December 2022 were identified from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry. Patients were classified based on prospectively documented treatment assessment as “resectable,” “potentially resectable,” or “unresectable.” The correlation between initial assessment of resectability and clinical outcome, and any impact of clinicopathologic factors were examined. Kaplan-Meier analysis assessed overall survival based on initial resectability assessment and resection status. Results: Of 4437 patients with mCRC identified through TRACC, 1250 (28%) had liver-only disease at presentation, with 497 (43%), 277 (24%), and 374 (33%) classified as “unresectable,” “potentially resectable,” and “resectable,” respectively. In total, 516 (41%) ultimately underwent surgical resection, including 30 (6%) of the “initially unresectable,” 148 (53%) of the “potentially resectable,” and 338 (90%) of the “resectable” at a median of 9.5, 5.9, and 2.4 months from the diagnosis of liver metastases, respectively. Resection in the “unresectable” patient population was associated with younger age (mean age 63 vs. 69, P = .0006), better performance status (ECOG 0-1 100% vs. 74%, P = .0017), and fewer comorbidities (Charlson index 0-3 in 73% vs. 53%, P = .0296) compared with no resection. Median overall survival was longer for resected versus nonresected patients across all categories: “unresectable” (59.2 vs. 17.6 months, P < .0001), “potentially resectable” (57.2 vs. 22.8 months, P < .0001), and “resectable” (108 vs. 55 months, P < .0001). ConclusionsThis real-world study demonstrates the potential for “initially unresectable” patients to become surgical candidates following systemic therapy, more likely in younger and fitter patients, with overall excellent survival outcomes in resected patients. This highlights the value of routine, repeated MDT assessments for patients with liver-only disease who are continuing to respond to systemic therapy, even for those initially considered never to be surgical candidates.

Expansion of a bacterial operon during cancer treatment ameliorates drug toxicity.

Dose-limiting toxicities remain a major barrier to drug development and therapy, revealing the limited predictive power of human genetics. Herein, we demonstrate the utility of a more comprehensive approach to studying drug toxicity through longitudinal study of the human gut microbiome during colorectal cancer (CRC) treatment ( NCT04054908 ) coupled to cell culture and mouse experiments. 16S rRNA gene sequencing revealed significant shifts in gut microbial community structure during oral fluoropyrimidine treatment across multiple patient cohorts, in mouse small and large intestinal contents, and in patient-derived ex vivo communities. Metagenomic sequencing revealed marked shifts in pyrimidine-related gene abundance during oral fluoropyrimidine treatment, including enrichment of the preTA operon, which is sufficient for the inactivation of active metabolite 5-fluorouracil (5-FU). preTA + bacteria depleted 5-FU in gut microbiota grown ex vivo and the mouse distal gut. Germ-free and antibiotic-treated mice experienced increased fluoropyrimidine toxicity, which was rescued by colonization with the mouse gut microbiota, preTA + E. coli , or preTA -high CRC patient stool. Finally, preTA abundance was negatively associated with fluoropyrimidine toxicity in patients. Together, these data support a causal, clinically relevant interaction between a human gut bacterial operon and the dose-limiting side effects of cancer treatment. Our approach is generalizable to other drugs, including cancer immunotherapies, and provides valuable insights into host-microbiome interactions in the context of disease. One Sentence Summary: Gut microbial enzymes can be used to predict and prevent anticancer drug toxicity.

SURGICAL TREATMENT OF RECTAL CANCER WITH PRESERVATION OF THE LEFT COLIC ARTERY AND ICG NAVIGATION

Goal. To analyze the peculiarities of surgical diagnosis of lymphogenic metastasis in patients with colorectal cancer. Generalization of data from Ukrainian and foreign literature, results of randomized studies and meta-analyses. The study is based on the results of observation of 88 patients with colorectal cancer (CRC) of the prospective study group. To analyze the features of surgical diagnostics of lymphogenic metastasis in patients with colorectal cancer. Materials and methods. The results of surgical treatment of 88 patients with rectal cancer were analyzed and systematized. These patients underwent examination and treatment in 2023-2024 at the "Prykarpattian Clinical Oncology Center of the Ivano-Frankivsk Regional Council." The study included patients with stage II-III colorectal cancer (T2-3N0-2M0) without complicated courses. All patients received treatment based on NCCN recommendations. Surgical treatment was performed in standard volume with the removal of all regional lymph node groups and preservation of the left colic artery using real-time lymph node mapping with indocyanine green. All patients were divided into two study groups: Group I included 45 patients who underwent anterior or low anterior resection of the rectum with preservation of the left colic artery. This group was subdivided into two subgroups: Ia – 13 patients who underwent intraoperative indocyanine green injection for real-time lymph node visualization. Ib – 32 patients who did not receive this drug but underwent the same volume of surgery. Group II consisted of 43 patients who underwent anterior or low anterior resection of the rectum with high ligation of the inferior mesenteric artery. This group served as the control group. Results. The main mechanisms of lymphogenic metastasis in colorectal cancer patients in Ivano-Frankivsk were characterized. Literature data on the features of surgical diagnostics of colorectal cancer metastasis were summarized. A review of literature shows the social significance of these studies, as this pathology often leads to patient disability, requiring surgical interventions and further palliative treatment due to the widespread metastasis associated with this disease. The priority task for researchers remains the search for the most effective treatment methods for this pathology, based on randomized studies of colorectal cancer treatment and international protocols. According to the literature, surgical treatment of colorectal cancer remains insufficiently effective at the current stage of oncology. Modern methods offer low 5-year survival rates, emphasizing the need to study factors for individualized treatment. The overall 5-year survival rate for colorectal cancer patients from 2018-2022 was (45.8±2.3)%. The effectiveness of using real-time ICG navigation for lymph node mapping and preservation of the left colic artery in stage II-III (T2-4N1-2M0) rectal cancer patients has been proven. This technique allows for optimal lymphadenectomy, reducing the frequency of surgical complications by 14.7% (p&lt;0.05). Conclusion. Ensuring radical resection of rectal cancer while maximizing blood supply preservation to the anastomosis is the main goal of colorectal surgeons. Over the past two decades, surgical techniques have significantly improved due to advancements in surgical equipment. It is anticipated that surgical technologies will further evolve towards enhancement and individualization in the future. Our procedure serves as an example of modern and personalized rectal cancer surgery.

Oxaliplatin triggered hypersensitivity reactions in colorectal cancer patients: Case report

Colorectal cancer stands as a significant global health concern, encompassing adenocarcinoma of both the colon and rectum. Recognized risk factors include advancing age and medical history of inflammatory bowel conditions like Crohn's disease or ulcerative colitis. Oxaliplatin, a platinum-based chemotherapy agent, serves as the frontline treatment for colorectal cancer due to its cytotoxic effects on cancerous cells. However, its use is not without complications, as hypersensitivity reactions can occur, posing challenges in patient management. This case report discusses two instances where patients undergoing chemotherapy for colorectal cancer developed grade two hypersensitivity reactions following oxaliplatin administration, the Naranjo probability scale was used to analyze the causation of the adverse drug reactions (ADRs), and a score of 6 was obtained, indicating oxaliplatin as a probable cause of the hypersensitivity reactions. In both cases, treatment was promptly halted upon manifestation of symptoms, and patients were administered intravenous steroids along with anti-histamines. This intervention resulted in significant improvement in the patients' conditions. Both genders are equally susceptible to such reactions, emphasizing the need for gender-neutral awareness and precautionary measures among medical practitioners. This case report serves as a reminder of the potential adverse effects associated with oxaliplatin therapy in colorectal cancer patients. Heightened awareness among healthcare professionals regarding the risk of hypersensitivity reactions is imperative to ensure timely detection and appropriate management, thereby optimizing patient outcomes. Consequently, while giving oxaliplatin to cancer patients, healthcare professionals need to use extreme caution.

Innovative Oral Nano/Gene Delivery System Based on Engineered Modified Saccharomyces cerevisiae for Colorectal Cancer Therapy.

The efficient delivery of RNA-based drugs to solid tumors remains a formidable obstacle. We aim to develop a safe and efficient oral drug delivery system compatible with RNA-based drugs that is urgently needed to overcome challenges such as enzymatic degradation and gastrointestinal barriers to facilitate effective treatment for treating colorectal cancer (CRC). To address these challenges, we utilized engineered modified Saccharomyces cerevisiae to evaluate the delivery efficacy of miR21-antagomir for treating CRC in preclinical mouse models, including adenomatosis polyposis coli mutant transgenic mice ApcMin/+ and in situ tumor-bearing mice. An orally deliverable gene delivery system, YS@NPs21, was designed. This gene delivery system demonstrated effectively suppressed tumor growth in both ApcMin/+ and in situ tumor-bearing mice models. This system exhibited tumor-targeting capability, effective inhibition of tumor growth, and low toxicity toward nontumor cells. Successful implementation of this innovative oral drug delivery system could offer a straightforward, safe, and RNA drug-compatible approach to CRC treatment, ultimately improving patient outcomes and reducing medical costs.

Antagonistic roles of cGAS/STING signaling in colorectal cancer chemotherapy.

FOLFOX, composed of 5-FU, oxaliplatin and leucovorin, is a first line chemotherapy regimen for colorectal cancer (CRC) treatment. In this study, we show that 5-FU and oxaliplatin induce DNA damage and activate cGAS/STING signaling leading to enhanced expression of interferon (IFN) β, IFN-stimulated genes and inflammatory cytokines in mouse and human colon cancer cells as well as increased intratumoral CD8+ T cells in mice. Crucially, 5-FU and oxaliplatin increase PD-L1 expression at the mRNA and protein levels, which has been shown to inhibit CD8+ T cell function. Depletion of cGAS, STING, IRF3, or IFNα/β receptor 1 (IFNAR1) abolishes this increase, indicating that 5-FU/oxaliplatin mediated upregulation of PD-L1 expression is dependent on tumor cell intrinsic cGAS/STING signaling. These results imply opposing roles for FOLFOX during cancer treatment. On one hand, 5-FU and oxaliplatin activate the innate immune response to facilitate anti-tumor immunity, and conversely upregulate PD-L1 expression to evade immune surveillance. Analysis of TCGA colon cancer dataset shows a positive correlation between expression of PD-L1 and components of the cGAS/STING pathway, supporting a role for cGAS/STING signaling in upregulating PD-L1 expression in colon cancer patients. Tumor studies in syngeneic immune competent mice demonstrate that the combination of 5-FU/oxaliplatin and anti-PD-1 significantly reduced tumor growth of colon cancer cells compared to 5-FU/oxaliplatin treatment alone. Taken together, our studies have identified a unique pathway leading to chemoresistance and provide a rationale to combine FOLFOX with anti-PD-1/PD-L1 as an effective CRC treatment.

Amphiregulin Upregulation in Visfatin-Stimulated Colorectal Cancer Cells Reduces Sensitivity to 5-Fluororacil Cytotoxicity.

Colorectal cancer (CRC) has become a prevalent and deadly malignancy over the years. Drug resistance remains a major challenge in CRC treatment, significantly affecting patient survival rates. Obesity is a key risk factor for CRC development, and accumulating evidence indicates that increased secretion of adipokines, including Visfatin, under obese conditions contributes to the development of resistance in CRC to various therapeutic methods. Amphiregulin (AREG) is a member of the epidermal growth factor (EGF) family, which activates the EGF receptor (EGFR), influencing multiple tumorigenic characteristics of cancers. Abnormal expression levels of AREG in cancer cells have been associated with resistance to anti-EGFR therapy in patients. However, it remains unclear whether this abnormal expression also impacts CRC resistance to other chemotherapeutic drugs. The aim of this study is to examine whether AREG expression levels could be affected in CRC cells under Visfatin stimulation, thereby initiating the development of resistance to 5-fluororacil (5-FU). Through our results, we found that Visfatin indeed increases AREG expression, reducing the sensitivity of HCT-116 CRC cells to 5-FU cytotoxicity. Moreover, AREG upregulation is regulated by STAT3-CREB transcription factors activated by JNK1/2 and p38 signaling. This study highlights the significant role of AREG upregulation in CRC cells in initiating chemotherapeutic resistance to 5-FU under Visfatin stimulation. These findings provide a deeper understanding of drug resistance development in CRC under obese conditions and offer new insights into the correlation between an abnormal increase in AREG levels and the development of 5-FU-resistance in CRC cells, which should be considered in future clinical applications.

The Anticancer Poperties of Diosgenin on Colorectal Cancer Cells Induced by Wnt/&amp;Beta; Catenin Signaling Pathway

Background: Colorectal cancer (CC) is one of the most prevalent cancers globally. Due to the severe side effects and the development of drug resistance in CC treatments, current therapeutic strategies often prove ineffective. As a result, there is a growing interest in exploring traditional medicinal plants as alternative treatment options for various human diseases. Diosgenin, a bioactive compound derived from plants, has shown potential in inhibiting the growth of human CC cells. The Wnt/β-catenin signaling pathway plays a critical role in colorectal tumorigenesis. Objectives: This study investigates the effects of Diosgenin on the Wnt/β-catenin pathway in CC cells. Methods: Colorectal cancer cells were treated with Diosgenin, and cell viability and plasma membrane integrity were assessed using the MTT assay and lactate dehydrogenase (LDH) activity assay, respectively. Apoptosis was evaluated through Annexin V/PI staining. The expression of Wnt/β-catenin-related genes was analyzed by quantitative PCR (qPCR). Results: Diosgenin significantly inhibited CC cell viability in a time- and concentration-dependent manner after 24, 48, 72, and 96 hours of exposure (P &lt; 0.05). The IC50 values were determined to be 203.55, 122.95, 70.11, and 7.34 µM at 24, 48, 72, and 96 hours, respectively. Diosgenin at its IC50 concentration induced a significant increase in cell apoptosis after 24 hours of treatment (P &lt; 0.05). Additionally, it caused a significant reduction in the expression of β-catenin, cyclin D1, and Pin1 (βCP). Conclusions: Diosgenin exhibits anti-CC effects by inhibiting the expression of βCP genes involved in the Wnt/β-catenin pathway, suggesting its potential as a therapeutic agent for CC.

M1 macrophages deliver CASC19 via exosomes to inhibit the proliferation and migration of colon cancer cells.

Colorectal cancer (CRC) continues to be one of the leading causes of cancer-related death worldwide. Exosomes have been established to play an important role in intercellular communication and that long non-coding RNA (lncRNA) CASC19 is enriched within M1 macrophage-derived exosomes (M1-exo). However, the biological functions and underlying molecular mechanisms of exosomal CASC19 from macrophages on CRC remain unknown. Cell proliferation and migration were evaluated by MTS and transwell assays. The exosomes were characterized by western blot, nanoparticle tracking analysis (NTA) and electron microscope imaging. The expression levels of CASC19 and its putative target miR-410-3p were quantified by reverse-transcription polymerase chain reaction (RT-qPCR). The interaction between CASC19 and miR-410-3p was detected by the pull-down assay. We found that the non-contact inhibition of M1 macrophages on the proliferation of colon cancer cells is largely dependent on the CASC19 released from M1 exosomes. M1 exosomes successfully delivered CASC19 to colon cancer cells, exerting an inhibitory effect on cell proliferation and migration. The exosomes secreted by M1 cells with CASC19 knockdown showed less inhibition effect on cell proliferation and migration. Mechanically, CASC19 exerted an inhibitory effect on colon cancer cells by sponging miR-410-3p via tube morphogenesis and TGF-β signaling pathway. We first proved that CASC19 in M1 macrophages is delivered into colon cancer cells via exosomes, exerting an inhibitory effect on their proliferation and migration by sponging miR-410-3p. The study may provide mechanistic insights into the roles of lncRNAs in CRC progression and a potential therapeutic target for the treatment of CRC.

The Double-Edged Sword Property of Mesenchymal Stem Cell-Derived Exosomal microRNAs in Colorectal Cancer.

Mesenchymal stem cells (MSCs)-based therapies are promising therapeutic strategies for cancer treatment, because of their strong immunomodulatory and tissue regeneration abilities. In case of colorectal cancer (CRC), MSCs indicate a double-edged sword activity. Some reports declared the inhibitory effects of MSCs on the proliferation, migration, and infiltration of cancer cells to suppress the CRC initiation and development, whereas others showed the tumor-promoter impacts of MSCs on the progression of CRC. Recent investigations have revealed that exosomal microRNAs (Exo-miRs) derived from MSCs (MSCs-Exo-miRs) are attributed to such paradoxical effect. Thus, the current review aimed to seek the role of MSCs-Exo-miRs in CRC progression and their therapeutic potential for the CRC treatment.

Aberrant FAM135B attenuates the efficacy of chemotherapy in colorectal cancer by modulating SRSF1-mediated alternative splicing.

Oxaliplatin is the frontline chemotherapy drug for the treatment of colorectal cancer (CRC) and its insensitivity is a major limitation on therapeutic efficacy. Genomic instability is the prominent feature of CRC and is considered to correlate with response to treatments. However, the underlying mechanism of insensitivity to oxaliplatin (L-OHP) remains largely unclear. Herein, sequence similarity 135 family member B (FAM135B) is identified as a frequently mutated gene in CRC and is critical for CRC proliferation and impaired response to L-OHP by controlling SRSF1-mediated alternative splicing. Specifically, FAM135B promotes the nuclear translocation of SRSF1 by synergistically binding with SRPK1 and regulates SRSF1-mediated splicing of DNA repair genes. FAM135B-induced exon IV inclusion of FAAP20 mediates its binding with FACNA and enhances the functional integrity of the FA core complex, thereby activating the FA pathway and resulting in inter-strand crosslink (ICL) lesion repair and L-OHP insensitivity. These findings reveal that the FAM135B-SRSF1 axis-mediated splicing contributes to DNA repair and chemotherapeutic insensitivity in CRC. Targeting FAM135B represents a potential strategy for CRC treatment.

Association Between Changes in Plasma Capecitabine Concentrations and Adverse Events in the Treatment of Colorectal Cancer

Association Between Changes in Plasma Capecitabine Concentrations and Adverse Events in the Treatment of Colorectal Cancer

KRAS, a New Target for Precision Medicine in Colorectal Cancer?

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, with significant public health concerns. This review examines the landscape of KRAS inhibition in colorectal cancer (CRC), focusing on recent advances in therapeutic strategies targeting this oncogene. Historically deemed undruggable due to its complex structure and essential role in tumorigenesis, KRAS mutations are prevalent in CRC and are associated with poor prognosis. However, breakthroughs in drug development have led to the emergence of KRAS inhibitors as promising treatment options. This review discusses various classes of KRAS inhibitors, including covalent and non-covalent inhibitors, as well as combination therapies aimed at enhancing efficacy and overcoming resistance mechanisms. It highlights recent clinical trials evaluating the efficacy of KRAS inhibitors either as monotherapy or in combination with other agents, such as anti-EGFR antibodies. Despite challenges such as resistance mechanisms and tumor heterogeneity, the development of KRAS inhibitors represents a significant advance in CRC treatment and holds promise for improving patient outcomes in the future.

Impact of metallic nanoparticles on gut microbiota modulation in colorectal cancer: A review.

Colorectal cancer (CRC) is the third most prevalent cancer. Ongoing research aims to uncover the causes of CRC, with a growing focus on the role of gut microbiota (GM) in carcinogenesis. The GM influences CRC development, progression, treatment efficacy, and therapeutic toxicities. For example, Fusobacterium nucleatum and Escherichia coli can regulate microbial gene expression through the incorporation of human small noncode RNA and potentially contribute to cancer progression. Metallic nanoparticles (MNPs) have both negative and positive impacts on GM, depending on their type. Several studies state that titanium dioxide may increase the diversity, richness, and abundance of probiotics bacteria, whereas other studies demonstrate dose-dependent GM dysbiosis. The MNPs offer cytotoxicity through the modulation of MAPK signaling pathways, NF-kB signaling pathways, PI3K/Akt signaling pathways, extrinsic signaling pathways, intrinsic apoptosis, and cell cycle arrest at G1, G2, or M phase. MNPs enhance drug delivery, enable targeted therapy, and may restore GM. However, there is a need to conduct well-designed clinical trials to assess the toxicity, safety, and effectiveness of MNPs-based CRC therapies.

Single-Cell Transcriptomics Reveals Cellular Heterogeneity and Drivers in Serrated Pathway-Driven Colorectal Cancer Progression

Serrated lesions are common precancerous pathways in colorectal cancer (CRC), but the process by which they progress to malignancy remains unclear. We aimed to elucidate this progression through a single-cell RNA landscape. We conducted single-cell RNA sequencing on three normal colonic tissues and fifteen SLs (including HPs, SSLs, SSLD, and TSAs) and integrated these data with datasets containing tumor samples. We identified three invasive malignant epithelial cell subtypes related to CRC progression: SLC1, SLC2, and tumor cell. SLC1, specific to SSLs, is involved in cell proliferation and shows a continuum of malignancy in gene expression. TSA-specific SLC2 exhibited FOXQ1 upregulation and active EMT, indicating invasiveness. The trajectory analysis showed that HPs do not progress to cancer, and different SL types are linked to the MSI status of advanced CRCs. We validated molecular drivers in premalignant lesions and later carcinogenesis. In the tumor microenvironment, CAF and pre-CAF fibroblast subtypes associated with progression were identified. During the premalignant stage, SLC1 triggered CD8+ T cell responses, while at the advanced stage, CAFs promoted tumor invasion and metastasis via FN1-CD44, influencing tumor progression and the treatment response. Our findings highlight transcriptional changes across serrated pathway stages, aiding in early CRC diagnosis and treatment.

Cabozantinib-encapsulated and maytansine-conjugated high-density lipoprotein for immunotherapy in colorectal cancer

Advanced colorectal cancer (CRC) responds poorly to current adjuvant therapies, partially due to its immunosuppressive intestinal microenvironment. We found that myeloid-derived suppressor cells (MDSCs) were enriched in orthotopic tumors due to treatment-induced succinate release, which activated tuft cells and upregulated interleukin 25 (IL-25) and interleukin 13 (IL-13). We engineered a cabozantinib (Cabo)-encapsulated and maytansine (DM1)-conjugated synthetic high-density lipoprotein (ECCD-sHDL) to modulate the tumor microenvironment. DM1 induced immunogenic cell death and promoted the maturation of dendritic cells. Meanwhile, Cabo alleviated DM1-induced succinate release, preventing tuft cell activation, downregulating IL-25 and IL-13 secretion, and reducing intratumoral MDSC infiltration. ECCD-sHDL increased the densities of active cytotoxic T lymphocytes (CTLs) and M1 macrophages in the tumors, effectively inhibiting tumor growth and metastasis, thereby prolonging survival in murine CRC models. Our study sheds light on the mechanism of treatment-induced immunosuppression in orthotopic CRC and demonstrates that this combinatorial therapy could be an effective treatment for CRC.

Anti-tumor activity of camptothecin analog conjugate of a RSPO4-based peptibody targeting LGR4/5/6 in preclinical models of colorectal cancer.

Antibody-drug conjugates (ADCs) have emerged as a major modality of targeted cancer therapy, yet no ADC has been approved for colorectal cancer (CRC). LGR4/5/6 (leucine-rich repeat containing, G protein-coupled receptor 4, 5, 6) are three related receptors that are expressed at high levels together or alternately in nearly all cases of CRC. ADCs targeting LGR5 have been shown to have robust anti-tumor potency, but not all CRC cells express LGR5 and LGR5-positive tumor cells may lose LGR5 expression due to cancer cell plasticity. R-spondin 4 (RSPO4) is a natural protein ligand of LGR4/5/6 with high affinity for all three receptors. We fused a mutant form of RSPO4 that retains high affinity binding to LGR4/5/6 to IgG1 Fc to create a peptibody designated R462. Conjugation of R462 with a camptothecin analog (CPT2) at eight drugs per peptibody led to the synthesis of R462-CPT2 that showed highly potent cytotoxic activity in vitro in CRC cell lines expressing any of LG4/5/6. In cell line xenograft and PDX models of CRC, R462-CPT2 demonstrated robust anti-tumor effect. Importantly, R462-CPT2 showed no major adverse effect at therapeutically effective dose levels. These results strongly support the use of RSPO ligand drug-conjugates that target LGR4/5/6 simultaneously for the treatment of CRC.

TRIM21 induces selective autophagic degradation of c-Myc and sensitizes regorafenib therapy in colorectal cancer

Kirsten rat sarcoma virus (KRAS) mutation is associated with malignant tumor transformation and drug resistance. However, the development of clinically effective targeted therapies for KRAS-mutant cancer has proven to be a formidable challenge. Here, we report that tripartite motif-containing protein 21 (TRIM21) functions as a target of extracellular signal-regulated kinase 2 (ERK2) in KRAS-mutant colorectal cancer (CRC), contributing to regorafenib therapy resistance. Mechanistically, TRIM21 directly interacts with and ubiquitinates v-myc avian myelocytomatosis viral oncogene homolog (c-Myc) at lysine 148 (K148) via K63-linkage, enabling c-Myc to be targeted to the autophagy machinery for degradation, ultimately resulting in the downregulation of enolase 2 expression and inhibition of glycolysis. However, mutant KRAS (KRAS/MT)-driven mitogen-activated protein kinase (MAPK) signaling leads to the phosphorylation of TRIM21 (p-TRIM21) at Threonine 396 (T396) by ERK2, disrupting the interaction between TRIM21 and c-Myc and thereby preventing c-Myc from targeting autophagy for degradation. This enhances glycolysis and contributes to regorafenib resistance. Clinically, high p-TRIM21 (T396) is associated with an unfavorable prognosis. Targeting TRIM21 to disrupt KRAS/MT-driven phosphorylation using the antidepressant vilazodone shows potential for enhancing the efficacy of regorafenib in treating KRAS-mutant CRC in preclinical models. These findings are instrumental for KRAS-mutant CRC treatment aiming at activating TRIM21-mediated selective autophagic degradation of c-Myc.

SHR-8068 combined with adebrelimab and bevacizumab in the treatment of refractory advanced colorectal cancer: study protocol for a single-arm, phase Ib/II study.

The third-line treatment for refractory colorectal cancer (CRC) has limited efficacy. This study aimed to evaluate the safety and efficacy of SHR-8068 (an anti-CTLA-4 antibody), combined with adebrelimab (an anti-PD-L1 antibody), and bevacizumab in refractory non-microsatellite instability-high (MSI-H) or proficient mismatch repair (pMMR) CRC. This study is a prospective, open-label, single-center phase Ib/II clinical trial. Patients with pathologically confirmed pMMR/non-MSI-H metastatic colorectal adenocarcinoma who have failed ≥2 lines prior standard systemic treatments will be enrolled (n=36). The Ib phase will evaluate two dosing regimens of SHR-8068 in combination therapy (n=9 each dosage): SHR-8068 (1 mg per kilogram, every six weeks, intravenously) or SHR-8068 (4 mg per kilogram, every twelve weeks, intravenously) combined with adebrelimab (1200 mg, every three weeks, intravenously) and bevacizumab (7.5 mg per kilogram, every three weeks, intravenously). The efficacy and adverse events (AEs) of these regimens will be assessed to determine the recommended phase II dose (RP2D) of SHR-8068. Those of RP2D group from the phase Ib will be included in the phase II. The study will go to include 18 additional patients according to the one-sample log-rank test design in the phase II. The primary endpoint of the Ib phase is safety, with secondary endpoints including the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and quality of life (QOL). The primary endpoint for phase II was PFS, with secondary endpoints including ORR, OS, DCR, safety, and QOL. Identifying biomarkers to predict the efficacy of this regimen is the exploratory study endpoint. This proof-of-concept study would provide safety and efficacy signals of this novel combination treatment for the MSS CRCs in the late-line setting. And it may offer new insights on the clinical application of dual immunotherapy combined with anti-angiogenic therapy in the MSS CRC.

Proteomic analysis of plasma exosomes in patients with metastatic colorectal cancer

BackgroundThe diagnosis and treatment of colorectal cancer (CRC), especially metastatic colorectal cancer (mCRC), is a major priority and research challenge. We screened for expression differences in the plasma exosomal proteomes of patients with mCRC, those with CRC, and healthy controls (HCs) to discover potential biomarkers for mCRC.MethodsPlasma samples from five patients with mCRC, five patients with CRC, and five HCs were collected and processed to isolate exosomes by ultracentrifugation. Exosomal protein concentrations were determined using the BCA kit, and liquid chromatography-mass spectrometry was utilized to identify and analyze the proteins.ResultsFrom the exosomes isolated from plasma samples, a total of 994 quantifiable proteins were detected, including 287 differentially expressed proteins identified by quantitative proteomics analyses. Totals of 965, 963 and 968 proteins were identified in mCRC patients, CRC patients, and HCs, respectively. The study identified 83 proteins with differential expression in the plasma exosomes of mCRC patients. The top 10 upregulated proteins in the mCRC group and CRC groups were ITGA4, GNAI1, SFTPA2, UGGT1, GRN, LBP, SMIM1, BMP1, HMGN5, and MFAP4, while the top 10 downregulated proteins were PSMB8, LCK, RAB35, PSMB4, CD81, CD63, GLIPR2, RAP1B, RAB30, and CES1. Western Blot validation data confirmed that ITGA4 and GNAI1 were unequivocally enriched in plasma-derived exosomes from mCRC patients.ConclusionsThese differential proteins offer potential new candidate molecules for further research on the pathogenesis of mCRC and the identification of therapeutic targets. This study sheds light on the potential significance of plasma exosome proteomics studies in our understanding and treatment of mCRC.