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Background: Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, and treatment options for advanced CRC are limited. The regulatory mechanisms of aberrant NAT10-mediated N4-acetylcytidine (ac4C) modifications in cancer progression remains poorly understood. Consequently, an integrated transcriptomic analysis is necessary to fully elucidate the role of NAT10-mediated ac4C modifications in CRC progression. Methods: NAT10 expression levels were analyzed in CRC samples and compared with those in corresponding normal tissues. The potential mechanisms of NAT10 in CRC were investigated using RNA sequencing, RNA immunoprecipitation sequencing, and acetylated RNA immunoprecipitation sequencing. Additional in vivo and in vitro experiments, including CCK-8 assays, colony formation and mouse xenograft models, were conducted to explore the biological role of NAT10-mediated ac4C modifications. We also evaluated and optimized a potential treatment strategy targeting NAT10. Results: We found that NAT10 is highly expressed in CRC samples and plays a pro-oncogenic role. NAT10 knockdown led to PI3K-AKT pathway inactivation, thereby inhibiting CRC progression. However, treatment with the NAT10 inhibitor Remodelin induced only a limited and reversible growth arrest in CRC cells. Further epigenetic and transcriptomic analysis revealed that NAT10 enhances the stability of ERRFI1 mRNA by binding to its coding sequence region in an ac4C-dependent manner. NAT10 knockdown decreased ERRFI1 expression, which subsequently activated the EGFR pathway and counteracted the inhibitory effects on CRC. Based on these findings, we demonstrated that dual inhibition of NAT10 and EGFR using Remodelin and the EGFR-specific monoclonal antibody cetuximab resulted in improved therapeutic efficacy compared to either drug alone. Moreover, we observed that 5-Fluorouracil promoted the interaction between NAT10 and UBR5, which increased the ubiquitin-mediated degradation of NAT10, leading to ERRFI1 downregulation and EGFR reactivation. Triple therapy with Remodelin, cetuximab, and 5-Fluorouracil enhanced tumor regression in xenograft mouse models of CRC with wild-type KRAS, NRAS and BRAF. Conclusions: Our study elucidated the mechanism underlying 5-Fu-induced NAT10 downregulation, revealing that NAT10 inhibition destabilizes ERRFI1 mRNA through ac4C modifications, subsequently resulting in EGFR reactivation. A triple therapy regimen of Remodelin, cetuximab, and 5-Fu showed potential as a treatment strategy for CRC with wild-type KRAS, NRAS and BRAF. [ABSTRACT FROM AUTHOR]

This study aims to monitor and identify adverse events (AEs) associated with cetuximab, a drug used to treat various late-stage (metastatic) tumors, to improve patient safety and guide drug use. This study retrospectively analyzed the cases reported in the FDA adverse event reporting system (FAERS) related to the application of cetuximab from 2013 Q1 to 2022 Q4. Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the empirical Bayesian geometric mean (EBGM) algorithms, were employed to quantify the signals of cetuximab-associated AEs. A total of 8364225 reports were contained in the FAERS database, of which 5186 reports of cetuximab were identified as 'primary suspected (PS)' AEs. The application of cetuximab resulted in AEs in 22 system organ classes (SOCs), which preserved 176 significant disproportionality preferred terms (PTs) through the computation of four algorithms. The main SOCs (Skin and subcutaneous tissue disorders, investigations, metabolism and nutrition disorders, and blood and lymphatic system disorders) accounted for 58.63%. Some AEs were not on the drug label: speech disorder, intervertebral discitis, glomerulonephritis rapidly progressive and disseminated intravascular coagulation. This study identified new signals of adverse drug reactions (ADRs) other than those mentioned in the specification associated with cetuximab, providing valuable insights into the relationship between ADRs and cetuximab use. The findings highlight the importance of continuous surveillance to detect and manage AEs effectively, ultimately improving patient safety during treatment with cetuximab. [ABSTRACT FROM AUTHOR]

Background: Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, and current treatments are limited by high toxicity and low survival rates, highlighting the need for new therapeutic approaches. Natural killer (NK) cells can identify and eliminate cancer cells without prior antigen exposure. Radiotherapy directly targets tumors and increases activating ligands on tumor cells, promoting NK cell interactions. Cetuximab, an EGFR-targeting antibody, enhances NK cell cytotoxicity. Additionally, anti-PD-1 antibodies may further boost NK cell function by blocking inhibitory signals. The study aimed to enhance HNSCC treatment efficacy by combining radiotherapy and targeted therapy with expanded NK cells. Methods: NK cells were isolated, activated, and expanded from healthy donors. The FaDu and SCC-47 cell lines were inoculated into NOD/SCID mice. The mice were treated with PD-1 inhibitors, cetuximab, and radiation, followed by intravenous injection of NK cells. Results: Radiation increased ligands that regulate NK cell sensitivity. The combination of cetuximab, radiotherapy, and expanded NK cells significantly suppressed cancer progression and improved survival rates. However, adding anti-PD-1 antibodies did not further enhance outcomes. Conclusion: This study suggests that a multimodal approach combining cetuximab, radiotherapy, and NK cells can significantly improve HNSCC therapy efficacy, offering a novel and promising treatment strategy. [ABSTRACT FROM AUTHOR]

Patients diagnosed with metastatic colorectal cancer (mCRC) have a poor prognosis with survival ranging 2–3 years. The prevalence of human epidermal growth factor receptor 2 (HER2) amplification is approximately 3–4% in mCRC and increases up to 8% in patients with KRAS/NRAS/BRAF wild-type (WT) CRC tumors. Tucatinib is a highly selective HER2-directed tyrosine kinase inhibitor that, in combination with trastuzumab, has demonstrated clinically meaningful activity in patients with chemotherapy-refractory, HER2-positive (HER2+), RAS WT mCRC in the MOUNTAINEER trial. The MOUNTAINEER-03 phase III trial is designed to investigate the efficacy and safety of first-line tucatinib in combination with trastuzumab and modified FOLFOX6 (mFOLFOX6) versus standard of care (mFOLFOX6 plus bevacizumab or cetuximab) in patients with untreated HER2+, RAS WT locally advanced unresectable or mCRC. MOUNTAINEER-03 will include two arms of approximately 400 patients randomized 1:1 to either treatment arm. The primary endpoint is progression-free survival per RECIST v1.1 by blinded independent central review (BICR). Key secondary endpoints are overall survival and confirmed objective response rate (according to RECIST v1.1 per BICR). Safety assessments will include surveillance and recording of adverse events, physical examination findings, vital signs, cardiac assessments, Eastern Cooperative Oncology Group performance status, concomitant medications, and laboratory tests. Clinical trial registration: NCT05253651 (ClinicalTrials.gov). Plain Language Summary Colorectal cancer is a common and leading cause of cancer deaths worldwide. Patients who have colorectal cancer that has spread to other parts of the body (metastasized) only live for 2 to 3 years after their diagnosis. Tucatinib is a medicine that has shown promising anti-tumor activity when it is given in combination with trastuzumab in patients with metastatic colorectal cancer that is of a certain type, called HER2-positive. HER2 is a protein that, when present in amounts above normal in cancer cells, can cause them to grow more and survive longer. The MOUNTAINEER-03 study is a trial in progress of patients with HER2-positive metastatic colorectal cancer. In this trial, researchers are investigating if tucatinib in combination with trastuzumab and chemotherapy increases the length of time patients live before their cancer grows or spreads (also called progression-free survival) and how long a person is alive after the start of treatment (also called overall survival) compared to standard of care treatment (chemotherapy combination). Researchers are also investigating whether this new tucatinib combination treatment makes the colorectal cancer shrink and stop spreading and if it is safe to use in patients with HER2-positive metastatic colorectal cancer. If the findings of the MOUNTAINEER-03 phase III trial are positive, the tucatinib combination treatment could be a new option for the first-line treatment of a patient population with a high unmet medical need. This paper describes the study design of the MOUNTAINEER-03 trial. [ABSTRACT FROM AUTHOR]

Anti-epidermal growth factor receptor (EGFR) therapy (cetuximab) shows a limited clinical benefit for patients with locally advanced or recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), due to the frequent occurrence of secondary resistance mechanisms. Here we report that cetuximab-resistant HNSCC cells display a peroxisome proliferator-activated receptor alpha (PPARα)-mediated lipid metabolism reprogramming, with increased fatty acid uptake and oxidation capacities, while glycolysis is not modified. This metabolic shift makes cetuximab-resistant HNSCC cells particularly sensitive to a pharmacological inhibition of either carnitine palmitoyltransferase 1A (CPT1A) or PPARα in 3D spheroids and tumor xenografts in mice. Importantly, the PPARα-related gene signature, in human clinical datasets, correlates with lower response to anti-EGFR therapy and poor survival in HNSCC patients, thereby validating its clinical relevance. This study points out lipid metabolism rewiring as a non-genetic resistance-causing mechanism in HNSCC that may be therapeutically targeted to overcome acquired resistance to anti-EGFR therapy. Resistance to anti-EGFR therapy is a clinical issue for patients with advanced head and neck cancers. Here, the authors show that therapy-resistant cancer cells enhance fatty acid metabolism, which can be therapeutically targeted by inhibiting peroxisome proliferator-activated receptor alpha (PPARα). [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the outcomes of cetuximab combination therapy in recurrent or metastatic head and neck cancer patients treated at a hospital in Southern Taiwan. A total of 67 patients were retrospectively analyzed, comparing two treatment regimens: CPF4, administered every four weeks during hospitalization, and CPF2, administered every two weeks as an outpatient procedure. The results showed a progression-free survival advantage for patients aged 46–60 years treated with CPF2, though no significant differences in overall survival were observed between CPF4 and CPF2 in any age group. CPF2 demonstrated practical benefits, including reduced hospitalization, lower infection risks, and improved patient convenience, making it a preferred choice for certain patients. These findings highlight the potential impact of age on treatment responses and the importance of balancing clinical outcomes with patient quality of life. Further large-scale studies are required to confirm these observations and refine treatment strategies. Background/Objectives: The aim of this study is to assess the effectiveness of cetuximab combination therapy in patients with recurrent or metastatic head and neck cancer treated at a hospital in Southern Taiwan. Methods: This study analyzed a retrospective cohort of 67 patients who were treated between January 2020 and May 2024 with two cetuximab regimens, cetuximab combined with cisplatin and 5-Fu, which were administered every four weeks during hospitalization (CPF4) and every two weeks as outpatient treatment (CPF2), respectively. The clinical outcomes, including overall survival and progression-free survival (PFS), were compared across the treatment regimens and age groups using Kaplan–Meier survival curves and Cox proportional hazard models. Results: The median overall survival was 11.1 months (95% confidence interval, 7.8–14.5), with CPF2 showing a potential PFS advantage in patients aged 46–60 years (p = 0.049). No significant differences in overall survival were observed between CPF2 and CPF4. CPF2, which was administered in an outpatient setting, was associated with improved convenience, reduced hospitalization, and potentially lower risks of hospital-acquired infections. Conclusions: CPF2 exhibits practical advantages and comparable effectiveness, making it the preferred treatment regimen for eligible patients. Further studies with larger populations and molecular stratifications are needed to confirm these findings and develop better treatment strategies. [ABSTRACT FROM AUTHOR]

Antibody-drug conjugates (ADCs) are an emerging strategy in cancer therapy, enhancing precision and efficacy by linking targeted antibodies to potent cytotoxic agents. This study introduces a novel ADC that combines ribonuclease A (RNase A) with cetuximab (Cet), an anti-EGFR monoclonal antibody, through a polyethylene glycol (PEG) linker (RN-PEG-Cet), aimed to induce apoptosis in KRAS mutant colorectal cancer (CRC) via a ROS-mediated pathway. RN-PEG-Cet was successfully synthesized and characterized for its physicochemical properties, retaining full enzymatic activity in RNA degradation and high binding affinity to EGFR. In KRAS mutant SW-480 cells, RN-PEG-Cet significantly reduced cell viability at lower doses, with an IC50 of 11.7 µg/mL at 72 h. Compared to free Cet, RN-PEG-Cet demonstrated a ~ 2-fold increase in apoptosis and a ~ 3.5-fold increase in ROS production. The conjugate also disrupted the Nrf2/Keap1 pathway, with a significant upregulation of Keap1 (FC = 3.7, p ≤ 0.01) and downregulation of Nrf2 (FC = 3.3, p < 0.01), highlighting its role in impairing antioxidant defenses and promoting ROS-mediated cytotoxicity. These findings emphasize the potential of RN-PEG-Cet as a novel therapeutic approach for KRAS mutant CRC, offering superior apoptosis induction and targeted cytotoxicity compared to conventional therapies. This ADC could represent a new strategy for improving CRC treatment outcomes by effectively overcoming resistance mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: The larynx organ preservation (LOP) trial DeLOS-II enrolled n = 173 patients with advanced laryngeal/hypopharyngeal squamous cell carcinoma (LHSCC) amenable (only curatively resectable) through total laryngectomy (TL) to receive induction chemotherapy (IC) with TPF [docetaxel (T), cisplatin (P), and 5-fluorouracil (F)] (arm A, 85 patients) or additional cetuximab (E) weekly (arm B, 88 patients). Responders with endoscopic estimated tumor surface shrinkage (ETSS) ≥30% after 1 cycle IC (IC-1) received a further two cycles of IC followed by radiotherapy (RT), whereas TL was recommended for non-responders. Arm B failed to show superior 24-month laryngectomy-free survival (LFS) and overall survival (OS), the protocol-specified primary and secondary endpoints. Ten years after the last per-protocol visit, we are interested in the long-term outcome of our clinic's DeLOS-II patients. Methods: Our cohort of 52 DeLOS-II patients accrued between 2007 and 2012 included 27 and 25 patients randomized to arms A and B, respectively. F was omitted because of severe toxicity with amendment 2 of the DeLOS-II protocol, leading to 21 and 31 patients receiving TPF and TP IC backbone, respectively. Follow-up data were collected using electronic health records and information from the German Centre for Cancer Registry Data to evaluate long-term LFS and OS in treatment groups. Results: According to ETSS ≥ 30%, 42 patients (80.8%; 21 and 21 corresponding to 77.8% and 84.0% in arms A and B, respectively) were responders to IC-1 and underwent the LOP attempt. Recommending early TL to non-responders (ETSS < 30%), eight patients (five and three in A and B, respectively) underwent early TL. At 125 months, 22 (eight and 14) patients were alive: 17 (six and 11) with a functioning larynx and five (two and three) without a larynx. Arm B had superior OS (p = 0.023). Disease-specific survival (DSS) and tumor-specific survival were not different, whereas non-cancer-related survival (NCRS) was impaired in arm A (p = 0.018). Receiving TP or TPF IC did not significantly influence survival. Pairwise comparing OS of patients receiving TP, TPF, TPE, and TPFE revealed a benefit from cetuximab in TPE vs. TP (p = 0.020). Conclusion: While the per-protocol DeLOS-II results earlier reported comparable 24-month LFS and OS in arms A and B, our subcohort's long-term follow-up data demonstrate a superior 125-month outcome in arm B. [ABSTRACT FROM AUTHOR]

Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells is a key mechanism in anti-cancer therapies with monoclonal antibodies, including cetuximab (EGFR-targeting) and avelumab (PDL1-targeting). Fc gamma receptor IIIa (FcγRIIIa) polymorphisms impact ADCC, yet their clinical relevance in NK cell functionality remains debated. We developed two complementary flow cytometry assays: one to predict the FcγRIIIa-V158F polymorphism using a machine learning model, and a 15-color flow cytometry panel to assess antibody-induced NK cell functionality and cancer-immune cell interactions. Samples were collected from healthy donors and metastatic colorectal cancer (mCRC) patients from the FIRE-6-Avelumab phase II study. The machine learning model accurately predicted the FcγRIIIa-V158F polymorphism in 94% of samples. FF homozygous patients showed diminished cetuximab-mediated ADCC compared to VF or VV carriers. In mCRC patients, NK cell dysfunctions were evident as impaired ADCC, decreased CD16 downregulation, and reduced CD137/CD107a induction. Elevated PD1+ NK cell levels, reduced lysis of PDL1-expressing CRC cells and improved NK cell activation in combination with the PDL1-targeting avelumab indicate that the PD1-PDL1 axis contributes to impaired cetuximab-induced NK cell function. Together, these optimized assays effectively identify NK cell dysfunctions in mCRC patients and offer potential for broader application in evaluating NK cell functionality across cancers and therapeutic settings. [ABSTRACT FROM AUTHOR]

The article in the Journal of Cutaneous Pathology discusses a case of Acantholytic PRIDE syndrome in a 63-year-old male with chronic myeloid leukemia who developed pus-filled lesions on his limbs after starting imatinib therapy. The patient was treated with topical clobetasol ointment, levocetirizine tablets, and moisturizers, showing improvement at a 3-month follow-up. The syndrome is linked to tyrosine kinase inhibitors like EGFRIs and presents with various cutaneous manifestations, requiring differentiation from other conditions like Grover disease and AGEP. The study highlights the need for further research to understand the exact mechanisms behind acantholysis in PRIDE syndrome. [Extracted from the article]

Background: Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease with poor prognosis. It is known that the activation of STAT3 signaling pathways promotes the development and progression of this neoplasia and it has been described the role of PTPRT as a negative regulator of STAT3. Then, we have evaluated the impact of them as biomarkers of outcome in a series of patients with recurrent and/or metastatic SCCHN treated with weekly paclitaxel‐plus‐cetuximab (ERBITAX) regimen. Patients and methods: Between 2008 and 2017, 52 patients with recurrent/metastatic SCCHN were treated with ERBITAX at our center, 34 of whom had available tumor samples. Phosphorylated STAT3 (pSTAT3) protein expression was analyzed by immunohistochemistry, STAT3 mRNA expression by qPCR, and PTPRT promoter methylation by methylation‐specific PCR. Molecular results were correlated with response rate (RR), progression‐free survival (PFS), and overall survival (OS). Results: pSTAT3 overexpression was detected in 67% and PTPRT promoter hypermethylation in 41% of tumor samples. PTPRT promoter hypermethylation showed a trend towards an association with lower RR (21% vs. 60%; p = 0.06). A lower RR was also observed in patients with pSTAT3 overexpression (36% vs. 54%) and in those with high STAT3 mRNA levels (43% vs. 64%), but these differences did not reach statistical significance. PTPRT promoter hypermethylation correlated with pSTAT3 overexpression (p = 0.009) but not with STAT3 mRNA overexpression. OS and PFS was shorter in patients with activated STAT3, but the difference did not reach statistical significance. Conclusions: Although this was a relatively small retrospective study, it provides preliminary indications of the potential role of the STAT3 pathway on outcome in SCCHN and confirms that PTPRT acts as a negative regulator of STAT3. Our findings warrant investigation in a larger patient cohort to determine if inactivating this pathway through specific targeted treatments could improve outcomes in recurrent/metastatic SCCHN patients. [ABSTRACT FROM AUTHOR]

Background: The FRESCO-2 trial established the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. However, its cost-effectiveness in the US context is not well documented. Objective: This study evaluates the cost-effectiveness of fruquintinib versus placebo for this patient population from the perspective of US payers. Methods: We developed a partitioned survival model on the basis of patient-level data reconstructed from the survival curves of the FRESCO-2 trial. Parametric estimation was conducted to estimate long-term clinical outcomes and medical costs over a lifetime horizon. Cost inputs and utilities were sourced from public data and previous literature. We used a discount rate of 3.0% per year for both clinical outcomes and costs. We adopted an incremental cost-effectiveness ratio (ICER) threshold of US$100,000 per quality-adjusted life-year (QALY) gained. We performed sensitivity and scenario analyses to examine the robustness of cost-effectiveness results. Results: Fruquintinib treatment resulted in incremental gains of 0.108 life years (LYs) and 0.073 QALYs compared with the placebo, at an additional cost of US$112,294, primarily driven by medication expenses. The ICER for fruquintinib versus placebo was calculated at US$1,037,855 per LY and US$1,546,619 per QALY gained, exceeding the predefined cost-effectiveness threshold. The cost-effectiveness results were robust across all sensitivity and scenario analyses. Conclusion and Relevance: Despite the survival benefit, fruquintinib was not cost-effective compared with the placebo in patients with refractory metastatic colorectal cancer in the US setting, on the basis of the conventional willingness-to-pay threshold. Our findings may provide a basis for informing the pricing and reimbursement decisions regarding fruquintinib. [ABSTRACT FROM AUTHOR]

Background: The objective of this study is to investigate the potential association between change in body composition before and after cetuximab-based therapy and the prognostic outcomes among individuals diagnosed with advanced colorectal cancer. Methods: A retrospective analysis was undertaken on a cohort of 81 patients diagnosed with RAS wild-type (WT) metastatic colorectal cancer (mCRC) who were treated with cetuximab-based first-line therapy. To assess relevant body composition parameters, quantitative computed tomography (QCT) scans were conducted both before and after cetuximab treatment. These parameters encompassed measurements of visceral fat area (VFA), subcutaneous fat area (SFA), total muscle area (TMA) at the third lumbar vertebra level (L3), and bone mineral density (BMD) at the first and second vertebrae levels (L1/2). The skeletal muscle index (SMI) was subsequently calculated, and changes in parameters (∆VFA, ∆SFA, ∆SMI, ∆BMD) were standardized. Results: The cut-off values for ∆VFA, ∆SFA, ∆SMI, and ∆BMD were 0.28%, -2.76%, -2.97%, and -7.98%, respectively. CEA, ∆VFA, ∆SMI, and ∆BMD were associated with poor outcomes of cetuximab-based first-line chemotherapy (P < 0.05). The risk of disease progression was higher when ∆VFA < 0.28%, ∆SFA < -2.76%, ∆SMI < -2.97%, and ∆BMD < -7.98%. Multivariate analysis indicated that CEA (HR: 0.396, 95% CI: 0.160–0.980, P = 0.045), ∆VFA (HR: 0.307, 95% CI: 0.145–0.651, P = 0.002), and∆SMI (HR: 0.725, 95% CI: 0.322–1.630, P = 0.001) have significant prognostic value for progression-free survival (PFS) in RAS WT mCRC patients treated with cetuximab-based first-line chemotherapy. Conclusions: CEA, ∆VFA, and ∆SMI are independent predictors for PFS in patients with advanced colorectal cancer. High levels of CEA, ∆VFA, and low levels of ∆SMI may indicate poorer outcomes. CEA, ∆VFA, and ∆SMI can be used to predict PFS in mCRC patients receiving cetuximab-based first-line chemotherapy. Trial registration: This study was approved by the Ethics Committee of Anhui Provincial Cancer Hospital of Anhui Medical University (Batch No:2024-ZNY-02). All subjects signed an informed consent form. [ABSTRACT FROM AUTHOR]

Cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody, has been shown to improve survival in nasopharyngeal carcinoma (NPC) patients. However, a correlation between the expression of EGFR and the response to cetuximab has not been observed, indicating that the mechanism underlying the effects of cetuximab needs to be further elucidated. The antitumour response involves immunotherapeutic mechanisms that target tumour-associated antigens, including complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC), act either alone or, more often, in combination. However, EBV infected NPC cells often develop resistance mechanisms that allow them to evade immune surveillance. Here, we found that overexpression of the complement-regulated protein CD55 in EBV-associated NPC cells mainly suppresses ADCC activity thus reduces the efficacy of cetuximab. Mechanistically, EBV latent membrane protein 1 (LMP1) mediated upregulation of CD55 through the NF-κB signalling pathway. The present study provides a rationale for the development of CD55 inhibitors to improve the clinical efficacy of cetuximab in NPC. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinomas (HNSCC) have an overall poor prognosis, especially in locally advanced and metastatic stages. In most cases, multimodal therapeutic approaches are required and show only limited cure rates with a high risk of tumor recurrence. Anti-PD-1 antibody treatment was recently approved for recurrent and metastatic cases but to date, response rates remain lower than 25%. Therefore, the investigation of the immunological tumor microenvironment and the identification of novel immunotherapeutic targets in HNSCC is of paramount importance. In our study, we used tissue samples of n = 116 HNSCC patients for the immunohistochemical detection of the intratumoral and peritumoral expression of T cell exhaustion markers (PD-1, LAG-3, TIM-3) on tumor infiltration leukocytes (TIL), as well as the expression level of stromal senescence markers (IL-8, MMP-3) on tumor-associated fibroblasts. The clinical parameter of the vitamin D serum status as well as the histopathological HPV infection status of the tumor was correlated with the expression rates of the biomarkers and the overall patient survival. An increased peritumoral and intratumoral expression of the biomarkers PD-1 and TIM-3 significantly correlated with improved overall patient survival. A high peritumoral expression of LAG-3 correlated with better overall survival. A positive HPV tumor status correlated with a significantly elevated expression of PD-1 and TIM-3. Biomarkers of stromal senescence showed no influence on the patient outcome. However, the vitamin D serum status showed no influence on patient outcomes or biomarker expressions. Our study identified PD-1, LAG-3, and TIM-3 as promising targets of a therapeutic strategy targeting the tumor microenvironment in HNSCC, particularly among HPV-positive patients, where a higher expression of these checkpoints correlated with an improved overall survival. These findings support the potential of antibodies targeting these immune checkpoints to enhance treatment efficacy, especially in the context of bispecific targeting. [ABSTRACT FROM AUTHOR]

The randomized FIRE‐4.5 (AIO KRK0116) trial compared first‐line therapy with FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus either cetuximab or bevacizumab in B‐Raf proto‐oncogene, serine/threonine kinase (BRAF) V600E‐mutant metastatic colorectal cancer (mCRC) patients. This study was accompanied by a prospective translational project analyzing cell‐free circulating tumor DNA (ctDNA) in plasma to test whether ctDNA analysis may help to guide clinical treatment decision making. FIRE‐4.5 included mCRC patients with BRAF V600E mutation detected by tissue‐based analyses. Liquid biopsies (LBs) were collected at baseline (pre‐treatment) and during therapy. Digital droplet PCR (ddPCR) technology was applied for determination of BRAF mutations and the in vitro diagnostics (IVD)‐certified ONCOBEAM RAS procedure for analysis of RAS mutations. The BRAF V600E variants in ctDNA were analyzable in 66 patients at start of the therapy, at baseline. No BRAF V600E mutations were detected in 26% (17/66) of patients and was associated with a significantly longer progression‐free survival (PFS: 13.2 vs 6.5 months; HR 0.47; P = 0.014) and overall survival (OS: 36.8 vs 13.2 months; HR 0.35; P = 0.02) as compared to ctDNA mutant patients. Patients with detectable BRAF mutations showed a clear superiority of FOLFOXIRI plus bevacizumab with regard to PFS (10.4 vs 5.7 months; HR 0.4; P = 0.009) and OS (16.6 vs 11.6 months; HR 0.5; P = 0.15), while this was not the case for BRAF wild‐type patients. Follow‐up LBs were obtained from 51 patients. Patients converting from BRAF V600E mutant to a BRAF V600 wild‐type status (36%, N = 18) had a superior PFS (8.6 vs 2.3 months; P = 0.0002) and OS (17.4 vs 5.1 months; P < 0.0001) compared to patients with stable or increased mutational allele frequency (12%, N = 6). Those patients also achieved a significantly greater disease control rate (89% vs 20%; P = 0.008). In conclusion, LB evaluating ctDNA is informative and may help to guide treatment in patients with BRAF V600E‐mutated mCRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths in the United States, with a 14% five-year survival rate when metastasized. Current treatment options for metastatic CRC (mCRC) include combination chemotherapy regimens, immune checkpoint therapy, and monoclonal antibodies (mAbs), such as those targeting the epidermal growth factor receptor (EGFR). However, efficacy of these therapies is limited. EGFR-targeted mAbs extend survival only in a subset of mCRC patients (10–20%), in part due to drug resistance. Thus, additional biomarkers are required to identify responsive patients and to develop novel targeting strategies that will overcome resistance. This review aims to provide a comprehensive overview of EGFR ligands epiregulin (EREG) and amphiregulin (AREG) as prognostic, predictive, and therapeutic targets in CRC. The epidermal growth factor receptor (EGFR) plays a critical role in regulating essential cellular processes that are frequently hijacked to promote cancer. In colorectal cancer (CRC) in particular, the EGFR signaling pathway is frequently hyperactivated via receptor and/or ligand overexpression and downstream oncogenic mutations. Current EGFR-targeted therapies for metastatic CRC (mCRC) include the mAbs cetuximab and panitumumab. However, intrinsic and acquired resistance to EGFR-targeted mAbs are commonly observed. Thus, additional biomarkers are necessary to better understand patient sensitivity to EGFR-targeted therapies. Furthermore, therapeutic targeting of alternative EGFR pathway components may serve as one mechanism to overcome EGFR-targeted mAb resistance. In this review, we discuss the mounting evidence supporting EGFR ligands epiregulin (EREG) and amphiregulin (AREG), which are overexpressed in CRC with potential key roles in tumor progression, as predictive biomarkers for EGFR-targeted therapy sensitivity, as well as mediators of therapy resistance, though further studies are necessary to validate the prognostic roles and mechanisms by which these ligands contribute to resistance. Additionally, we review recent advances towards therapeutic targeting of EREG and AREG in cancer through the development and use of EREG- and AREG-targeted mAbs as well as antibody–drug conjugates (ADCs). We conclude with a discussion on the roadblocks to clinical implementation of EREG and AREG as biomarkers, as well as approaches to enhance the efficacy of current EREG- and AREG-targeted strategies. [ABSTRACT FROM AUTHOR]

Metastatic (m) colorectal cancer (CRC) is an incurable disease with a poor prognosis and thus remains an unmet clinical need. Immune checkpoint blockade (ICB)-based immunotherapy is effective for mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRC patients, but it does not benefit the majority of mCRC patients. NK cells are innate lymphoid cells with potent effector responses against a variety of tumor cells but are frequently dysfunctional in cancer patients. Memory-like (ML) NK cells differentiated after IL-12/IL-15/IL-18 activation overcome many challenges to effective NK cell anti-tumor responses, exhibiting enhanced recognition, function, and in vivo persistence. We hypothesized that ML differentiation enhances the NK cell responses to CRC. Compared to conventional (c) NK cells, ML NK cells displayed increased IFN-γ production against both CRC cell lines and primary patient-derived CRC spheroids. ML NK cells also exhibited improved killing of CRC target cells in vitro in short-term and sustained cytotoxicity assays, as well as in vivo in NSG mice. Mechanistically, enhanced ML NK cell responses were dependent on the activating receptor NKG2D as its blockade significantly decreased ML NK cell functions. Compared to cNK cells, ML NK cells exhibited greater antibody-dependent cytotoxicity when targeted against CRC by cetuximab. ML NK cells from healthy donors and mCRC patients exhibited increased anti-CRC responses. Collectively, our findings demonstrate that ML NK cells exhibit enhanced responses against CRC targets, warranting further investigation in clinical trials for mCRC patients, including those who have failed ICB. [ABSTRACT FROM AUTHOR]

The two current antivenom products available in the United States (US) for North American pit viper envenomation include ovine-derived Crotalidae polyvalent immune Fab (FabAV, Crofab®) and equine-derived Crotalidae Immune (F(ab′)2, Anavip®). Both products contain the oligosaccharide, galactose-alpha-1,3-galactose (alpha-gal), and may lead to a hypersensitivity reaction commonly referred to as alpha-gal syndrome (AGS). We report two patients receiving antivenom for pit viper envenomation who developed anaphylactic reactions and had confirmed abnormal titers of alpha-gal-specific IgE. We suggest clinicians seek a history of red meat allergy and administer AV cautiously in endemic areas of AGS. [ABSTRACT FROM AUTHOR]

Objective. To analyze the effect of cetuximab combined with radiotherapy in patients with rectal carcinoma (RC) by imaging analysis. Methods. The clinical data of 104 RC patients at our hospital from February 2021 to February 2022 were retrospectively analyzed. They were separated into control group (n = 52) and experimental group (n = 52) according to the order of admission, with the former treated with radiotherapy alone and the latter receiving cetuximab and radiotherapy. The clinical efficacy, tumor marker levels and imaging parameters of different treatment regimens were compared, and Quality of Life questionnaire (QLQ-C30) was used to evaluate the quality of life. Results. The incidence of tumor regression grade (TRG) downgrade, T stage downgrade and N stage downgrade was remarkably higher in the experimental group than in the control group (P < 0.05). The experimental group had remarkably lower tumor marker levels (P < 0.001) and higher mean score of EORTC Core QLQ-C30 (P < 0.001) than those in the control group. The relative signal intensity of tumor (SIT/M), relative signal intensity reduction rate of tumor (SIT/MRR) and apparent diffusion coefficient (ADC) values were remarkably higher (P < 0.001) and the absolute signal intensity of tumor (SIT) value was remarkably lower (P < 0.001) in the experimental group than the control group. Conclusion. Treatment with cetuximab and radiotherapy can greatly reduce serum tumor marker levels in RC patients and bring them health benefits, and further studies will help establish a better solution for such patients. [ABSTRACT FROM AUTHOR]

Purpose: Radiotherapy (RT) with concomitant cisplatin (CRT) or cetuximab (ERT) are accepted treatment options for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Long-term adverse events (AEs) have a vast impact on patients' quality of life. This study explored tissue biomarkers which could help predict late toxicity. Methods/patients: Single-institution prospective study including patients aged ≥ 18 with histologically confirmed newly diagnosed LA-SCCHN treated with RT and either concomitant cisplatin q3w or weekly cetuximab, according to institutional protocols. All patients underwent pre- and post-treatment skin biopsies of neck regions included in the clinical target volume. Angiogenesis, macrophages, and extracellular matrix (ECM) markers were evaluated by immunohistochemistry (IHC). Results: From April 15, 2016, to December 11, 2017; 31 patients were evaluated [CRT = 12 (38.7%) and ERT = 19 (61.3%)]. 27 patients (87%) had received induction chemotherapy. All patients finished RT as planned. IHC expression of vasculature (CD34) and collagen (Masson's Trichrome) did not differ significantly between and within CRT and ERT arms. Conversely, an increased CD68 and CD163 macrophage infiltration expression was observed after treatment, without significant impact of treatment modality. Patients with higher late toxicity showed lower expression of macrophage markers in pre-treatment samples compared with those with lower late toxicity, with statistically significant differences for CD68. Conclusions: Angiogenesis and ECM biomarkers did not differ significantly between CRT and ERT. Macrophage markers increased after both treatments and deserve further investigation as predictors of late toxicity in LA-SCCHN patients. [Protocol code: TOX-TTCC-2015-01/Spanish registry of clinical studies (REec): 2015-003012-21/Date of registration: 27/01/2016]. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) inhibition is crucial in treating RAS wild-type metastatic colorectal cancer, yet current testing methods may miss rare RAS variants affecting treatment efficacy. We analyzed 4122 colorectal cancer patients receiving anti-EGFR antibodies from the Center for Cancer Genomics and Advanced Therapeutics database, identifying 54 patients (1.3%) with rare RAS variants undetectable by standard testing. These patients showed significantly lower response rates to anti-EGFR therapy (28.3%) compared to RAS wild-type cases (44.6%, p = 0.003). Disease control rates were also lower in rare variant cases (60.9%) versus wild-type cases (80.0%). Most common rare variants included KRAS Q22K, A59E, and A11_G12insGA. Comprehensive genomic profiling revealed additional alterations in TP53 (90.7%), APC (87.0%), and non-V600E BRAF mutations (25.9%). Our findings suggest that rare RAS variants predict poor anti-EGFR therapy response, highlighting the potential benefit of comprehensive genomic profiling before treatment initiation. This study provides real-world evidence supporting the clinical relevance of rare RAS variants in treatment decision-making for colorectal cancer. Future studies should focus on developing cost-effective comprehensive testing strategies and evaluating alternative treatment approaches for patients with rare RAS variants.

INTRODUCTION: The development of new and changing melanocytic lesions has been increasingly reported as an adverse dermatologic toxicity of BRAF inhibitor therapy. Melanocytic lesions and melanomas induced by BRAF inhibitor therapy that lack BRAF V600E expression have been less commonly described. One mechanism that has been proposed for the development of BRAF inhibitor-induced melanocytic lesions, including those lacking BRAF V600E expression, is the paradoxical activation of the MAPK signaling pathway in BRAF wild-type (BRAFWT) cells. CASE PRESENTATION: Herein, we report a rare case of a 39-year-old woman who developed numerous BRAF V600E-negative eruptive melanocytic nevi following encorafenib, cetuximab, and binimetinib combination therapy, the current standard of care for the treatment of BRAF-mutant metastatic colorectal cancer. CONCLUSION: Patients treated with BRAF inhibitors, with or without related combination therapies, who develop BRAFWT melanocytic lesions are at risk for developing both dysplastic nevi and melanoma, thereby warranting baseline dermatoscopic evaluation prior to the initiation of therapy as well as regular follow-up during and after treatment.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a debilitating disease with poor survival rates. While the epidermal growth factor receptor (EGFR)-targeting antibody Cetuximab is approved for treatment, responses are limited and the molecular mechanisms driving resistance remain incompletely understood. METHODS: To better understand how cells survive without EGFR activity, we developed an EGFR knockout derivative of the UM-SCC-92 cell line using CRISPR/Cas9 technology. We then characterized changes to the transcriptome with RNAseq and changes in response to kinase inhibitors with resazurin cell viability assays. Finally, we tested if inhibitors with activity in the EGFR knockout model also had synergistic activity in combination with EGFR inhibitors in either wild type UM-SCC-92 cells or a known Cetuximab-resistant model. RESULTS: Functional and molecular analysis showed that knockout cells had decreased cell proliferation, upregulation of FGFR1 expression, and an enhanced mesenchymal phenotype. In fact, expression of common EMT genes including VIM, SNAIL1, ZEB1 and TWIST1 were all upregulated in the EGFR knockout. Surprisingly, EGFR knockout cells were resistant to FGFR inhibitor monotherapies, but sensitive to combinations of FGFR and either XIAP or IGF-1R inhibitors. Accordingly, both wild type UM-SCC-92 and Cetuximab-resistant UM-SCC-104 cells with were sensitive to combined inhibition of EGFR, FGFR and either XIAP or IGF-1R. CONCLUSIONS: These data offer insights into EGFR inhibitor resistance and show that resistance to EGFR knockout likely occurs through a complex network of kinases. Future studies of cetuximab-resistant HNSCC tumors are warranted to determine if this EMT phenotype and/or multi-kinase resistance is observed in patients.

Radiation recall presents as an acute inflammatory reaction triggered by systemic therapy, usually chemotherapy, and is typically limited to an area that was previously irradiated. Radiation recall reactions are generally self-limiting and most commonly occur in the skin. Many systemic agents have been described to elicit a radiation recall reaction, but the exact pathogenesis is largely unknown. Here, we describe the first reported case of radiation recall dermatitis following cetuximab. While cetuximab is associated with other skin reactions, oncologists should not exclude radiation recall dermatitis as a potential complication of cetuximab infusion in patients with prior radiation, and special attention should be paid to the pattern of skin changes both in terms of location and chronology.

Author(s): Madhu Muralee [1]; M Srinidhi (corresponding author) [1]; V M Bharath [2]; C D Sivanandan [3] Introduction Isolated vaginal metastasis from colorectal cancer is a very rare entity with [...], Isolated vaginal metastasis from colorectal cancer is a rare entity with very few reports in the literature. Here we report a patient who presented with bleeding per vagina from a vaginal mucosal lesion. Biopsy of the vaginal lesion indicated a metastatic adenocarcinoma from a colorectal primary. Further workup of the patient with colonoscopy and Positron emission tomography (PET CT) indicated a primary in the sigmoid colon. As the patient had a single site of metastasis, she was planned for definitive management. The colonic primary, as well as the vaginal deposit were managed surgically. Further, the patient received adjuvant chemotherapy as well as adjuvant external beam radiation to the site of the vaginal lesion. Vaginal metastases from colorectal primary are usually part of systemic dissemination with multiple metastatic sites and hence has poor prognosis. When the patient presents with an isolated metastasis in the vagina., the survival appears reasonable as per the few reports available in the literature. Due to the rarity of the presentation, there are no standard treatment guidelines available. Surgical management, radiation and adjuvant chemotherapy have been used in varying combinations in the reports available in the literature. To conclude, vaginal metastasis should be included in the differential diagnosis of patients presenting with vaginal bleeding, especially with a history of colorectal carcinoma. Available limited evidence suggests that isolated vaginal metastasis from colorectal cancer that is amenable to local surgical resection has a reasonable outcome. Hence, isolated vaginal metastasis should be treated with curative intent in a multidisciplinary context like other sites of oligometastatic disease. Keywords: Vaginal metastases, Colorectal cancer, metastatectomy

Background: Metastatic colorectal cancer (mCRC) remains a significant clinical challenge. While anti-EGFR inhibitors have improved survival rates, their long-term efficacy is limited by disease progression, which is often associated with the development of acquired resistance mutations. However, some patients may regain sensitivity to anti-EGFR agents after alternative therapies, suggesting a potential benefit for rechallenge strategies. Our study aims to conduct a systematic review and meta-analysis to comprehensively evaluate the efficacy and safety of EGFR rechallenge in patients with mCRC. Methods: A systematic search of the MEDLINE, EMBASE, and Cochrane databases was conducted between October 28 and December 24, 2023, to identify clinical trials investigating treatment regimens incorporating panitumumab or cetuximab as a rechallenge strategy. Pooled proportions or hazard ratios (HR) were calculated using a random effects model. Inter-study heterogeneity was assessed using the I2. Results: Among the 2105 articles identified through the search, 13 met the predetermined inclusion criteria. Of these, 12 were phase II studies, encompassing 92.3% of the patient population. Cetuximab was administered to 302 patients (75.1%), whereas panitumumab was utilized in 100 patients (24.9%).A pooled analysis of eight studies demonstrated an objective response rate of 20.50% (95% CI 7.94 to 33.07) and a disease control rate of 67.35% (95% CI 58.60 to 76.09). The median progression-free survival was estimated at 3.5 months (95% CI 2.68–6.69), with a median OS of 9.8 months (95% CI 6.71–12.89). Patients exhibiting RAS wild-type status in circulating tumor DNA (ctDNA) analysis derived enhanced benefits from anti-EGFR rechallenge (HR: 0.41; 95% CI 0.28–0.60, I2 = 60%). Common grade 3 or higher treatment-related adverse events included neutropenia (22.8%) and rash (14.9%). Conclusion: This meta-analysis underscores the efficacy and safety of anti-EGFR rechallenge as a promising therapeutic approach for a subset of patients afflicted with mCRC. The observed correlation between wild-type RAS status, as determined through ctDNA analysis, and improved OS signals the prospect of precision oncology in guiding treatment decisions. [ABSTRACT FROM AUTHOR]

Abstract Present work aims to prepare Soluplus stabilized, phospholipid-modified, and cetuximab-conjugated paclitaxel nanocrystals (NCs) as stable nanocarriers for targeted drug delivery. The NCs, prepared using concurrent antisolvent precipitation cum cold crystallization method followed by probe sonication, were found to be monodispersed particles with sub-200 nm size. The microscopic analysis uncovered rod and spherical anisotropy for Soluplus stabilized (PTX-NCs) and phospholipid modified (Lipid/PTX-NCs) nanocrystals, respectively. The formation of amorphous PTX-NCs and subsequent coating with phospholipid was confirmed by solid-state characterization using differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform Infrared Spectroscopy (FTIR). X-ray Photoelectron Spectroscopic (XPS) analysis, indicated successful conjugation of cetuximab on NCs surface. Lipid coating rendered a sustained drug release behaviour to NCs at physiological pH. In vitro cell line studies confirmed the improved cellular internalization and better apoptosis induction capability of NCs, consequently resulting in enhanced efficacy of PTX against A549 cancer cells. Moreover, in Benzo[a] pyrene-induced lung cancer model, Cmab/Lipid/PTX-NCs showed significant improvement in tumor inhibition potential in comparison to pure PTX. The prepared Cmab/Lipid/PTX-NCs also exhibited improved pharmacokinetics performance, avoided off-target distribution, and showed a reduction in systemic toxicity. The findings of this study indicate the promising potential of the prepared cetuximab-functionalized phospholipid-coated paclitaxel nanocrystals in lung cancer therapy.

Abstract The chloride channel transmembrane protein 16A (TMEM16A) possesses a calcium-activated property linked to tumor-promoting malignant phenotype and electrophysiological stability. Numerous studies have shown that TMEM16A exhibits aberrant amplification in various squamous cell carcinomas such as esophageal squamous cell carcinoma (ESCC) and is correlated with unfavorable outcomes of ESCC patients. Therefore, TMEM16A is considered as a promising therapeutic target for ESCC. Because of its intricate structure, the development of therapeutic antibodies directed against TMEM16A has not been documented. In this study, we produced a series of novel monoclonal antibodies targeting TMEM16A and identified mT16#5 as an antibody capable of inhibiting ESCC cells migration, invasion and TMEM16A ion channel activity. Additionally, based on the validation that TMEM16A was positively correlated with expression of EGFR and the interaction between them, the mT16#5 exhibited a synergistic inhibitory effect on ESCC metastasis and growth when administered in combination with Cetuximab in vivo. In terms of mechanism, we found that mT16A#5 inhibited the phosphorylation of PI3K, AKT and JNK. These results highlight the anti-growth and anti-metastasis capacity of the combination of mT16A#5 and Cetuximab in the treatment of ESCC by targeting TMEM16A and EGFR, and provide a reference for combinational antibody treatment in ESCC.

Abstract Background Near-infrared fluorescence (NIRF) imaging is an excellent choice for image-guided surgery due to its simple operation and non-invasiveness. Developing tumor-specific fluorescent molecular probes is key to fluorescence imaging-guided surgery. EGFR (epidermal growth factor receptor) is closely related to the proliferation and growth of tumor cells and is highly expressed in epithelial ovarian cancer (EOC). The study aims to construct a NIR fluorescent molecular probe using cetuximab (an EGFR monoclonal antibody) and investigate its feasibility for targeting EOC in vivo through fluorescence imaging. Methods We determined the expression of EGFR in EOC. NIR fluorescent molecular probe with cetuximab (cetuximab-Cy7) was chemically engineered and identified. The subcutaneous xenografted tumor model of EOC was induced using SKOV3-Luc cell line with positive expression of EGFR. Cetuximab-Cy7 was used for in vivo fluorescence imaging, and phosphate-buffered saline, free Cy7 dye and mouse isotype immunoglobulin G-Cy7 were used as controls. NIRF imaging system was performed to study the distribution and targeting of the probes. Tumors were imaged in situ and ex vivo, and fluorescent intensity was quantified. Resected specimens were analyzed to confirm diagnosis, and immunohistochemical (IHC) staining was used to identify EGFR expression. Results EGFR expression was increased in EOC tissues than fallopian tube tissues. The high expression of EGFR was significantly correlated with well-differentiation, residual lesions ≤ 1 cm, no recurrence and increased survival. NIRF imaging showed that the cetuximab-Cy7 enabled detection of tumor lesions in EOC-bearing mice with the optimal dose of 30 µg. The suitable imaging time window may be 24–96 h post-injection. Ex vivo fluorescence imaging indicated that fluorescent signal was mainly detected in the tumor and the lung. IHC results confirmed that xenografts were EGFR positive. Conclusion Cetuximab-Cy7 can specifically target the tumors of EOC xenografted nude mice. This research lays the foundation for future studies on EOC surgery navigation.

Context: Colorectal cancer (CRC) is a major global health concern as innovative therapeutic strategies to enhance treatment outcomes. This study investigates the therapeutic potential of the ethanol extract derived from Volvariella volvacea in combination with cetuximab for CRC. Aims: To evaluate the inhibition of topoisomerase II alpha (TOP2A) and include the peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator of cell growth and differentiation. Methods: The method used computational modeling and molecular docking to assess the binding affinities and interactions between the bioactive components, cetuximab, TOP2A, and PPARγ. In vitro experiments were conducted using CRC cell lines. Cells were treated with cetuximab alone or in combination with V. volvacea extract. Cell viability and immunofluorescence were conducted to evaluate the effect of combination therapy on TOP2A and PPARγ. Results: The results unveiled compelling binding interactions, suggesting the potential for dual targeting of TOP2A and PPARγ. The results demonstrated a reduction in cell viability, downregulation of TOP2A, and modulation of PPARγ. These findings indicate the potential of V. volvacea extract as an adjuvant therapy to cetuximab in CRC. Targeting both TOP2A and PPARγ enhances the efficacy of CRC treatment. Conclusions: Moreover, it highlights the importance of harnessing natural compounds and molecular insights to develop innovative combinatorial therapies for complex diseases like CRC.

Abstract Background In recent years, the addition of cetuximab to chemotherapy has improved treatment outcomes for patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). In this study, we present the real-world survival data of R/M HNSCC patients who received cetuximab-containing regimens from thirteen medical centers in Taiwan, as well as a three-level risk stratification model for this patient population. Methods This study enrolled R/M HNSCC patients from thirteen medical centers in Taiwan who received cetuximab-containing regimens from January 1, 2017 to June 6, 2022. The cases were divided into a training cohort and a validation cohort based on the start of treatment. Overall survival (OS) was evaluated in both cohorts and exploratory analysis was performed to identify associated adverse clinical and laboratory factors. The results of the exploratory analysis were used to construct a three-level risk stratification prediction model for OS. Results A total of 1434 patients with R/M HNSCC were enrolled in this study and received cetuximab-containing regimens. The overall population had a median OS of 8.57 months (95% CI: 8.07 – 9.08). Multivariate analysis of the training cohort identified poor ECOG performance status, heavy alcohol consumption, and prior adjuvant CCRT or lack of prior RT as adverse prognostic factors. Comparison of laboratory data between patients with OS≦6 and OS > 6 also revealed unfavorable factors, including increased white blood cell count, decreased hemoglobin level, increased platelet count, increased absolute neutrophil count, decreased absolute lymphocyte count, and increased neutrophil-to-lymphocyte ratio. Using forward prediction, a three-level risk stratification prediction model was constructed using the variables of ECOG performance status, alcohol consumption, skin metastasis, modality of radiation therapy, hemoglobin level, and neutrophil-to-lymphocyte ratio. The median OS in the low-risk, intermediate-risk, and high-risk groups were 12.02 months (95% CI 10.44–13.61), 7.5 months (95% CI 7.33–8.17), and 4.01 months (95% CI 3.94–4.08), respectively, with a log-rank test p-value

Abstract Introduction Cetuximab, used to treat head and neck squamous cell carcinoma and metastatic colorectal cancer, can cause severe infusion reactions. Case presentation We report an 87-year-old East Asian woman with stage IV ileocecal signet ring cell carcinoma who experienced severe allergic reactions to cetuximab despite pre-treatment. A dose escalation method, involving weekly incremental doses with comprehensive pre-treatment and close monitoring, was employed, successfully reducing allergic reactions and allowing safe administration. Conclusion This approach demonstrates a viable alternative for patients with hypersensitivity to cetuximab, warranting further research for personalized treatment optimization.

Objective: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Engineeredbiomolecules can be used as a targeted tool to deliver drugs directly to tumors that reduce the adverse effects of conventionaltreatments. We aimed to prepare non-targeted oxaliplatin-loaded chitosan nanoparticles (OXPT-CS NPs) and targetedOXPT-CS NPs decorated with cetuximab single-chain variable fragment (scFv) to send both NPs to epidermal growth factorreceptor (EGFR) overexpressing HCT 116 cells, a human colorectal carcinoma cell line, for comparing their cytotoxicity.Materials and Methods: In this experimental study, OXPT-CS NPs were synthesized using a fluid system. Encapsulationefficiency percentage (EE%) and oxaliplatin release rate were evaluated. Western blot and cell-based ELISA confirmed scFvproduction and its binding ability to EGFR, respectively. The Fourier transform infrared spectroscopy (FTIR) determinedthe conjugation of scFv to OXPT-CS NPs. The NPs were characterized, and their toxicity against the HCT 116 cells wasevaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and flow cytometry assays.Results: The EE% of OXPT-CS NPs was 93%, and the average diameters were 75.85 ± 8.81 nm and 92.48 ± 9.51before and after scFv conjugation, respectively. The scFv was purified via affinity chromatography. The western blotmethod and cell-based ELISA revealed successful purification of scFv and its attachment to EGFR on HCT 116 cells.The FTIR analysis determined the interactions between the scFv and OXPT-CS NPs. According to MTT and flowcytometry results, the targeted delivery system significantly reduced HCT 116 cancer cell viability and increasedapoptosis induction up to 99.8%.Conclusion: The scFv-OXPT-CS NPs demonstrated an increased cytotoxic function due to the presence of scFv in itsformulation. This delivery system offers a promising method for delivering chemotherapy drugs to cancer cells. Moreresearch is needed on the best strategies for improving treatment efficacy by targeting cancer cells.

Fang Fang,1,&ast; Yun Yan Chen,1,&ast; Xin-Ming Zhang,2 Jin Tang,1 Yu-Hao Liu,1 Chen-Shuo Peng,1 Yu Sun1,3 1School of Pharmacy, Wannan Medical College, Wuhu, 241002, People’s Republic of China; 2School of Chemistry and Materials Science, Anhui Normal University, Wuhu, 241002, People’s Republic of China; 3Institute of Synthesis and Application of Medical Materials, Wannan Medical College, Wuhu, 241002, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu Sun, School of Pharmacy, Wannan Medical College, Wuhu, 241002, People’s Republic of China, Tel +86 553 3932026, Email whsunyu@163.comBackground: Epidermal growth factor receptor (EGFR) is a major target for the treatment of colorectal cancer. Thus, anti-EGFR antibody conjugated lipid-polymer hybrid nanoparticles can offer a potential means of enhancing the efficacy of chemotherapeutics in EGFR overexpressing cancers. In addition, the combination of chemotherapy and photothermal therapy is a promising strategy for cancer treatment. Hence, it is highly desirable to develop a safe and effective delivery system for colorectal tumor therapy.Methods: In this study, EGFR-targeted and NIR-triggered lipid-polymer hybrid nanoparticles (abbreviated as Cet-Iri-NPs) were prepared with copolymer PPG-PEG, lipids DSPE-PEG-Mal and lecithin as carriers, CPT-11 as an anticancer chemotherapeutic agent, indocyanine green (ICG) as a photothermal agent, and cetuximab as a surface-targeting ligand.Results: In vitro analyses revealed that Cet-Iri-NPs were spherical with size of 99.88 nm, charge of 29.17 mV, drug entrapment efficiency of 51.72%, and antibody conjugation efficiency of 41.70%. Meanwhile, Cet-Iri-NPs exhibited a remarkable photothermal effect, and pH/NIR-triggered faster release of CPT-11 with near infrared (NIR) laser irradiation, which induced enhanced cytotoxicity against SW480 cells. Furthermore, the promoted tumor-growth suppression effect of Cet-Iri-NPs on SW480 tumor xenograft nude mice was achieved under NIR laser irradiation.Conclusion: These results indicate that the well-defined Cet-Iri-NPs are a promising platform for targeted colorectal cancer treatment with chemo-photothermal therapy. Keywords: Chemo-photothermal therapy, Targeted cancer therapy, Nanoparticles, Cetuximab, Indocyanine green

The clinical significance of FOLFOXIRI (5-FU, leucovorin, oxaliplatin, and irinotecan) plus anti-EGFR monoclonal antibody using cetuximab for metastatic colorectal cancer (mCRC) remains controversial. We report results from a randomized phase 2 DEEPER trial (UMIN000018217, jRCTs061180022) to test the superiority of modified (m)-FOLFOXIRI plus weekly cetuximab over bevacizumab in patients with RAS wild-type (wt) mCRC. Primary endpoint was depth of response (DpR). Secondary endpoints included objective response rate (ORR), early tumor shrinkage (ETS) at week 8, progression-free survival (PFS), overall survival (OS), time to tumor growth (TTG), time to treatment failure (TTF), association between tumor shrinkage and prognosis, association between TTG and prognosis, R0 resection rate, and safety. In 359 enrolled patients with RAS wt mCRC, median DpR was significantly better in cetuximab (57.3% vs 46.0%, p = 0.0029); however, ORR, ETS, R0 resection rate, TTG, TTF, PFS and OS were similar between 2 treatments. There was a weak association between DpR and survival time in both treatments. The correlation between TTG and OS was slightly stronger in cetuximab. The post-hoc exploratory analysis showed that cetuximab produced greater PFS (15.3 vs 11.7 months; HR 0.68) and OS (53.6 vs 40.2 months; HR 0.54) in patients with left-sided and RAS/BRAF wt tumors. m-FOLFOXIRI plus cetuximab has clinical benefit for tumor shrinkage in RAS wt mCRC. The survival benefit for RAS/BRAF wt and left-sided mCRC needs further investigation. Anti-EGFR therapy plus doublet chemotherapy is standard of care for patients with RAS wild-type metastatic colorectal cancer (mCRC) but the role of triplet chemotherapy is unclear. Here, the authors report a randomised phase 2 trial testing the superiority of adding cetuximab (anti-EGFR) over bevacizumab (anti-VEGF) to modified FOLFOXIRI (5-FU, leucovorin, oxaliplatin and irinotecan) in patients with RAS wild-type mCRC. [ABSTRACT FROM AUTHOR]

Present work aims to prepare Soluplus stabilized, phospholipid-modified, and cetuximab-conjugated paclitaxel nanocrystals (NCs) as stable nanocarriers for targeted drug delivery. The NCs, prepared using concurrent antisolvent precipitation cum cold crystallization method followed by probe sonication, were found to be monodispersed particles with sub-200 nm size. The microscopic analysis uncovered rod and spherical anisotropy for Soluplus stabilized (PTX-NCs) and phospholipid modified (Lipid/PTX-NCs) nanocrystals, respectively. The formation of amorphous PTX-NCs and subsequent coating with phospholipid was confirmed by solid-state characterization using differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform Infrared Spectroscopy (FTIR). X-ray Photoelectron Spectroscopic (XPS) analysis, indicated successful conjugation of cetuximab on NCs surface. Lipid coating rendered a sustained drug release behaviour to NCs at physiological pH. In vitro cell line studies confirmed the improved cellular internalization and better apoptosis induction capability of NCs, consequently resulting in enhanced efficacy of PTX against A549 cancer cells. Moreover, in Benzo[a] pyrene-induced lung cancer model, Cmab/Lipid/PTX-NCs showed significant improvement in tumor inhibition potential in comparison to pure PTX. The prepared Cmab/Lipid/PTX-NCs also exhibited improved pharmacokinetics performance, avoided off-target distribution, and showed a reduction in systemic toxicity. The findings of this study indicate the promising potential of the prepared cetuximab-functionalized phospholipid-coated paclitaxel nanocrystals in lung cancer therapy. [ABSTRACT FROM AUTHOR]

The chloride channel transmembrane protein 16A (TMEM16A) possesses a calcium-activated property linked to tumor-promoting malignant phenotype and electrophysiological stability. Numerous studies have shown that TMEM16A exhibits aberrant amplification in various squamous cell carcinomas such as esophageal squamous cell carcinoma (ESCC) and is correlated with unfavorable outcomes of ESCC patients. Therefore, TMEM16A is considered as a promising therapeutic target for ESCC. Because of its intricate structure, the development of therapeutic antibodies directed against TMEM16A has not been documented. In this study, we produced a series of novel monoclonal antibodies targeting TMEM16A and identified mT16#5 as an antibody capable of inhibiting ESCC cells migration, invasion and TMEM16A ion channel activity. Additionally, based on the validation that TMEM16A was positively correlated with expression of EGFR and the interaction between them, the mT16#5 exhibited a synergistic inhibitory effect on ESCC metastasis and growth when administered in combination with Cetuximab in vivo. In terms of mechanism, we found that mT16A#5 inhibited the phosphorylation of PI3K, AKT and JNK. These results highlight the anti-growth and anti-metastasis capacity of the combination of mT16A#5 and Cetuximab in the treatment of ESCC by targeting TMEM16A and EGFR, and provide a reference for combinational antibody treatment in ESCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck cancer (HNC), especially oral squamous cell carcinoma (OSCC), is a common and increasingly prevalent cancer worldwide. OSCC is challenging to treat due to its aggressive nature and resistance to standard therapies like surgery, radiation, and chemotherapy, particularly in advanced stages. Cetuximab, a drug targeting EGFR (a protein that supports cancer cell growth), is often used but has limitations in effectiveness. This study explores a new approach by combining Cetuximab with drugs that target proteins involved in cell division, specifically MPS-1, Aurora-B, and KSP. These proteins help cancer cells progress through the cell cycle and are crucial for tumor survival. By blocking both EGFR and these cell division proteins, the study aimed to increase the effectiveness of Cetuximab in killing OSCC cells. Results showed that targeting MPS-1, Aurora-B, or KSP alongside EGFR led to more cancer cell death, suggesting that this combined approach could reduce treatment resistance. Analysis of patient samples confirmed that these proteins are significant in OSCC. This combined therapy strategy shows promise for improving outcomes in OSCC and potentially other head and neck cancers. Background/Objectives: Head and neck cancer (HNC) is among the most common cancer types globally, with its incidence expected to increase significantly in the coming years. Oral squamous cell carcinoma (OSCC), the predominant subtype, exhibits significant heterogeneity and resistance to treatment. Current therapies, including surgery, radiation, and chemotherapy, often result in poor outcomes for advanced stages. Cetuximab, an EGFR inhibitor, is widely used but faces limitations. This study explores the combined inhibition of EGFR and mitotic proteins to enhance treatment efficacy. Methods: We analyzed the effects of co-treating OSCC cells with small molecules targeting MPS-1 (BAY1217389), Aurora-B (Barasertib), or KSP (Ispinesib), alongside Cetuximab. The rationale is based on targeting EGFR-mediated survival pathways and the mitotic checkpoint, addressing multiple cell cycle phases and reducing resistance. Results: Our findings indicate that inhibiting MPS-1, Aurora-B, or KSP enhances Cetuximab's therapeutic potential, promoting increased cancer cell death. Additionally, we examined EGFR, MPS-1, Aurora-B, and KSP expression in OSCC patient samples, revealing their clinicopathologic significance. Conclusions: This combinatorial approach suggests a promising strategy to improve treatment outcomes in OSCC. [ABSTRACT FROM AUTHOR]

Abstract: The metabolism of zinc and manganese plays a pivotal role in cancer progression by mediating cancer cell growth and metastasis. The SLC30A family proteins SLC30A3 and SLC30A10 mediate the efflux of zinc, manganese, and probably other transition element ions outside the cytoplasm to the extracellular space or into intracellular membrane compartments. The SLC39A family members SLC39A8 and SLC39A14 are their functional antagonists that transfer these ions into the cytoplasm. Recently, the SLC30A10 gene was suggested as a promising methylation biomarker of colorectal cancer. Here, we investigated whether forced overexpression or inactivation of SLC30A and SLC39A family genes has an impact on the phenotype of cancer cells and their sensitivity to cancer therapeutics. In the human colon adenocarcinoma HCT-15 and duodenal adenocarcinoma HuTu80 cell lines, we generated clones with knockouts of the SLC39A8 and SLC39A14 genes and forced overexpression of the SLC30A3, SLC30A10, and SLC39A8 genes. Gene expression in the mutant and control cells was assessed by RNA sequencing. The cell growth rate, mitochondrial activity, zinc accumulation, and sensitivity to the drugs cetuximab and cisplatin were investigated in functional tests. Overexpression or depletion of SLC30A or SLC39A family genes resulted in the deep reshaping of intracellular signaling and provoked hyperactivation of mitochondrial respiration. Variation in the expression of the SLC30A/SLC39A genes did not increase the sensitivity to cetuximab but significantly altered the sensitivity to cisplatin: overexpression of SLC30A10 resulted in an ~2.7–4 times increased IC50 of cisplatin, and overexpression of SLC30A3 resulted in an ~3.3 times decreased IC50 of cisplatin. The SLC30A/SLC39A genes should be considered as potential cancer drug resistance biomarkers and putative therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Near-infrared fluorescence (NIRF) imaging is an excellent choice for image-guided surgery due to its simple operation and non-invasiveness. Developing tumor-specific fluorescent molecular probes is key to fluorescence imaging-guided surgery. EGFR (epidermal growth factor receptor) is closely related to the proliferation and growth of tumor cells and is highly expressed in epithelial ovarian cancer (EOC). The study aims to construct a NIR fluorescent molecular probe using cetuximab (an EGFR monoclonal antibody) and investigate its feasibility for targeting EOC in vivo through fluorescence imaging. Methods: We determined the expression of EGFR in EOC. NIR fluorescent molecular probe with cetuximab (cetuximab-Cy7) was chemically engineered and identified. The subcutaneous xenografted tumor model of EOC was induced using SKOV3-Luc cell line with positive expression of EGFR. Cetuximab-Cy7 was used for in vivo fluorescence imaging, and phosphate-buffered saline, free Cy7 dye and mouse isotype immunoglobulin G-Cy7 were used as controls. NIRF imaging system was performed to study the distribution and targeting of the probes. Tumors were imaged in situ and ex vivo, and fluorescent intensity was quantified. Resected specimens were analyzed to confirm diagnosis, and immunohistochemical (IHC) staining was used to identify EGFR expression. Results: EGFR expression was increased in EOC tissues than fallopian tube tissues. The high expression of EGFR was significantly correlated with well-differentiation, residual lesions ≤ 1 cm, no recurrence and increased survival. NIRF imaging showed that the cetuximab-Cy7 enabled detection of tumor lesions in EOC-bearing mice with the optimal dose of 30 µg. The suitable imaging time window may be 24–96 h post-injection. Ex vivo fluorescence imaging indicated that fluorescent signal was mainly detected in the tumor and the lung. IHC results confirmed that xenografts were EGFR positive. Conclusion: Cetuximab-Cy7 can specifically target the tumors of EOC xenografted nude mice. This research lays the foundation for future studies on EOC surgery navigation. [ABSTRACT FROM AUTHOR]