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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]

BackgroundMethodsResultsConclusionHead 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.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.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.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]

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]

Patient-derived xenografts (PDXs) are tumour fragments engrafted into mice for preclinical studies. PDXs offer clear advantages over simpler in vitro cancer models - such as cancer cell lines (CCLs) and organoids - in terms of structural complexity, heterogeneity, and stromal interactions. Here, we characterise 231 colorectal cancer PDXs at the genomic, transcriptomic, and epigenetic levels, along with their response to cetuximab, an EGFR inhibitor used clinically for metastatic colorectal cancer. After evaluating the PDXs' quality, stability, and molecular concordance with publicly available patient cohorts, we present results from training, interpreting, and validating the integrative ensemble classifier CeSta. This model takes in input the PDXs' multi-omic characterisation and predicts their sensitivity to cetuximab treatment, achieving an area under the receiver operating characteristics curve > 0.88. Our study demonstrates that large PDX collections can be leveraged to train accurate, interpretable drug sensitivity models that: (1) better capture patient-derived therapeutic biomarkers compared to models trained on CCL data, (2) can be robustly validated across independent PDX cohorts, and (3) could contribute to the development of future therapeutic biomarkers. Patient-derived xenografts (PDX) could contribute to understanding how colorectal cancer (CRC) responds to targeted therapies like cetuximab. Here, the authors characterise the response to cetuximab in 231 CRC PDXs using multiomics and develop an integrative ensemble classifier - CeSta - to predict sensitivity to cetuximab. [ABSTRACT FROM AUTHOR]

BRAFV600E-mutant colorectal cancer (CRC) is resistant to most first-line therapeutics, including the BRAF inhibitor dabrafenib and epidermal growth factor receptor (EGFR) inhibitor cetuximab. Although copper depletion shows promise in reversing dabrafenib/cetuximab resistance in BRAFV600E-mutant CRC, its application is limited by the potential for excessive copper depletion in non-tumor objects. In this study, we have developed a hydrogel platform for confined copper depletion in BRAFV600E-mutant CRC cells, which effectively reverses dabrafenib/cetuximab resistance and enhancing therapeutic efficiency. The hydrogel platform enables precise intracellular copper depletion through localized administration, acidity-triggered drug release, and oxidized activation of a copper prochelator. The dosage of this prochelator is 37.5 μg/kg in mouse models, which is significantly lower than the commonly used tetrathiomolybdate. Furthermore, both dabrafenib and the prochelator are preloaded into acid-responsive nanoparticles before being embedded in the hydrogel matrix to facilitate efficient endocytosis and acid-activatable drug release. Confined copper depletion inhibits MEK1 signaling and suppresses the MAPK signaling pathway when combined with BRAF and EGFR inhibitors. Moreover, the hydrogel platform inhibits tumor growth and prolongs survival in subcutaneous and postsurgical models of BRAFV600E-mutant CRC. This study provides an innovative strategy for overcoming dabrafenib/cetuximab resistance in BRAFV600E-mutant CRC through precise intracellular copper depletion. A combinational therapeutic strategy was developed based on confined copper depletion to combat BRAFV600E-mutant colorectal cancer (CRC). Dabrafenib and a copper prochelator were loaded in acidity-responsive nanoparticles, and then loaded in peptide hydrogel along with cetuximab. The hydrogel platform conducted depletion of intracellular copper to block MAPK signaling pathway, thus reversing dabrafenib/cetuximab resistance in BRAFV600E-mutant CRC and improving therapeutic efficiency in mouse tumor models. [Display omitted] • Hydrogel platform enables confined copper depletion in BRAFV600E-mutant CRC. • Acidity-responsive nanoparticles deliver dabrafenib and copper prochelator to inhibit the MAPK signaling. • Hydrogel platform blocks MAPK signaling, reversing dabrafenib/cetuximab resistance. [ABSTRACT FROM AUTHOR]

High Epidermal growth factor receptor (EGFR) in Cutaneous Squamous Cell Carcinoma (cSCC) is associated with poor prognosis and advanced metastatic stages, severely impeding the efficacy of EGFR-targeting immunotherapy. This is commonly attributed to the combinatory outcomes of hypoxic tumor microenvironment (TME) and immunosuppressive effector cells together. Herein, a novel paradigm of EGFR-targeting oxygen-saturated nanophotosensitizers, designated as CHPFN-O 2 , has been specifically tailored to mitigate tumor hypoxia in EGFR-positive cSCC and achieve Cetuximab (CTX) - mediated immunotherapy (CIT). The conjugated CTX in CHPFN-O 2 serves to initiate immune responses by recruiting Fc receptor (FcR)-expressing immune effector cells towards tumor cells, thereby eliciting antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular trogocytosis (ADCT) and antibody-dependent cellular cytotoxicity (ADCC). Besides, CHPFN-O 2 can engender a shift from a tumor-friendly to a tumor-hostile one through improved tumor oxygenation, contributing to oxygen-elevated photodynamic therapy (oxPDT). Notably, the combination of oxPDT and CIT eventually promotes T-cell-mediated antitumor activity and successfully inhibits the growth of EGFR-expressing cSCC with good safety profiles. This comprehensive oxPDT/CIT integration aims not only to enhance therapeutic efficacy against EGFRhigh cSCC but also to extend its applicability to other EGFRhigh malignancies, thus delineating a new avenue for the highly efficient synergistic treatment of EGFR-expressing malignancies. EGFR-targeting oxygen-saturated nanophotosensitizers are meticulously designed to improve tumor selectivity, alleviate tumor hypoxia, reverse tumor immunosuppression, and recruit immune effector cells, thus resulting in the synergy of Cetuximab-based immunotherapy (CIT) and oxygen-elevated photodynamic therapy (oxPDT) for remarkably enhancing T cell-mediated antitumor efficacy against EGFR-expressing cSCC with great clinical value. [Display omitted] • CHPFN-O 2 demonstrates promising antitumor activity and high biosafety. • CHPFN-O 2 alleviates tumor hypoxia and initiates CIT-mediated immune responses. • CHPFN-O 2 presenting a new treatment paradigm of synergistic oxPDT/CIT. • CHPFN-O 2 improves the tumor microenvironment of EGFR-expressing cSCC. • The clinical prospects of CHPFN-O 2 can be extended to other forms of cSCC. [ABSTRACT FROM AUTHOR]

Afatinib (AT), an FDA-approved aniline-quinazoline derivative, is a first-line treatment for metastatic non-small cell lung cancer (NSCLC). Combining it with cetuximab (CX), a chimeric human-murine derivative immunoglobulin-G1 monoclonal antibody (mAb) targeting the extracellular domain of epidermal growth factor receptor (EGFR), has shown significant improvements in median progression-free survival. Previously, we developed cetuximab-conjugated immunoliposomes loaded with afatinib (AT-MLP) and demonstrated their efficacy against NSCLC cells (A549 and H1975). In this study, we aimed to explore the potential of pulmonary delivery to mitigate adverse effects associated with oral administration and intravenous injection. We formulated AT-MLP dry powders (AT-MLP-DPI) via freeze drying using tert-butanol and mannitol as cryoprotectants in the hydration medium. The physicochemical and aerodynamic properties of dry powders were well analyzed firstly. In vitro cellular uptake and cytotoxicity study revealed concentration- and time-dependent cellular uptake behavior and antitumor efficacy of AT-MLP-DPI, while Transwell assay demonstrated the superior inhibitory effects on NSCLC cell invasion and migration. Furthermore, in vivo pharmacokinetic study showed that pulmonary delivery of AT-MLP-DPI significantly increased bioavailability, prolonged blood circulation time, and exhibited higher lung concentrations compared to alternative administration routes and formulations. The in vivo antitumor efficacy study carried on tumor-bearing nude mice indicated that inhaled AT-MLP-DPI effectively suppressed lung tumor growth. Graphical abstract was created with BioRender software (https://biorender.com/) [ABSTRACT FROM AUTHOR]

Despite numerous screening tools for colorectal cancer (CRC), 25 % of patients are diagnosed with advanced disease. Novel diagnostic technologies that are early, accurate, and rapid are imperative to assess the therapeutic efficacy of clinical drugs and identify new biomarkers of treatment response. Here Raman spectroscopy (RS) was used to track metabolic reprogramming in KRAS‐mutant HCT116 and SW837 cells, and KRAS wild‐type CC cells. RS combined with multivariate analysis methods distinguished nonresponsive, partially responsive, and responsive cells treated with cetuximab, a monoclonal antibody for EGFR inhibition, sotorasib, a clinically approved KRAS inhibitor, and various doses of trametinib, an inhibitor of the MAPK pathway. Cells treated with a combination of subtoxic doses of trametinib and BKM120, an inhibitor of the PI3K pathway, showed a synergistic response between the two pathways. Using a supervised machine learning regression model, we established a scoring methodology trained to a priori predict therapeutic response to new treatment combinations. RS metabolites were verified with mass spectrometry, and enrichment pathways were identified, including amino acid, purine, and nicotinate and nicotinamide metabolism that differentiated monotherapy from combination therapy. Our approach may ultimately be applicable to patient‐derived primary cells and cultures of patient tumors to predict effective drugs for individualized care. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is diagnosed in more than 71,000 patients each year in the United States, with nearly 16,000 associated deaths. One significant hurdle in the treatment of HNSCC is acquired and intrinsic resistance to existing therapeutic agents. Over the past several decades, the University of Wisconsin has formed a multidisciplinary team to move basic scientific discovery along the translational spectrum to impact the lives of HNSCC patients. In this review, we outline key discoveries made throughout the years at the University of Wisconsin to deepen our understanding of therapeutic resistance in HNSCC and how a strong, interdisciplinary team can make significant advances toward improving the lives of these patients by combatting resistance to established therapeutic modalities. We are profoundly grateful to the many scientific teams worldwide whose groundbreaking discoveries, alongside evolving clinical paradigms in head and neck oncology, have been instrumental in making our work possible. [ABSTRACT FROM AUTHOR]

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 < 0.001. Conclusion: This study presents a three-level risk stratification model with strong prediction ability for OS in R/M HNSCC patients who received cetuximab-containing regimens. The results are based on real-world data and may provide valuable information for clinicians in treatment planning and future drug development. [ABSTRACT FROM AUTHOR]

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

Cetuximab was initially developed and approved as a first‐line treatment in patients with unresectable metastatic colorectal cancer (mCRC) for weekly administration (250 mg/m2 Q1W with 400 mg/m2 loading dose). An every‐2‐weeks schedule (500 mg/m2 Q2W) was approved recently by several health authorities. Being synchronized with chemotherapy, Q2W administration should improve patients' convenience and healthcare resource utilization. Herein, we present evidence of non‐inferiority of Q2W cetuximab, compared with Q1W dosing using pharmacometrics modeling and clinical trial simulation (CTS). Pooled data from five phase I–III clinical trials in 852 patients with KRAS wild‐type mCRC treated with Q1W or Q2W cetuximab were modeled using a population exposure–tumor size (TS) model linked to overall survival (OS); exposure was derived from a previously established population pharmacokinetic model. A semi‐mechanistic TS model adapted from the Claret model incorporated killing rate proportional to cetuximab area under the concentration‐time curve over 2 weeks (AUC) with Eastern Cooperative Oncology Group (ECOG) status as covariate on baseline TS. The OS was modeled with Weibull hazard using ECOG, baseline TS, primary tumor location, and predicted percent change in TS at 8 weeks as covariates. Model‐based simulations revealed indistinguishable early tumor shrinkage and survival between Q2W vs. Q1W cetuximab. CTS evaluated OS non‐inferiority (predefined margin of 1.25) in 1,000 trials, each with 2,000 virtual patients receiving Q2W or Q1W cetuximab (1:1), and demonstrated non‐inferiority in 94% of cases. Taken together, these analyses provide model‐based evidence for clinical non‐inferiority of Q2W vs. Q1W cetuximab in mCRC with potential benefits to patients and healthcare providers. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the prognostic value of peripheral blood inflammation indexes in patients with metastatic Colorectal Cancer (CRC) and to establish a predictive scoring system. A total of 324 CRC patients diagnosed through pathological examination from January 2017 to July 2022 at the Third Affiliated Hospital of Kunming Medical University were included. The prognosis of patients with metastatic CRC was examined, and the correlation between IL-10 expression in pathological tissues and IL-10 expression in serum was analyzed. The results showed that the prognosis of CRC was poorer when metastasis occurred (P < 0.001). Additionally, IL-10 was highly expressed in the metastatic CRC group (P = 0.018), and the expression of IL-10 in pathological tissues of patients with metastatic CRC was positively correlated with the expression of IL-10 in serum (P = 0.037). The neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-white blood cell ratio (LWR), aggregate index of systemic inflammation (AISI), monocyte-to-lymphocyte ratio (MLR), systemic inflammatory response index (SIRI), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI), and interleukin-10 (IL-10) were calculated and determined by ROC curve. The critical values were 2.135, 3.735, 353.745, 0.265, 1.025, 52.975, 353.635, and 11.25, respectively. Inflammatory indexes with an AUC of more than 0.6 were selected, and each colorectal cancer patient with any of these risk factors was assigned a score of one. The 324 patients were then divided into two groups: 0–4 for the low-risk group and 4–8 for the high-risk group. The occurrence of distant metastases in the two groups was statistically analyzed. The results showed that the OS and PFS of the low-risk group were significantly superior to those of the high-risk group (P < 0.05). These findings indicate that NLR, LWR, AISI, MLR, SIRI, PNI, ALI, and IL-10 are risk factors for distant metastasis in CRC patients. Therefore, the prediction scores of these indexes can be used to effectively evaluate the prognosis of patients with metastatic CRC. [ABSTRACT FROM AUTHOR]

The interplay between immune components and the epithelium plays a crucial role in the development and progression of head and neck squamous cell carcinoma (HNSCC). Natural killer (NK) cells, one of the main tumor-killing immune cell populations, have received increasing attention in HNSCC immunotherapy. In this review, we explore the mechanism underlying the interplay between NK cells and HNSCC. A series of immune evasion strategies utilized by cancer cells restrict HNSCC infiltration of NK cells. Overcoming these limitations can fully exploit the antineoplastic potential of NK cells. We also investigated the tumor-killing efficacy of NK cell-based immunotherapies, immunotherapeutic strategies, and new results from clinical trials. Notably, cetuximab, the most essential component of NK cell-based immunotherapy, inhibits the epidermal growth factor receptor (EGFR) signaling pathway and activates the immune system in conjunction with NK cells, inducing innate effector functions and improving patient prognosis. In addition, we compiled information on other areas for the improvement of patient prognosis using anti- EGFR receptor-based monoclonal antibody drugs and the underlying mechanisms and prognoses of new immunotherapeutic strategies for the treatment of HNSCC. [ABSTRACT FROM AUTHOR]

Background/Objectives: Cetuximab, formulated in Erbitux® (5 mg/mL), is a therapeutic monoclonal antibody (mAb) widely used in several cancer treatments. Currently, there is insufficient knowledge about the behavior of cetuximab with regard to the risk associated with its routine handling or unintentional mishandling in hospitals. Forced degradation studies can simulate these conditions and provide insights into the biophysical and biochemical properties of mAbs. Methods: In this study, we conducted a deep physicochemical and functional characterization of the critical quality attributes of cetuximab in control samples and under controlled degraded conditions, including freeze–thaw cycles, heat, agitation, and light exposure. To achieve this purpose, we used a set of proper analytical techniques, including CD, IT-FS, DLS, SE/UHPLC-UV, UHPLC-MS/MS, and ELISA, to check functionality based on antigen–antibody binding. Results: The results revealed that light exposure was the stress stimuli with the greatest impact on the drug product, leading to the formation of non-natural oligomers, fragmentation, and oxidation of methionine residues. Additionally, cetuximab (Erbitux®, 5 mg/mL) showed a tendency to aggregate when submitted to 60 °C for 1 h. In terms of functionality, cetuximab (Erbitux®, 5 mg/mL) samples were found to be affected when subjected to freeze–thaw cycles, 60 °C (1 h), and when exposed to light (daylight with room temperature excursion and accelerated light exposure). Conclusions: Thus, we suggest that Erbitux® (5 mg/mL) should be shielded from these environmental conditions, as they compromise both the safety and efficacy of the drug product. [ABSTRACT FROM AUTHOR]

Skin cancer is a high-incidence complex disease, representing a significant challenge to public health, with conventional treatments often having limited efficacy and severe side effects. Nanocarrier-based systems provide a controlled, targeted, and efficacious methodology for the delivery of therapeutic molecules, leading to enhanced therapeutic efficacy, the protection of active molecules from degradation, and reduced adverse effects. These features are even more relevant in dual-loaded nanosystems, with the encapsulated drug molecules leading to synergistic antitumor effects. This review examines the potential of improving the treatment of skin cancer through dual-loaded liposomal systems. The performed analysis focused on the characterization of the developed liposomal formulations' particle size, polydispersity index, zeta potential, encapsulation efficiency, drug release, and in vitro and/or in vivo therapeutic efficacy and safety. The combination of therapeutic agents such as doxorubicin, 5-fluorouracil, paclitaxel, cetuximab, celecoxib, curcumin, resveratrol, quercetin, bufalin, hispolon, ceramide, DNA, STAT3 siRNA, Bcl-xl siRNA, Aurora-A inhibitor XY-4, 1-Methyl-tryptophan, and cytosine–phosphate–guanosine anionic peptide led to increased and targeted anticancer effects, having relevant complementary effects as well, including antioxidant, anti-inflammatory, and immunomodulatory activities, all relevant in skin cancer pathophysiology. The substantial potential of co-loaded liposomal systems as highly promising for advancing skin cancer treatment is demonstrated. [ABSTRACT FROM AUTHOR]

Laryngeal cancer (LC) is the second most common head and neck cancer and has a decreasing 5-year survival rate worldwide. Circular RNAs (circRNAs) regulate cancer development in diverse ways based on their distinct biogenesis mechanisms and expansive regulatory roles. However, currently, there is little research on how exosomal circRNAs are involved in the development of LC. Here, we demonstrated that circPVT1, a circRNA derived from the well-studied long noncoding RNA PVT1, is correlated with disease progression in LC and promotes angiogenesis both in vivo and in vitro. Mechanistically, circPVT1 is loaded into LC cell-secreted exosomes and taken up by vascular epithelium cells. By sponging miR-30c-5p, exosomal circPVT1 promotes Rap1b expression, which dramatically enhances vascular endothelial growth factor receptor 2 and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation, ultimately resulting in the induction of angiogenesis. Furthermore, our xenograft models demonstrated that the combination of short hairpin RNA-circPVT1 and cetuximab showed high efficacy in inhibiting tumor growth and angiogenesis. Collectively, these findings uncover a novel mechanism of exosomal circRNA-mediated angiogenesis modulation and provide a preclinical rationale for testing this analogous combination in patients with LC. [ABSTRACT FROM AUTHOR]

Background Early studies showed promise of combined anti-epidermal growth factor receptor (EGFR) plus anti–vascular endothelial growth factor (VEGF) antibodies for advanced colorectal cancer (CRC), yet this was later rejected as toxic and ineffective in studies not selected for RAS status. We studied advanced KRAS wild-type CRC, as second-line treatment, using irinotecan-cetuximab with or without the anti-VEGF receptor antibody ramucirumab. Methods Patients with 1 prior regimen including fluoropyrimidine, oxaliplatin, and bevacizumab, with KRAS wild-type tumors were stratified by Eastern Cooperative Oncology Group Performance Score, time since last chemotherapy, and progression on oxaliplatin to irinotecan-cetuximab (IC) (180 mg/m2 and 500 mg/m2 every 2 weeks) vs modified ICR (irinotecan-cetuximab with ramucirumab 150 mg/m2 and 400 mg/m2 plus 6 mg/kg, respectively). A total of 102 patients were compared for progression-free survival (PFS) as primary endpoint (85% power for 70% improvement in median PFS from 4.5 to 7.65 months). Results Of the 102 enrolled, 44 treated with irinotecan-cetuximab and 45 with modified ramucirumab were evaluable. Median PFS was 6.0 months vs 9.2 months, respectively (hazard ratio = 0.75, P = .07; statistically significant by study design for P  < .128). Response rate was 23% vs 36% (P = .27), and disease-control rate was 52% vs 73% (P  = .05). Grade 3 or higher toxicity was equivalent. Overall survival was not significantly different at approximately 19 months. Conclusion Previous phase 3 trials without RAS genotyping rejected combining anti-epidermal growth factor receptor and anti-VEGF drugs. In this randomized multicenter phase 2 study for KRAS wild-type CRC (all previously bevacizumab treated), the addition of ramucirumab to irinotecan and cetuximab improved PFS and disease control rate, showing the combination is feasible and effective. Further, phase 3 trials with appropriate patient-selection are required. (NCT01079780) [ABSTRACT FROM AUTHOR]

Background/Aim: We previously reported that patients with metastatic colorectal cancer (mCRC) and baseline liver metastasis are at a higher risk of developing grade ≥2 overall skin toxicities when treated with antiepidermal growth factor receptor (EGFR) monoclonal antibody. This study aimed to identify additional factors associated with skin toxicities induced by anti-EGFR treatment in patients with liver metastatic CRC. Patients and Methods: Patients with liver metastatic CRC who initially received anti- EGFR monoclonal antibody-containing treatment (n=77) were retrospectively assessed. The primary endpoint was to identify the factor(s) responsible for the development of grade ≥2 overall skin toxicities. Additionally, factors for grade ≥2 rash and paronychia were evaluated. Results: The incidence of grade ≥2 overall skin symptoms, rash, and paronychia was 62.3%, 31.2%, and 28.6%, respectively. Multivariate Cox proportional hazard regression analyses revealed that age <65 years and anemia were independent baseline risk factors for grade ≥2 overall skin toxicities (adjusted hazard ratio 2.09, 95% confidence interval=1.10-3.97, p=0.02 for age; 2.36, 1.20-4.61, p=0.01 for anemia). In contrast, combination prophylaxis using systemic minocycline and corticosteroid ointment was a preventive factor (0.47, 0.25-0.88, p=0.02). Males and age <65 years were baseline risk factors for grade ≥2 rash, and combination prophylaxis was identified as a preventive factor. No factors were identified for paronychia. Conclusion: Age <65 years and anemia were identified as independent baseline risk factors. Additionally, combination prophylaxis was found to be a preventive factor against anti-EGFR monoclonal antibody-induced grade ≥2 overall skin toxicities in patients with liver metastatic CRC. [ABSTRACT FROM AUTHOR]

This article explores the significance of precision dosing in medicine and the factors that contribute to achieving accurate dosages. It emphasizes the integration of data, digital health, and advanced technologies to achieve precision dosage. The article discusses the implications of incorrect dosing, such as adverse reactions and failed clinical trials. It also examines the evolution of dose selection methods and the complexities involved in determining the right dose for different therapeutic approaches. The article highlights the shift towards precision medicine and the importance of personalized dosing that considers individual patient characteristics. It explores the use of advanced quantitative methodologies, real-world data, digital health technologies, and artificial intelligence in optimizing dosing regimens. The article addresses the challenges and ethical considerations associated with these innovations and emphasizes the need for collaboration among stakeholders to drive advancements in precision dosing. [Extracted from the article]

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 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.

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

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

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]

Squamous cell carcinoma of the head and neck is the sixth most common cancer worldwide. However, malignant tumors of the middle ear are extremely rare. Squamous cell carcinoma is the most common histologic type of tumor in this area, accounting for more than 50% of cases. Complex anatomical and topographic features of the inner ear and inapparent clinical symptoms result in delayed diagnosis of this disease. A case of a patient with highly differentiated middle ear squamous cell carcinoma is presented. The patient received complex treatment, including drug antitumor therapy according to the TPEx protocol: docetaxel + cisplatin + cetuximab. Being highly effective, this protocol requires a multidisciplinary approach in order to ensure maximum safety of therapy. The case illustrates the classic “portrait” of a patient with recurrent or metastatic squamous cell carcinoma of the head and neck and also provides a comprehensive description of the spectrum of adverse events faced by such patients and their oncologists. Based on this clinical case, the features of management of such adverse events are analyzed.

Abstract Background Advanced head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, and new treatment options are needed. Combining immunotherapies with differing mechanisms of action may enhance clinical benefits compared with single-agent immunotherapy. Epacadostat, an indoleamine 2,3 dioxygenase 1 inhibitor, plus pembrolizumab, a PD-1 inhibitor, showed promising activity in advanced HNSCC in the phase 1/2 KEYNOTE-037/ECHO-202 trial. Methods KEYNOTE-669/ECHO-304 is a randomized, open-label, phase 3 study evaluating the efficacy and safety of pembrolizumab plus epacadostat, pembrolizumab monotherapy, and the EXTREME regimen (cetuximab with a platinum [carboplatin or cisplatin] and 5-fluorouracil) in recurrent/metastatic (R/M) HNSCC. Participants had no prior systemic therapy for R/M HNSCC and were randomly assigned (2:1:2) to pembrolizumab 200 mg intravenously every 3 weeks plus epacadostat 100 mg orally twice daily, pembrolizumab monotherapy, or EXTREME. The primary endpoint was objective response rate (ORR; investigator assessment). Secondary endpoints were safety and tolerability. Change in serum kynurenine was an exploratory endpoint. Study enrollment was discontinued early as a strategic decision on May 2, 2018, and response assessment was discontinued after first on-study imaging assessment at week 9. Data cut-off was January 17, 2019. Results Between December 1, 2017, and May 2, 2018, 89 patients were randomly allocated to pembrolizumab plus epacadostat (n = 35), pembrolizumab monotherapy (n = 19), or EXTREME (n = 35). ORR (95% CI) was 31% (17%–49%) for pembrolizumab plus epacadostat, 21% (6%–46%) for pembrolizumab monotherapy, and 34% (19%–52%) for EXTREME. Treatment-related adverse events (TRAEs) occurred in 82% (n = 28) of patients receiving pembrolizumab plus epacadostat, 63% (n = 12) receiving pembrolizumab monotherapy, and 100% (n = 34) receiving EXTREME. Grade 3–4 TRAEs occurred in 24% (n = 8) of patients receiving pembrolizumab plus epacadostat, 16% (n = 3) receiving pembrolizumab monotherapy, and 82% (n = 28) receiving EXTREME. No deaths occurred due to AEs. Pembrolizumab plus epacadostat treatment reduced kynurenine levels but not to that of healthy subjects. Conclusions Pembrolizumab plus epacadostat and pembrolizumab monotherapy provided a similar response rate to EXTREME and demonstrated a manageable safety profile in patients with R/M HNSCC. Trial registration NCT03358472. Date of trial registration: November 30, 2017.

Introduction. Chemotherapy in combination with targeted therapy (CT + TT) using a monoclonal antibody against epidermal growth factor receptor (EGFR) cetuximab and subsequent maintenance targeted therapy (CT + TT/TT) is the leading 1st line therapy of recurrent/metastatic head and neck squamous cell carcinoma to achieve objective response irrespective of programmed cell death-ligand 1 (pD-L1) expression level. However, often in clinical practice patient profile does not match characteristics of patients included in registration studies. Therapy selection is based on massive advancement of the tumor, low performance status of the patient, use of various chemotherapy regimes which often decreases therapy effectiveness. This creates a necessity of identification of clinical markers of effectiveness based on the drug's pharmacodynamics and mechanism of action.Aim. To analyze the effect of clinical characteristics, peripheral blood markers, and systemic inflammation on long-term results of CT + TT/TT with cetuximab in cancer of the mucosa of the head and neck.Materials and methods. The prospective observational study performed at the Oncology Department with a course on thoracic surgery of the Kuban State Medical University, included 52 patients with head and neck squamous cell carcinoma receiving CT + TT/TT between 2020 and 2023. Clinical characteristics and results of peripheral blood tests were retrospectively analyzed, indices of inflammatory reaction prior to treatment and 12-16 weeks after CT + TT/TT with cetuximab were calculated. Statistical analysis was performed using the med Calc ver. 20.218 and IBM SPSS Statistics 22 software.Results. CT + TT/TT with cetuximab significantly increased red blood cell count (RBC), lymphocyte-monocyte ratio (LMR), and decreased systemic inflammatory markers (SIM) (p 3.27 after 12-16 weeks of therapy (AUC = 0.685; 95 % CI 0.486-0.885; p = 0.0691). median survival of patients after the start of CT + TT/TT with cetuximab was 28 months (95 % CI 17-48), progression-free survival was 8 months (95 % CI 5-36). For RBC count >3.8 x 1012/L 12-16 weeks after the start of therapy, risk of progression decreased by 79 % (hazard ratio 0.21; 95 % CI 0.07-0.62; p = 0.0047). Partial response after 12-16 weeks of CT + TT/TT decreased progression risk more than 4-fold (p

Introduction: N-glycosylation is a post-translational modification that is highly important for the development of monoclonal antibodies (mAbs), as it regulates their biological activity, particularly in terms of immune effector functions. While typically added at the Fc level, approximately 15-25% of circulating antibodies exhibit glycosylation in the Fab domains as well. To the best of our knowledge, cetuximab (Erbitux®) is the only therapeutic antibody presenting Fab glycosylation approved world-wide targeting the epidermal growth factor receptor for the treatment of metastatic-colorectal and head and neck cancers. Additionally, it can trigger antibody-dependent cell cytotoxicity (ADCC), a response that typically is influenced by N-glycosylation at Fc level. However, the role of Fab glycosylation in cetuximab remains poorly understood. Hence, this study aims to investigate the structural role of Fab glycosylation on the conformational behavior of cetuximab. Methods: The study was performed in silico via accelerated molecular dynamics simulations. The commercial cetuximab was compared to its form without Fab glycosylation and structural descriptors were evaluated to establish conformational differences. Results: The results clearly show a correlation between the Fab glycosylation and structural descriptors that may modulate the conformational freedom of the antibody, potentially affecting Fc effector functions, and suggesting a negative role of Fab glycosylation on the interaction with FcgRIIIa. Conclusion: Fab glycosylation of cetuximab is the most critical challenge for biosimilar development, but the differences highlighted in this work with respect to its aglycosylated form can improve the knowledge and represent also a great opportunity to develop novel strategies of biotherapeutics. [ABSTRACT FROM AUTHOR]

Background: To investigate the effectiveness and safety of maintenance regimens based on cetuximab, we conducted a real-world, single-arm, retrospective study at a single center. Methods: In Fujian Medical University Union Hospital, patients with unresectable metastatic colorectal cancer (mCRC) who received cetuximab-based maintenance therapy between December 2020 and December 2021 were included. All patients had RAS and BRAF wild-type. The maintenance regimen consisted of 6-12 cycles of cetuximab plus irinotecan (Phase 1) and cetuximab (Phase 2). Patients could receive reintroduction therapy in case of disease progression during Phase 2. Progression-free survival (PFS), overall survival (OS), and safety data were collected. Results: According to the inclusion and exclusion criteria of the study, a total of 108 subjects who received maintenance therapy were included-51 experienced disease progression during Phase 1, with PFS (1) of 7.3 months. Among the 52 patients who entered Phase 2, 17 were still in this phase at the end of follow-up, with PFS (2) of 10.1 months. In Phase 2, 35 patients experienced disease progression, of whom 24 received reintroduction therapy, with PFS (3) of 6.7 months. The overall PFS (total) during the maintenance period was 11.9 months, and the OS was 39.2 months. Grade III or higher adverse events were 4.6% during Phase 1 and 0% during Phase 2. Conclusion: Innovative cetuximab-based maintenance therapy showed a trend toward improving the prognosis of mCRC patients with RAS and BRAF wild-type, while the toxic side effects of maintenance therapy were manageable. [ABSTRACT FROM AUTHOR]

Cisplatin (DDP)-based combined chemotherapy or concurrent chemoradiotherapy is the mainstay treatment for advanced-stage nasopharyngeal carcinoma (NPC), but needs improvement due to its severe side effects. Capsaicin (CAP) can enhance the anti-tumor activity of cytotoxic drugs. The aim of this study was to investigate the anti-metastasis activity of CAP in combination with DDP in NPC. Herein, CAP and DDP showed synergistic cytotoxic effects on NPC cells. CAP alone and DDP alone inhibited NPC migration and invasion in vitro and in vivo , and the combination of CAP and DDP had the greatest effect. Moreover, CAP upregulated the mRNA and protein expressions of serpin family B member 2 (SERPINB2). Further results showed that both SERPINB2 mRNA and protein expressions were downregulated in NPC cell lines and tissues and SERPINB2 overexpression inhibited NPC migration and invasion in vitro and in vivo , while silencing SERPINB2 acted oppositely. In addition, SERPINB2 was abnormally expressed in head and neck squamous cell carcinoma and other multiple cancers, and downregulation of SERPINB2 predicted poor prognosis in head and neck squamous cell carcinoma according to the Cancer Genome Atlas database. We further found that SERPINB2 overexpression inhibited epithelial–mesenchymal transition (EMT) and the phosphorylated extracellular signal-regulated kinase (p-ERK), and the inhibitory effect was enhanced by CAP and DDP. Altogether, our results suggest that the combined inhibition of CAP and DDP on NPC metastasis may be related to the inhibition of epithelial–mesenchymal transition and ERK signals mediated by SERPINB2, and CAP may help to improve the efficacy of DDP in the treatment of NPC and develop new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: As a substantial waiting time is usually required for radical surgery, safe and effective preoperative neoadjuvant chemotherapy (NAC) is desired for the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC). However, the significance of NAC in advanced HNSCC is still unclear. This study aimed to assess the safety and efficacy of NAC using the paclitaxel, carboplatin, and cetuximab (PCE) regimen. Methods: We retrospectively evaluated the background characteristics, incidence of adverse events, overall response rate (ORR), pathological response, recurrence-free survival (RFS), and overall survival (OS) in 26 patients. Patients receiving the PCE regimen were further divided into two groups based on the number of chemotherapy cycles (one cycle or more) and eligibility for cisplatin. Patients aged ≥ 75 years and those with an estimated glomerular filtration rate (eGFR) < 60 mL/min were classified as ineligible for cisplatin. Results: The median age was 70 (27–81) years. The median eGFR at treatment initiation was 63.2 (41.1–89.7) mL/min. Fourteen (53.8%) patients were ineligible for cisplatin. Grade 3 or higher neutropenia was observed in 11 of 25 (42.3%) patients. No delay in or withdrawal from surgery was observed. The ORR was 65.4%. The 2-year RFS and OS were 61.5% and 76.7%, respectively. No significant differences in safety and efficacy between the number of chemotherapy cycles and cisplatin eligibility were observed. Conclusion: NAC using the PCE regimen for patients with locally advanced HNSCC, including cisplatin-ineligible patients, has acceptable toxicity and favorable efficacy. [ABSTRACT FROM AUTHOR]

Triplet chemotherapy plus cetuximab showed promising results in phase II trials in unsystematically selected RAS population. We evaluated FOLFIRINOX+cetuximab efficacy as first-line treatment in extended RAS wild-type metastatic colorectal cancer (mCRC) patients. We retrospectively analyzed patients treated with FOLFIRINOX+cetuximab, using data from clinical trials and real-life practice. Extended mutation analysis was performed when RAS/BRAF status was unavailable. The primary endpoint was progression-free survival (PFS). Seventy patients (61.4 % male, median age 58.7 years) were analyzed. Eighty percent had left-sided mCRC and 97.1 % had liver metastases. Median PFS and overall survival (OS) were 13.3 and 48.5 months, respectively. The objective response rate was 85.7 %, with 20 % complete response. Primary tumor location did not affect OS and PFS. BRAF wild-type patients (n = 65) had longer PFS (13.3 vs. 6.0 months; p = 0.005) and OS (50.1 vs. 21.2 months; p = 0.007) than BRAF mutated patients (n = 5, including four BRAFV600E). Median OS was significantly longer in resected patients (n = 39, 55.1 vs. 30.7 months; p = 0.030). Main toxicities were diarrhea (31.4 %) and neutropenia (21.4 %). FOLFIRINOX+cetuximab provides good PFS, high response rate and prolonged disease control in initially unresectable extended RAS wild-type mCRC. This combination is particularly interesting for selected patients with liver-limited disease eligible to secondary resection. [ABSTRACT FROM AUTHOR]

Analysis of rechallenge with nivolumab as 5th-line therapy for locally and nodally failed laryngeal squamous cell carcinoma following conventional therapeutic modalities: radiotherapy, surgery and chemotherapy. A 70-year-old male, with local and nodal progression of laryngeal squamous cell carcinoma after treatment with chemoradiotherapy and surgery, was initially treated for recurrence with carboplatin, 5-fluorouracile (FU) and cetuximab, followed by second-line nivolumab, and then two lines of conventional chemotherapy with paclitaxel and cetuximab followed by carboplatin and cetuximab. He underwent rechallenge with nivolumab in 5th line, achieving 12 months' response, ongoing at the time of writing, and 42.5 months' survival since initiation of exclusive systemic management after failure of conventional treatment. This case report highlights the benefit of nivolumab rechallenge in 5th line following previous failure as stand-alone therapy in 2nd line for a patient with laryngeal squamous cell carcinoma locally and nodally uncontrolled after conventional treatment. Clinical trials evaluating the efficacy of this approach are necessary to assess its contribution, as it is currently not a standard therapeutic option. [ABSTRACT FROM AUTHOR]

Background: 5-Fluorouracil (5-FU) has been used as a standard first-line treatment for colorectal cancer (CRC) patients. Although 5-FU-based chemotherapy and immune checkpoint blockade (ICB) have achieved success in treating CRC, drug resistance and low response rates remain substantial limitations. Thus, it is necessary to construct a 5-FU resistance-related signature (5-FRSig) to predict patient prognosis and identify ideal patients for chemotherapy and immunotherapy. Methods: Using bulk and single-cell RNA sequencing data, we established and validated a novel 5-FRSig model using stepwise regression and multiple CRC cohorts and evaluated its associations with the prognosis, clinical features, immune status, immunotherapy, neoadjuvant therapy, and drug sensitivity of CRC patients through various bioinformatics algorithms. Unsupervised consensus clustering was performed to categorize the 5-FU resistance-related molecular subtypes of CRC. The expression levels of 5-FRSig, immune checkpoints, and immunoregulators were determined using quantitative real-time polymerase chain reaction (RT‒qPCR). Potential small-molecule agents were identified via Connectivity Map (CMap) and molecular docking. Results: The 5-FRSig and cluster were confirmed as independent prognostic factors in CRC, as patients in the low-risk group and Cluster 1 had a better prognosis. Notably, 5-FRSig was significantly associated with 5-FU sensitivity, chemotherapy response, immune cell infiltration, immunoreactivity phenotype, immunotherapy efficiency, and drug selection. We predicted 10 potential compounds that bind to the core targets of 5-FRSig with the highest affinity. Conclusion: We developed a valid 5-FRSig to predict the prognosis, chemotherapeutic response, and immune status of CRC patients, thus optimizing the therapeutic benefits of chemotherapy combined with immunotherapy, which can facilitate the development of personalized treatments and novel molecular targeted therapies for patients with CRC. [ABSTRACT FROM AUTHOR]

Background: It is unclear witch regimen is optimal as salvage chemotherapy (SCT) after immune checkpoint inhibitor (ICI) monotherapy for recurrent or metastatic head and neck cancer (RM‐HNC). Methods: This study enrolled 109 patients. Overall survival (OS) and progression‐free survival 2 (PFS2) were compared between patients stratified by SCT regimen. Results: Of the 109 patients, 55 underwent SCT after the failure of ICI monotherapy. The OS of these 55 patients was longer than that of patients who did not undergo SCT. The OS and PFS2 were similar between patients treated with paclitaxel (PTX) and cetuximab (Cmab) combination and those treated with PTX monotherapy. The occurrence of irAEs did not impact PFS2 nor OS. Conclusions: SCT can improve the survival outcomes of patients with RM‐HNC. In addition to PTX and Cmab, PTX monotherapy is also considered an effective SCT regimen. SCT is effective regardless of the presence or absence of irAEs. [ABSTRACT FROM AUTHOR]

Background: The treatment of stage I-III HPV+ oropharyngeal squamous cell carcinoma (HPV-OPSCC) is based on either surgery ± adjuvant therapy or exclusive radio±chemotherapy. We sought to compare these two therapeutic strategies in terms of efficacy, tolerance and quality of life (QoL). Methods: Patients treated for stage I-III HPV-OPSCC from 2010 to 2021 in 3 academic centers were included and sorted according to the treatment strategy: surgery or exclusive radio±chemotherapy. Efficacy and tolerance were retrospectively assessed, and a transversal exploratory QoL assessment was performed using QoL instruments. Results: A total of 83 patients were included, with 21 undergoing non-minimally invasive surgery and 62 receiving definitive radio-±chemotherapy. 2-year progression-free survival (PFS) and overall survival (OS) were respectively 80% and 86% in the surgical group and 92% and 95% in the non-surgical group, with no significant difference. At the end of treatment, 64.5% of patients presented with a grade III toxicity, without significant difference between the two groups. No patient had late grade III toxicity at 24 months. Forty-five patients (11 in the surgical group, 34 in the non-surgical group) participated in an exploratory quality-of-life analysis. Patients reported significantly more fatigue and loss of appetite after surgery, whereas patients in the radio±chemotherapy group described significantly more salivary and oral problems and difficulty swallowing, but the median time between treatment completion and the response to the questionnaires. Conclusion: There was no significant difference in efficacy, physician-reported toxicity and overall patient-reported quality of life was found between non-minimally invasive surgery and radio±chemotherapy in the treatment of stage I-III HPV-OPSCC. [ABSTRACT FROM AUTHOR]

Background: Advanced head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, and new treatment options are needed. Combining immunotherapies with differing mechanisms of action may enhance clinical benefits compared with single-agent immunotherapy. Epacadostat, an indoleamine 2,3 dioxygenase 1 inhibitor, plus pembrolizumab, a PD-1 inhibitor, showed promising activity in advanced HNSCC in the phase 1/2 KEYNOTE-037/ECHO-202 trial. Methods: KEYNOTE-669/ECHO-304 is a randomized, open-label, phase 3 study evaluating the efficacy and safety of pembrolizumab plus epacadostat, pembrolizumab monotherapy, and the EXTREME regimen (cetuximab with a platinum [carboplatin or cisplatin] and 5-fluorouracil) in recurrent/metastatic (R/M) HNSCC. Participants had no prior systemic therapy for R/M HNSCC and were randomly assigned (2:1:2) to pembrolizumab 200 mg intravenously every 3 weeks plus epacadostat 100 mg orally twice daily, pembrolizumab monotherapy, or EXTREME. The primary endpoint was objective response rate (ORR; investigator assessment). Secondary endpoints were safety and tolerability. Change in serum kynurenine was an exploratory endpoint. Study enrollment was discontinued early as a strategic decision on May 2, 2018, and response assessment was discontinued after first on-study imaging assessment at week 9. Data cut-off was January 17, 2019. Results: Between December 1, 2017, and May 2, 2018, 89 patients were randomly allocated to pembrolizumab plus epacadostat (n = 35), pembrolizumab monotherapy (n = 19), or EXTREME (n = 35). ORR (95% CI) was 31% (17%–49%) for pembrolizumab plus epacadostat, 21% (6%–46%) for pembrolizumab monotherapy, and 34% (19%–52%) for EXTREME. Treatment-related adverse events (TRAEs) occurred in 82% (n = 28) of patients receiving pembrolizumab plus epacadostat, 63% (n = 12) receiving pembrolizumab monotherapy, and 100% (n = 34) receiving EXTREME. Grade 3–4 TRAEs occurred in 24% (n = 8) of patients receiving pembrolizumab plus epacadostat, 16% (n = 3) receiving pembrolizumab monotherapy, and 82% (n = 28) receiving EXTREME. No deaths occurred due to AEs. Pembrolizumab plus epacadostat treatment reduced kynurenine levels but not to that of healthy subjects. Conclusions: Pembrolizumab plus epacadostat and pembrolizumab monotherapy provided a similar response rate to EXTREME and demonstrated a manageable safety profile in patients with R/M HNSCC. Trial registration: NCT03358472. Date of trial registration: November 30, 2017. [ABSTRACT FROM AUTHOR]

Metastatic melanoma, a deadly form of skin cancer, often develops resistance to the BRAF inhibitor drug vemurafenib, highlighting the need for understanding the underlying mechanisms of resistance and exploring potential therapeutic strategies targeting integrins and TGF-β signalling. In this study, the role of integrins and TGF-β signalling in vemurafenib resistance in melanoma was investigated, and the potential of combining vemurafenib with cilengitide as a therapeutic strategy was investigated. In this study, it was found that the transcription of PAI1 and p21 was induced by acquired vemurafenib resistance, and ITGA5 levels were increased as a result of this resistance. The transcription of ITGA5 was mediated by the TGF-β pathway in the development of vemurafenib resistance. A synergistic effect on the proliferation of vemurafenib-resistant melanoma cells was observed with the combination therapy of vemurafenib and cilengitide. Additionally, this combination therapy significantly decreased invasion and colony formation in these resistant cells. In conclusion, it is suggested that targeting integrins and TGF-β signalling, specifically ITGA5, ITGB3, PAI1, and p21, may offer promising approaches to overcoming vemurafenib resistance, thereby improving outcomes for metastatic melanoma patients. [ABSTRACT FROM AUTHOR]

The epidermal growth factor receptor (EGFR) is an important target for cancer therapies. Many head and neck cancer (HNC) cells have been reported to overexpress EGFR; therefore, anti‐EGFR therapies have been attempted in patients with HNC. However, its clinical efficacy is limited owing to the development of drug resistance. In this study, we developed an EGFR‐targeting immunotoxin consisting of a clinically proven anti‐EGFR IgG (cetuximab; CTX) and a toxin fragment (LR‐LO10) derived from Pseudomonas exotoxin A (PE) using a novel site‐specific conjugation technology (peptide‐directed photo‐crosslinking reaction), as an alternative option. The immunotoxin (CTX‐LR‐LO10) showed specific binding to EGFR and properties of a typical IgG, such as stability, interactions with receptors of immune cells, and pharmacokinetics, and inhibited protein synthesis via modification of elongation factor‐2. Treatment of EGFR‐positive HNC cells with the immunotoxin resulted in apoptotic cell death and the inhibition of cell migration and invasion. The efficacy of CTX‐LR‐LO10 was evaluated in xenograft mouse models, and the immunotoxin exhibited much stronger tumor suppression than CTX or LR‐LO10. Transcriptome analyses revealed that the immunotoxins elicited immune responses and altered the expression of genes related to its mechanisms of action. These results support the notion that CTX‐LR‐LO10 may serve as a new therapeutic agent targeting EGFR‐positive cancers. [ABSTRACT FROM AUTHOR]

Background: The significance of induction chemotherapy (IC) in the treatment of squamous cell carcinoma of the head and neck (SCCHN) with unresectable locoregional recurrence after curative surgery has not been clarified. The aim of this study was to evaluate the efficacy of IC followed by chemoradiotherapy (CRT) in these patients. Methods: Among patients with unresectable locoregional recurrent SCCHN who had not undergone prior irradiation and were eligible for cisplatin, we conducted a retrospective analysis of patients who received CRT following IC with paclitaxel, carboplatin, or cetuximab (IC-PCE group) and those who received CRT without prior IC (CRT group) between June 2013 and August 2021. Result: Forty-two patients were included. The CRT group and IC-PCE group consisted of 15 and 27 patients, respectively. Primary site was the oral cavity (n=25), oropharynx (n=3), hypopharynx (n=13) and larynx (n=1). Objective response rate (ORR) with IC-PCE was 55.6%; 24 patients (88.9%) subsequently received CRT. ORR after completion of CRT was significantly better in the IC-PCE group (95.8% in the IC-PCE group vs. 66.7% in the CRT group, p=0.024). Progression-free survival (PFS) of the total population on median follow-up of 2.4 years (range: 0.8-7.3) tended to be better in the IC-PCE group (2-year PFS: 55.6% in the IC-PCE group vs. 33.3% in the CRT group, log-rank p=0.176), especially in oral cancer (2-year PFS: 37.5% in the IC-PCE group vs. 0% in the CRT group, log-rank p=0.015). Conclusion: Therapeutic strategies including IC-PCE in patients with unresectable locoregional recurrent SCCHN after curative surgery may contribute to improved prognosis, especially in oral cancer. [ABSTRACT FROM AUTHOR]

This article discusses a case of acantholytic PRIDE syndrome in a 63-year-old male with chronic myeloid leukemia who was taking imatinib. The patient had pus-filled lesions on the limbs, itching, and dryness. Treatment included topical clobetasol ointment, levocetirizine tablets, and moisturizers, resulting in symptom improvement. The article also provides information on the cutaneous manifestations of tyrosine kinase inhibitors and lists case studies on adverse effects of epidermal growth factor receptor inhibitors, such as papulopustular eruption, xerosis, paronychia, changes in hair and nail growth patterns, mucositis, and pyogenic granuloma-like granuloma. The studies highlight symptoms, treatments, and the potential for resolution of skin lesions over time. [Extracted from the article]

Primary anal cancer accounts for 1% to 3% of gastrointestinal cancers. The most common histology is squamous cell carcinoma, with an incidence of 0.5 to 2 per 100,000 people. The main risk factor is infection with the human papillomavirus, particularly subtypes 16 and 18, which represent 85% to 93% of cases. Treatment and prognosis depend on the stage of the tumor. Localized tumors can be treated with curative surgery, but locally advanced stages require a combination of chemotherapy and radiation. Advanced-stage tumors (IIIC and IV) have a poor prognosis even with chemotherapy. In recent years, immunotherapy and targeted therapies have shown promise in improving survival for patients with advanced, recurrent, or difficult-to-treat disease. We present the case of a 69-year-old woman with moderately differentiated squamous cell carcinoma (T2N1M0, stage IIIA) of the anal canal who, after treatment with chemoradiotherapy and checkpoint inhibitors and subsequent disease progression, received targeted therapy (cetuximab) and achieved complete remission with a sustained response for over 18 months. This case highlights the challenges of treating advanced anal cancer and the potential benefits of targeted therapy, particularly cetuximab, in achieving long-term responses. Further research and large-scale studies are needed to determine the role of targeted therapy and immunotherapy in the treatment of anal canal cancer. [ABSTRACT FROM AUTHOR]

Objective: To discuss the effect of sialic acid-binding immunoglobulin-like lectin-15(Siglec15) derived from M2 tumor-associated macrophages (M2-TAMs) on promoting the malignant biological behavior of the esophageal squamous cell carcinoma (ESCC) through bioinformatics analysis, and to validate the findings through cell experiment. Methods: The Tumor Immune Estimation Resource (TIMER) online Database was used to analyze the expression differences and immune infiltration of Siglec15 in pan-cancer and adjacent normal tissues. Real-time fluorescence quantitative PCR (RT-qPCR) method was used to detect the expression levels of Siglec15 mRNA in M2-TAMs and ESCC EC109 and KYSE150 cells. Based on the non-contact co-culture of M2-TAMs and ESCC cells, the following groups were set up，such as EC109/KYSE150 group, EC109/KYSE150+si-NC group (transfected with si-NC sequence), and EC109/KYSE150+si-Siglec15 group (transfected with si-Siglec15#1 and si-Siglec15#2 sequences). CCK-8 method was used to detect the proliferation activities of the cells in various groups; wound healing assay was used to detect the wound healing rates of the cells in various groups; Transwell chamber assay was used to detect the numbers of migration and invasion cells in various groups; flow cytometry was used to detect the apoptotic rates of the cells in various groups. Results: The bioinformatics analysis results showed that compared with adjacent normal tissue, the expression levels of Siglec15 mRNA in pan-cancer tissues such as esophageal cancer, colon cancer, and head and neck squamous cell carcinoma tissues were increased (P<0. 05 or P<0. 01), and the expression level of Siglec15 mRNA in esophageal cancer tissue was significantly positively correlated with the infiltration of the macrophages (P<0. 05). Compared with the EC109 cells and KYSE150 cells, the expression level of Siglec15 mRNA in M2-TAMs was significantly increased (P<0. 01). There was no significant difference in the proliferation rate of the cells among EC109/KYSE150 group, EC109/KYSE150+si-NC group, and EC109/KYSE150+si-Siglec15 group(P>0. 05). Compared with EC109/KYSE150 group, after treated for 24 and 48 h, the wound healing rate of the cells in EC109/KYSE150+si-NC group was increased (P<0. 01), the numbers of migration and invasion cells were increased (P<0. 05), and the apoptotic rate was decreased (P<0. 01). Compared with EC109/KYSE150+si-NC group, the wound healing rates of the cells in EC109/ KYSE150+si-Siglec15#1 group and EC109/KYSE150+si-Siglec15#2 group were decreased (P< 0. 05), the numbers of migration and invasion cells were decreased (P<0. 05), and the apoptotic rates of the cells had no significant difference (P>0. 05). Conclusion: Siglec15 derived from M2-TAMs may be a key factor in promoting the migration and invasion of the ESCC cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Cetuximab is a treatment widely used to treat advanced, metastatic colorectal cancer (CRC), and it works by blocking epidermal growth factor receptor signaling. Unfortunately, patients inevitably develop resistance to cetuximab. The most common resistance mechanisms are well established, but there are still patients that become resistant to cetuximab due to unknown mechanisms. The small guanosine triphosphatases (GTPases) RAC1 and RAC1B have been shown to contribute to CRC progression, but their role in cetuximab resistance is unclear. This review highlights the known cetuximab resistance mechanisms and summarizes how RAC1 and RAC1B could contribute to these resistance mechanisms to propose RAC1 and RAC1B as additional therapeutic targets that could increase the efficacy of cetuximab. Colorectal cancer (CRC) is one of the most diagnosed cancers and a leading contributor to cancer-related deaths in the United States. Clinically, standard treatment regimens include surgery, radiation, and chemotherapy; however, there has been increasing development and clinical use of targeted therapies for CRC. Unfortunately, many patients develop resistance to these treatments. Cetuximab, the first targeted therapy approved to treat advanced CRC, is a monoclonal antibody that targets the epidermal growth factor receptor and inhibits downstream pathway activation to restrict tumor cell growth and proliferation. CRC resistance to cetuximab has been well studied, and common resistance mechanisms include constitutive signal transduction through downstream protein mutations and promotion of the epithelial-to-mesenchymal transition. While the most common resistance mechanisms are known, a proportion of patients develop resistance through unknown mechanisms. One protein predicted to contribute to therapy resistance is RAC1, a small GTPase that is involved in cytoskeleton rearrangement, cell migration, motility, and proliferation. RAC1 has also been shown to be overexpressed in CRC. Despite evidence that RAC1 and its alternative splice isoform RAC1B play important roles in CRC and the pathways known to contribute to cetuximab resistance, there is a need to directly study the relationship between RAC1 and RAC1B and cetuximab resistance. This review highlights the recent studies investigating RAC1 and RAC1B in the context of CRC and suggests that these proteins could play a role in resistance to cetuximab. [ABSTRACT FROM AUTHOR]

Upon first exposure to cetuximab, hypersensitivity reactions can occur. We aimed to assess the utility of the basophil activation test (BAT) to alpha-gal and cetuximab for predicting severe reactions. We prospectively recruited 38 patients and evaluated sIgE to alpha-gal in all patients before the first application of cetuximab. In all alpha-gal-sensitized patients, we evaluated skin tests to meat extracts, gelatine, and cetuximab and performed BAT with alpha-gal and cetuximab. In 24% (9/38) of patients, sIgE to alpha-gal was >0.10 kUA/L, and 8/9 reacted to the cetuximab. Basophil activation tests with alpha-gal were positive in all sensitized patients and were higher in those with severe reactions (18.3% in grade 4 [n = 4] vs. 1.8% in grade 2 [n = 3] or no reaction [n = 1] at 3.3 ng/mL of alpha-gal; p = 0.03). All patients with severe grade 4 reactions had a positive CD63 BAT response to cetuximab compared to patients with moderate or no reaction, who all had negative BAT (57.7% vs. 0.9% at 500 µg/mL, 63.2% vs. 4.1% at 100 µg/mL, 58.2% vs. 2.7% at 10 µg/mL, and 32.1% vs. 3.3% at 1 µg/mL of cetuximab, respectively; p ≤ 0.001). In summary, before initiating cetuximab treatment, sIgE to alpha-gal should be assessed in all patients. To predict the severity of the reaction and to assess the risk of cetuximab-induced anaphylaxis, we should perform BATs with alpha-gal or more discriminative BATs with cetuximab. [ABSTRACT FROM AUTHOR]