Search Results (330)

Combining immune checkpoint inhibitors (ICIs) and anti-angiogenic pharmacologic agents is an encouraging therapeutic approach in the treatment of non-small cell lung cancer (NSCLC). Currently, the only FDA-approved therapy combining an immune checkpoint inhibitor and a vascular endothelial growth factor (VEGF) inhibitor is atezolizumab, bevacizumab, and chemotherapy in first-line metastatic NSCLC patients. However, the combination of nivolumab, a programmed death-1 (PD-1) inhibitor, and bevacizumab has also shown encouraging results in patients with NSCLC with minimal adverse effects, respectively. This communication aims to highlight the efficacy of nivolumab and bevacizumab in NSCLC patients without sensitizing mutations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or ROS proto-oncogene 1 (ROS1). In addition, the combination of nivolumab/atezolizumab and bevacizumab with other therapeutic agents is also discussed. We also underscore the adverse effects and limitations of such combinations in NSCLC patients. Future studies should focus on large-scale trials and biomarker identification to establish the benefits of these combination therapies in NSCLC patients. Full article

Aralia chinensis L. has shown potential in breast cancer treatment, yet its pharmacodynamically active components and mechanisms remain undefined. To systematically identify the bioactive constituents absorbed into the bloodstream and elucidate their multi-target mechanisms against breast cancer, we employed ultra-high-performance liquid chromatography in conjunction with Q Exactive Orbitrap mass spectrometry (UHPLC-Q Exactive Orbitrap-MS) alongside serum pharmacochemistry to analyze the chemical constituents of total saponins derived from A. chinensis (TSAC) and to identify the blood-absorbed prototypes in a rat model. Network pharmacology predicted targets and pathways of serum prototypes, validated by molecular docking and in vitro experiments. We identified 38 triterpenoid saponins, 3 steroidal saponins, and 8 triterpenoids in TSAC, with 22 prototype compounds detected in serum. An integrative analysis encompassing 486 compound targets and 1747 genes associated with breast cancer elucidated critical pathways, notably the PI3K-Akt signaling pathway and resistance mechanisms to EGFR tyrosine kinase inhibitors. Molecular docking confirmed strong binding of araloside A and elatoside L to SRC, PIK3R1, PIK3CA, STAT3, and EGFR. In MCF-7 cells, TSAC suppressed proliferation and migration while downregulating Src, PI3K, and EGFR expression at the gene and protein levels. This study successfully identified TSAC’s serum-absorbed bioactive components and demonstrated their anti-breast cancer effects via multi-target mechanisms involving the Src/PI3K/EGFR axis, providing a crucial pharmacological foundation for developing A. chinensis-derived breast cancer therapies. Full article

Steroid hormones play critical roles in the development and progression of NSCLC through both genomic and non-genomic pathways. This review summarizes the expression profiles and molecular functions of estrogen, progesterone, androgen, and glucocorticoid receptors in NSCLC. Estrogen and progesterone receptors exhibit gender-specific prognostic significance, while glucocorticoid receptors influence tumor growth and immune responses. Emerging evidence supports the use of anti-estrogen therapies and glucocorticoids as adjuncts to existing treatment strategies, including immunotherapy. The crosstalk between hormone signaling and oncogenic pathways such as EGFR or immune checkpoints offers opportunities for novel combination therapies. However, challenges remain in biomarker development, drug resistance, and managing the dual effects of glucocorticoids. A deeper understanding of hormone–tumor–immune interactions is essential to optimize hormone-targeted interventions in NSCLC. Full article

Background and Objectives: Non-small-cell lung cancer (NSCLC) often has epidermal growth factor receptor (EGFR) mutations, which are key targets for therapy. EGFR mutation subtypes, especially exon 19 deletions and exon 21 L858R mutations, influence responses to EGFR tyrosine kinase inhibitors (TKIs) and patient survival. Despite progress in TKI treatments, resistance and different responses remain challenges. This study explores the relationship between EGFR mutation subtypes, PD-L1 expression, and patient outcomes after anti-EGFR therapy. Materials and Methods: We studied 176 cases of EGFR mutation-positive NSCLC. Next-generation sequencing was used to analyze EGFR and other mutations, while PD-L1 expression was evaluated through immunohistochemistry. We analyzed EGFR mutation subtypes, PD-L1 status, treatments, and survival outcomes. Results: Among 176 cases, 88.6% were adenocarcinomas. Within the EGFR mutation spectrum, exon 19 deletions were the most common subtype, accounting for 40.9% of cases, followed by the point mutation in exon 21, which occurred in 35.8% of cases. Less frequent alterations, making up 23.3% of all detected mutations, included mutations in exon 18, insertions, and point mutations such as S768I and T790M in exon 20, as well as changes in exon 2, exon 7, and other less frequently affected regions. Exon 19 mutations were associated with older age, female sex, adenocarcinoma, and bone metastasis (p < 0.05). TP53 was the most common concurrent mutation (44.3%). PD-L1 positivity (TPS ≥ 1%) was observed in 48.3%, with high expression (TPS ≥ 50%) in 25.9%. Exon 21 mutations were significantly linked to PD-L1 negativity (p = 0.008). The median overall survival was longest with TKI therapy (51 months), and this was also observed in PD-L1-positive patients, although the difference was not statistically significant. The median progression-free survival for patients treated with TKIs and those with EGFR mutations was 14 months. PD-L1-positive patients receiving TKIs had significantly longer survival than those who did not (51 vs. 17 months, p = 0.003). Conclusions: EGFR mutation subtypes and PD-L1 expression seem to affect treatment outcomes and survival in NSCLC. The observed links emphasize the potential value of combining molecular and immunological markers to guide therapy choices. Full article

Background: Colorectal liver metastasis (CRLM) represents a major clinical challenge in oncology, affecting 25–50% of colorectal cancer patients and significantly impacting survival. While multimodal therapies—including surgical resection, systemic chemotherapy, and local ablative techniques—have improved outcomes, prognosis remains heterogeneous due to variations in tumor biology, patient factors, and institutional practices. Methods: This review synthesizes current evidence on prognostic factors influencing CRLM management, encompassing clinical (e.g., tumor burden, anatomic distribution, timing of metastases), biological (e.g., CEA levels, inflammatory markers), and molecular (e.g., RAS/BRAF mutations, MSI status, HER2 alterations) determinants. Results: Key findings highlight the critical role of molecular profiling in guiding therapeutic decisions, with RAS/BRAF mutations predicting resistance to anti-EGFR therapies and MSI-H status indicating potential responsiveness to immunotherapy. Emerging tools like circulating tumor DNA (ctDNA) and radiomics offer promise for dynamic risk stratification and early recurrence detection, while the gut microbiome is increasingly recognized as a modulator of treatment response. Conclusions: Despite advancements, challenges persist in standardizing resectability criteria and integrating multidisciplinary approaches. Current guidelines (NCCN, ESMO, ASCO) emphasize personalized strategies but lack granularity in terms of incorporating novel biomarkers. This exhaustive review underscores the imperative for the development of a unified, biomarker-integrated framework to refine CRLM management and improve long-term outcomes. Full article

Patients undergoing epidermal growth factor receptor inhibitor (EGFRI) therapy frequently experience dermatologic side effects, notably papulopustular rash, which impacts 50–90% of recipients. This rash typically appears on the face, chest, and back within weeks of treatment, resembling acne but stemming from distinct pathophysiological mechanisms, causing significant discomfort and reduced quality of life. Prophylactic measures and symptom-based treatment are recommended, emphasizing patient education, topical agents, and systemic therapies for severe cases. A 41-year-old female with advanced colonic mucinous adenocarcinoma developed severe acneiform rash and pruritus during EGFRI therapy with panitumumab. Initial standard treatment with oral doxycycline was discontinued after two days due to severe gastrointestinal intolerance characterized by intense nausea and dyspepsia. With limited access to dermatological consultation, treatment with rose stem cell-derived exosomes (RSCEs) provided rapid symptom relief. Significant improvement was observed within 24 h, with complete resolution of pruritus and substantial reduction in inflammatory lesions within 72 h. RSCEs demonstrate anti-inflammatory effects through the modulation of pro-inflammatory cytokines including interleukin-6, interleukin-1β, and tumor necrosis factor-α, while promoting fibroblast proliferation and collagen synthesis enhancement. They may represent a possible alternative to corticosteroids, avoiding associated side effects such as skin atrophy, delayed wound healing, and local immunosuppression. This case underscores the potential of innovative treatments like RSCEs in managing EGFRI-induced skin complications when standard therapies are not tolerated, particularly in healthcare systems with limited dermato-oncological resources. Full article

Background: Anti-EGFR therapy, combined with chemotherapy, represents the standard therapeutic approach for triple wild-type (KRAS/NRAS and BRAF), left-sided, microsatellite stable (MSS) metastatic colorectal cancer (mCRC). However, acquired resistance develops in approximately 50% of patients. This study evaluated the efficacy of anti-EGFR therapy re-challenge and analyzed circulating tumor DNA (ctDNA) for potential resistance mechanisms. Methods: Eleven patients with triple wild-type, MSS, HER2-negative, left-sided mCRC were included. All patients received Cetuximab with chemotherapy as the first-line treatment, with three patients subsequently receiving Cetuximab re-challenge. Twenty-one plasma samples were collected at baseline and at each response assessment for retrospective ctDNA analysis using next-generation sequencing with a 16-gene panel. Results: Genetic alterations were detected in only 14.2% of ctDNA samples. In one re-challenge patient, the KRAS: c.35G>A mutation appeared during progression. No RAS mutations were identified in four patients who progressed on first-line Cetuximab treatment. Conclusions: This preliminary study suggests that clinically based anti-EGFR re-challenge may benefit selected mCRC patients. The low detection rate of resistance-conferring mutations indicates potential alternative resistance mechanisms beyond RAS pathway alterations. Our findings, while limited by sample size and the retrospective design of ctDNA testing, contribute to the growing evidence supporting anti-EGFR re-challenge strategies in mCRC management. Full article

Background: Organic anion transporter 3 (OAT3) in the kidney proximal tubule cells plays a critical role in renal clearance of numerous endogenous metabolites and exogenous drugs and toxins. In this study, we discovered that epidermal growth factor (EGF) regulates the expression and activity of OAT3 through palmitoylation, a novel mechanism that has never been described in the OAT field. Methods/Results: Our results showed that treatment of OAT3-expressing cells with EGF led to a ~40% increase in OAT3 expression and OAT3-mediated transport of estrone sulfate, a prototypical substrate for OAT3. EGF-stimulated OAT3 transport activity was abrogated by H-89, a protein kinase A (PKA) inhibitor, indicating that an EGF-PKA signaling pathway is involved in the regulation of OAT3. We also showed that treatment of OAT3-expressing cells with EGF resulted in an enhancement of OAT3 palmitoylation, a novel type of post-translational modification for OATs, and such an enhancement was blocked by H-89, suggesting that the EGF-PKA signaling pathway participated in the modulation of OAT3 palmitoylation. Palmitoylation was catalyzed by a group of palmitoyltransfereases, and we showed that OAT3 palmitoylation and expression were inhibited by 2-BP, a general inhibitor for palmitoyltransfereases. We also explored the relationship among EGF/PKA signaling, OAT palmitoylation, and OAT transport activity. We treated OAT3-expressing cells with EGF or Bt2-cAMP, a PKA activator, in the presence and absence of 2-BP, followed by the measurement of OAT3-mediated transport of estrone sulfate. We showed that both EGF- and Bt2-cAMP-stimulated OAT3 transport activity were abolished by 2-BP, suggesting that palmitoylation mediates the regulation of EGF/PKA on OAT3. Finally, we showed that osimertinib, an anti-cancer drug/EGFR inhibitor, blocked EGF-stimulated OAT3 transport activity. Conclusions: In summary, we provided the first evidence that palmitoylation transduces the EGF/PKA signaling pathway to the modulation of OAT3 expression and function. Our study also provided an important implication that during comorbidity therapies, EGFR inhibitor drugs could potentially decrease the transport activity of renal OAT3, which would subsequently alter the therapeutic efficacy and toxicity of many co-medications that are OAT3 substrates. Full article

Non-small-cell lung cancer (NSCLC) can harbour different HER2 alterations: HER2 protein overexpression (2–35%), HER2 gene amplification (2–20%), and gene mutations (1–4%). The discovery of the HER2 gene in the 1980s raised great expectations for the treatment of several tumours. However, it was only in 2004 that HER2 mutations were identified, and they currently represent a key druggable target in NSCLC. Despite numerous strengths, there is only one FDA/EMA-approved targeted therapy, an antibody-drug conjugate (ADC) called trastuzumab deruxtecan for pretreated patients with HER2 mutant NSCLC. In the first-line treatment, the standard of care (SoC) remains chemotherapy with or without immunotherapy. In the past, pan-HER tyrosine kinase inhibitors (TKIs) were extensively studied with poor results. But, two newly developed HER2-specific TKIs with low EGFR WT inhibition (BAY2927088 and zongertinib) reported encouraging results and received the breakthrough therapy designation from the FDA. Ongoing clinical trials are investigating new agents. This review focuses on HER2 alterations. Additionally, the anti-HER2 therapies explored so far will be discussed in detail, including the following: HER2 inhibitors (pan-inhibitors and selective inhibitors), monoclonal antibodies (mAbs), and ADCs. A section of this paper is dedicated to the role of immunotherapy in HER2-altered NSCLC. The last section of this paper focuses on the drugs under development and their challenges. Full article

The current treatment for refractory BRAF-V600E mutant metastatic colorectal cancer (mCRC) involves combined inhibition of BRAF and the epidermal growth factor receptor (EGFR). However, tumour responses are often short-lived due to a rebound in mitogen-activated protein kinase (MAPK) activity. In this study, we combined short-term cell viability assays with long-term regrowth assays following drug removal over a period of three weeks. This allowed assessment of regrowth after therapy discontinuation. We tested the effect of combined BRAF inhibition (encorafenib) and EGFR inhibition (afatinib) on BRAF-V600E mutant CRC patient-derived organoids (PDOs). Combined EGFR/BRAF inhibition initially caused a major reduction in PDO growth capacity in BRAF-V600E mutant PDOs. This was followed by rapid regrowth after drug removal, mirroring clinical outcomes. EGFR inhibition in BRAF-V600E mutant PDOs led to activation of the insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R). The IGF1R/IR inhibitor linsitinib prevented the rebound in MAPK activity following removal of afatinib and encorafenib, prevented regrowth of CRC PDOs, and improved the anti-tumour response in an in vivo model. PDO regrowth assays allow the identification of pathways driving tumour recurrence. IR/IGF1R-inhibition prevents regrowth following golden standard MAPK pathway-targeted therapy and provides a strategy to improve the treatment of BRAF-V600E mutant CRC Full article

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with unmet therapeutic needs. This study investigates the therapeutic potential of Periplaneta americana L. extract (PAE) and its molecular mechanisms, integrating network pharmacology and experimental validation. Liquid chromatography–mass spectrometry identified 1355 compounds in PAE. Network pharmacology analysis revealed that inosine, vidarabine, and adenosine 5′-monophosphate (AMP) were core components and the core components synergistically regulated key targets and acted on inflammation-related pathways, thereby establishing a multi-target anti-inflammatory regulatory network. In vivo experiments demonstrated that these compounds significantly alleviated colitis symptoms in dextran sulfate sodium-induced mice, as evidenced by reduced disease activity index scores, preserved colonic mucosal architecture, and decreased inflammatory infiltration. Mechanistically, core compounds down-regulated granulocyte-macrophage colony-stimulating factor (GM-CSF), inducible nitric oxide synthase (iNOS)/NOS2, monocyte chemoattractant protein 1 (MCP-1), and transforming growth factor beta 1 (TGF-β1), while they up-regulated interleukin-10 (IL-10) and epidermal growth factor (EGF). Additionally, they activated epidermal growth factor receptor (EGFR)-mediated pathways. Molecular docking analysis revealed that adenosine analogs preferentially bound to A1/A2a receptors, triggering signaling cascades essential for epithelial repair and inflammation resolution. This study established the multi-component, multi-pathway mechanism of PAE in UC, highlighting its dual role in suppressing inflammation and promoting mucosal healing. By bridging traditional herbal use with modern molecular insights, these findings provided a translational foundation for developing PAE-based therapies for UC. Full article

Background: Colorectal cancer (CRC) is a significant global health burden, with liver metastases representing a key prognostic factor. Neoadjuvant chemotherapy (NAC) has improved outcomes in metastatic CRC (mCRC), and tumor regression is commonly assessed using the Rubbia–Brandt classification. The Poultsides classification defines ≥40% fibrosis as an independent prognostic factor, particularly in patients treated with cetuximab (45.71%). However, the predictive value of this threshold remains under debate, warranting further investigation. Methods: This study evaluates the extent of fibrosis (≥40%) induced by NAC plus anti-epidermal growth factor receptor (anti-EGFR) therapy vs. NAC plus anti-vascular endothelial growth factor (anti-VEGF) therapy in mCRC patients. It also examines the prognostic relevance of the Poultsides and Rubbia–Brandt classifications. A total of 108 patients undergoing liver resection for CRC metastases were included. Statistical analyses were performed using SPSS 28.0 version and R software 4.5 version to compare fibrosis rates and survival outcomes. Results: From September 2005 to January 2023, 108 patients were analyzed: 54 received chemotherapy plus anti-EGFR (Cohort 1), and 54 received chemotherapy plus anti-VEGF (Cohort 2). Fibrosis was significantly higher in Cohort 1 (median 40.0%, IQR: 25.4–53.2) than in Cohort 2 (median 20.6%, IQR: 8.07–36.9), p < 0.001. Overall survival was similar between both cohorts (p = 0.96), with a median follow-up of 41.6 months. Conclusions: Anti-EGFR therapy is associated with greater fibrosis than anti-VEGF, despite similar survival outcomes. The Poultsides classification may be a useful prognostic tool for resected liver metastases in mCRC. Full article

Colorectal cancer (CRC) remains the leading cause of morbidity and mortality for both men and women worldwide. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) of solid tumors, including CRC. These macrophages are found in the pro-inflammatory M1 and anti-inflammatory M2 forms, with the latter increasingly recognized for its tumor-promoting phenotypes. Many signaling molecules and pathways, including AMPK, EGFR, STAT3/6, mTOR, NF-κB, MAPK/ERK, and HIFs, are involved in regulating TAM polarization. Consequently, researchers are investigating several potential predictive and prognostic markers, and novel TAM-based therapeutic targets, especially in combination therapies for CRC. Macrophages of the gastrointestinal tract, including the normal colon and rectum, produce growth hormone-releasing inhibitory peptide/somatostatin (SRIF/SST) and five SST receptors (SSTRs, SST1-5). While the immunosuppressive function of the SRIF system is primarily known for various tissues, its role within CRC-associated TAMs remains underexplored. This review focuses on the following three aspects of TAMs: first, the role of macrophages in the normal colon and rectum within the broader context of macrophage biology; second, the various bioactive factors and signaling pathways associated with TAM function, along with potential strategies targeting TAMs in CRC; and third, the interaction between the SRIF system and macrophages in both normal tissues and the CRC microenvironment. Full article

Background: The epidermal growth factor receptor (EGFR) is overactive in many tumors. This phase I trial evaluated the safety and preliminary efficacy of afatinib plus capecitabine in refractory pancreatic ductal adenocarcinoma (PDA), biliary tract cancers (BTC), and other solid tumors. Patients and Methods: The phase Ia study had a 3 + 3 design with capecitabine 1000 mg/m² twice daily on days 1–14 and afatinib 20 mg, 30 mg, or 40 mg daily in 21-day cycles. In phase Ib, 15 patients, each with PDA and BTC, were treated at maximum tolerated dose (MTD). Results: A total of 41 patients were enrolled. No dose-limiting toxicities were observed, and the MTD was 40 mg afatinib plus capecitabine. Among 36 response-evaluable patients, one had a partial response (3%), and eight (22%) had stable disease. Median progression-free survival (PFS) was 1.9 months (95% CI 1.0, 2.0) for PDA and 1.9 months (95% CI 1.6, 3.4) for BTC. Median overall survival (OS) was 3.2 months (95% CI 2.0, 5.8) for PDA, and 4.6 months (95% CI 1.9, 6.1) for BTC. Median OS was 5.8 months (95% CI 2.0, 9.6) for KRAS^WT PDA, and 5.0 months (95% CI 1.6, 6.1) for KRAS^WT BTC, vs. 3.9 months (95% CI 1.9, 5.8) for KRAS^MUT PDA and 3.1 months (95% CI 1.0, 22.8) for KRAS^MUT BTC, respectively. Conclusions: Afatinib plus capecitabine is tolerable but does not have clinically meaningful efficacy in refractory PDA/BTC. Future studies should test novel anti-EGFR/HER2 therapies in KRAS^WT cancers further selected with a comprehensive molecular profile. Full article

Glioblastoma is one of the most aggressive and lethal forms of brain cancer, with limited therapeutic options and poor patient prognosis. Recent research has identified the TMED family of proteins as key regulators of tumor progression and aggressiveness across multiple cancer types. TMED members are cargo receptors expressed within the early secretory pathway and involved in bidirectional traffic of various proteins including EGFR, TGF-ɑ and WNT. In this study, we explored the therapeutic potential of genetic and pharmacologic inhibition of the cargo receptor TMED9 in glial tumor models. Our findings demonstrate that TMED9 expression is upregulated in glioma and that this upregulation is associated with poor patient survival. Using patient-derived glioma tumor cells, we demonstrate that TMED9 is highly expressed in the cancer stem cell population and that this upregulation promotes the cells’ self-renewal and migration. This is the first time, to the best of our knowledge, that TMED9 has been shown to play a major role in the function and tumorigenesis of brain tumor cancer stem cells. BRD4780, a small molecule that targets TMED9, effectively reduced TMED9 abundance, resulting in decreased viability, migration and stemness of patient-derived glioma stem cells. Moreover, BRD4780 mitigated the proliferation and migration of differentiated glioma tumor cells. When applied together with temozolomide, an established glioblastoma treatment, BRD4780 elicited an enhanced anti-tumor response. Lastly, to demonstrate the broad applicability of our findings, we targeted TMED9 in pediatric glioma cells and showed efficient inhibition of various oncogenic functions. Collectively, our study identifies TMED9 inhibition as a promising therapeutic approach that impairs the tumorigenesis and aggressiveness of brain tumors, with high efficacy against the tumor stem cell population. The effectiveness of TMED9 targeting in different tumor cell populations, the potential of combining this strategy with established therapies and the broad applicability of this approach to multiple cancer types highlight the significance of these findings. Full article