Search Results (1,819)

Alterations in the human epidermal growth factor receptor 2 (HER2) gene are well-recognized oncogenic drivers and therapeutic targets in non-small cell lung cancer (NSCLC). The first anti-HER2 inhibitor, trastuzumab-deruxtecan, was approved for previously treated advanced NSCLC with HER2 mutations, which accounts for 2–4% of NSCLC. The first anti-HER2 antibody, trastuzumab, was approved for HER2-positive metastatic breast cancer in 1998, and a combination therapy comprising trastuzumab, pertuzumab, and docetaxel demonstrated efficacy in the first-line setting. Some EGFR-tyrosine kinase inhibitors (TKIs) have been evaluated as pan-HER TKIs but have shown limited benefits in HER2-altered NSCLC. However, HER2-specific TKIs, such as zongertinib and BAY2927088, have demonstrated encouraging results. Zongertinib was the first HER2-specific TKI to be approved by the FDA in 2025 for previously treated ERBB2-mutated advanced NSCLC. In this narrative review, we have summarized the latest research on the biology of HER2 signaling, HER2 alterations, HER2-targeting therapies, and challenges of treating HER2-overexpressing or -mutated NSCLC. Despite different targets of HER2 mutations in NSCLC and HER2 amplification/overexpression in breast cancer, the development of HER2-targeting agents has been more advanced in breast cancer than in NSCLC. Therefore, pivotal clinical studies in breast cancer may help in identifying more effective therapies for NSCLC. Full article

Background: Small cell lung cancer (SCLC) is a malignant carcinoma characterized by high proliferative rate and early metastatization with limited treatment options and poor prognosis. The approval of ICIs has established a new standard of care for extensive-stage (ES)-SCLC (5). Atezolizumab, an anti PD-L1 monoclonal antibody, has been the first immune checkpoint inhibitor (ICI) to be approved for SCLC patients. This study aims to retrospectively evaluate the real-world effectiveness and safety of atezolizumab in a cohort of patients with ES-SCLC. Methods: We conducted a monocentric retrospective analysis of SCLC patients who received atezolizumab in addition to chemotherapy, between January 2020 and December 2023. Study design endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Results: A total of 134 patients were included in this study. Out of 134 patients who began the CEA protocol, 100 continued maintenance. Currently, 25 are alive, 17 still on atezolizumab, 5 on second-line therapy, and 3 receiving best supportive care. The median age was 65 years. Patients received a median of four cycles of CEA (range 1–6 cycles), while the median number of atezolizumab maintenance cycles was eight (range 0–75). The overall median survival was 15 months, with patients who received more than 30 cycles of atezolizumab showing OS of 46.7% at 48 months. Common adverse events included skin disorders, pneumonitis, colitis, alanine, and aspartate deaminase increment, dysthyroidism, and blood disorders with only 3% of patients experiencing grade 3 or higher toxicities. Conclusions: In this real-world cohort, atezolizumab demonstrated comparable effectiveness to clinical trial results, with a manageable safety profile. These findings support the use of atezolizumab as a viable treatment option for ES-SCLC in routine clinical practice. Full article

Background: Despite considerable advances to improve colorectal cancer (CRC) survival over the last decade, therapeutic challenges remain due to the rapid metastatic dissemination of primary tumors. This study revealed the apoptotic and anti-growth mechanism of VTD, a previously used anti-hypertensive supplement, can elevate UBXN2A, a known tumor suppressor protein in CRC, and simultaneously enhance intrinsic and extrinsic apoptosis in metastatic cancer cells. Methods and Results: An AOM/DSS mouse model of CRC showed that UBXN2A haplosufficient (UBXN2A +/−) mice treated with VTD had less tumor burden than mice with the full UBXN2A gene treated with vehicle. We have previously shown that casein-coated mesoporous silica nanoparticles (MSNs) offer an effective local delivery of drugs at tumor sites. Our findings demonstrate that the high rate of extracellular release of matrix metalloproteinases (MMPs), particularly MMP-7, by metastatic colon cancer cells, triggers the release of VTD from casein-coated mesoporous MSNs. This shows the “Zip Code” mechanism for the local enrichment of VTD at the tumor sites. After in vitro drug release verification, two independent mouse experiments, a xenograft and a splenolepatic metastatic mouse model of CRC, were used to evaluate the therapeutic efficacy of VTD-loaded and casein-coated carboxylated mesoporous silica nanoparticles, MSN-COOH/VTD/CAS (VTD, 0.2 mg/kg). Animal experiments revealed that MSN-COOH/VTD/CAS (VTD, 0.2 mg/kg) slows down the progress of tumors. Mass spectrometry (MS) revealed improved pharmacokinetics (PK) profile as MSN-COOH/VTD/CAS had less VTD accumulation in non-cancerous organs compared to pure VTD. We further improved nanoparticle targeting and drug release by shifting to calcium-based particles (CBPs). The engineered CBPs demonstrated higher drug-releasing performance. Without the MMPs trigger, MSNs show slow and continuous “drug leak” over longer period of time whereas CCSMPs stops leakage within an hour. Additionally, CBPs showed higher sensitivity to MMP-7 than MMP-9, enhancing the targetability of CBPs for CRC metastatic tumors with excessive extracellular MMP-7. Conclusions: This study introduces a new platform utilizing nanoparticle-based site-specific delivery of a plant-based anti-metastatic molecule, veratridine, with enhanced safety and therapeutic efficacy for the treatment of metastatic CRC. Full article

Background: Immune checkpoint inhibitors (ICIs) are effective against various advanced and metastatic cancers, but patient responses vary and can change over time, complicating treatment prediction. Therefore, better tools for patient stratification, response prediction, and response assessment are needed. This study presents the development and clinical translation of a fluorescently labelled ICI tracer pair used to perform multispectral fluorescent molecular imaging and simultaneously gain spatial and temporal insight in both programmed death ligand 1 (PD-L1) and programmed death receptor 1 (PD-1) expression. Methods: We conjugated the anti-PD-L1 antibody durvalumab to IRDye 680LT and the anti-PD-1 antibody nivolumab to IRDye 800CW. Tracers were developed and optimized for conjugation efficiency and purity to allow use in clinical trials. Stability was tested up to 12 months. An extended single-dose toxicity study in mice was performed for durvalumab-680LT and the unconjugated IRDye 680LT to demonstrate safety for first-in-human administration. Results: Durvalumab-680LT and nivolumab-800CW were successfully conjugated and purified. Conjugation optimization resulted in a robust production with labelling efficiencies of ≥88%. Long-term stability study of both tracers showed all parameters within end of shelf-life specifications for at least 12 months at 2–8 °C. No toxic effects were observed in doses up to 1000x the intended human dose for both IRDye 680LT and durvalumab-680LT, which are therefore considered safe for first-in-human use. Conclusions: We succeeded in the development and clinical translation of two novel fluorescent ICI tracers, durvalumab-680LT and nivolumab-800CW. Moreover, we demonstrated for the first time the safety of IRDye 680LT and durvalumab-680LT, enabling first-in-human use. Together, this makes durvalumab-680LT and nivolumab-800CW suitable for phase I/II clinical trials. Full article

Importance: Understanding trends in the use of hormonal therapy (HT) for prostate cancer (PCa) is crucial to optimize treatment strategies, particularly for older men with locally advanced and metastatic disease. Objective: To evaluate changes in the patterns of adjuvant and primary HT use over time in older U.S. men diagnosed with locally advanced and metastatic prostate cancer. Design, Setting, and Participants: This cohort study utilized SEER-Medicare data, which covers approximately 48% of the U.S. population and links cancer registry data with Medicare claims, including 149,515 men aged ≥66 years diagnosed with PCa between 2010 and 2019. We analyzed trends in the use of adjuvant HT for higher-risk and primary HT for lower-risk PCa. Multivariable logistic regression models were used to adjust for clinical and demographic factors. Main Outcomes and Measures: The primary outcome was the proportion of men receiving any form of HT within 6 months of PCa diagnosis. HT included injectable Gonadotropin-releasing hormone (GnRH) agonists and antagonists, orchiectomy, and anti-androgens agents. Results: The rate of adjuvant HT in higher-risk PCa patients increased significantly from 53.6% in 2010 to 68.1% in 2019 (p < 0.0001), with a steady rise in the last four years. In contrast, the rate of men with lower-risk disease receiving primary HT declined from 25% in 2010 to 16.9% in 2013, then peaked at 28.2% in 2015, and stabilized between 25% and 27.3% from 2017 to 2019. The overall HT usage increased from 33.5% in 2010 to 45.2% in 2019, showing a consistent increase over the years. These patterns persisted after adjusting for clinical and demographic factors. Conclusions and Relevance: The increasing use of adjuvant HT in higher-risk PCa patients aligns with evolving treatment guidelines, while the stable rate of primary HT in lower-risk patients represents persistent inappropriate use and highlights the need for further efforts to optimize treatment choices. While previous studies focused on men with intermediate-risk PCa receiving radiation therapy, our study broadens the scope to include men who did not undergo radiation therapy, providing a more inclusive view of HT trends. Future research should focus on refining strategies to reduce inappropriate primary HT use and improve adjuvant HT administration. Full article

Survival rates for those with metastatic osteosarcoma (OS) have not improved over the last four decades. It is imperative that novel approaches to treating and curing OS be sought. We, therefore, turned our attention to Brusatol (Bru), a naturally occurring Nrf2 inhibitor reported to elicit anti-cancer effects in a multitude of tumour models. Importantly there is emerging evidence that Nrf2 is implicated in chemoradiotherapy resistance in OS and that inhibiting Nrf2 may represent a desirable route to treating OS. Surprisingly, using the human OS cell line, MG63, we actually found that Bru promoted cell growth. Compared to control, normoxic cultures, the application of Bru (50 nM) over 3 days led to an increase in cell number by approximately 1.7-fold. A similar outcome occurred for cells under hypoxic conditions, although the extent of cell growth was significantly less at around 1.3-fold. Furthermore, Bru prevented MG63 differentiation in response to co-treatment with the calcitriol analogue, EB1089, and the lipid growth factor, lysophosphatidic acid. The extent of inhibition was profound at approximately 2.8-fold. The application of the Nrf2 activator, dimethyl fumarate, did not rescue these phenotypes. Whilst Bru has shown promise in other cancer models, it would appear, from our findings, that this agent may not be suitable for the treatment of OS. Full article

Elevated cholesterol levels play important mitogenic roles. Pseurotin A (PsA) is a fermentation product that has recently been reported as a dual inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) secretion and protein-protein interaction (PPI) with the LDLR. PsA showed a high acute safety profile and therapeutic potential against metastatic castration-resistant prostate cancer (mCRPC). The study aims to uncover the chronic safety, distribution, and anti-mCRPC genomic and molecular mechanistic insights of PsA. A 90-day chronic safety assessment of PsA up to 80 mg/kg in Swiss albino mice showed no signs of hematological, biochemical, or major organ toxicity. PsA demonstrated rapid intravenous distribution and elimination in Swiss albino mice. PsA is biodistributed to multiple key organs but was not detected in the brain, indicating its inability to cross the blood-brain barrier. PsA effectively suppressed the recurrence of nude mice xenografted mCRPC, which was subjected to a neoadjuvant docetaxel and enzalutamide regimen, followed by surgical excision. Collected PsA and vehicle control-treated recurrent tumors were subjected to RNA-sequencing and pathway enrichment analysis (PEA) of differentially expressed genes (DEGs). PsA-treated tumors revealed multiple significantly enriched pathways associated with promoting tumor apoptosis and inhibiting both invasion and migration. The PPI network analyses for the downregulated DEGs displayed prominent networks of genes associated with the ubiquitin-proteasome system. Results provide comprehensive mechanistic and preclinical validations for PsA’s potential as a novel PC recurrence suppressive lead entity. Full article

Peritoneal carcinomatosis (PC) and malignant pleural effusions (MPE) are two common complications of cancers metastatic to the respective body cavities. A PC diagnosis indicates metastasis to the tissue lining the abdominal cavity and is most common in patients with gastrointestinal and gynecological cancers. It is often accompanied by ascites, an accumulation of serous fluid in the abdomen. MPE presents as the accumulation of fluid in the space between the lungs and chest wall. It is a common terminal event in patients diagnosed with breast cancer, lung cancer, lymphoma, and mesothelial cancers, and less commonly, in a wide variety of other epithelial cancers. Due to the aggressive nature of cavitary tumors, the outcome of current treatments for both PC and MPE remains bleak. Although PC and MPE are characteristically affected by different sets of primary tumors (lung/breast/mesothelioma for MPE and gynecologic/gastrointestinal for PC), their environments share common cytokines and cellular components. Owing to the unique cytokine and chemokine content, this environment promotes aggressive tumor behavior and paradoxically both recruits and suppresses central memory and effector memory T cells. The cellular and secretomic complexity of the cavitary tumor environment renders most currently available therapeutics ineffective but also invites approaches that leverage the robust T-cell infiltrate while addressing the causes of local suppression of anti-tumor immunity. Interactions between the heterogeneous components of the tumor environment are an area of active research. We highlight the roles of the immune cell infiltrate, stromal cells, and tumor cells, and the soluble products that they secrete into their environment. A more comprehensive understanding of the cavitary tumor environment can be expected to lead to better immunotherapeutic approaches to these devastating conditions. Full article

Background/Objectives: The combination of anti-programmed death-1 (PD-1) inhibitors and chemotherapy is the standard first-line treatment for unresectable or metastatic esophageal squamous cell carcinoma (ESCC). However, real-world data remain limited, particularly regarding prognostic biomarkers. Methods: This multi-institutional retrospective study analyzed patients with metastatic or unresectable ESCC who received first-line pembrolizumab or nivolumab plus fluoropyrimidine and platinum-based chemotherapy. Treatment regimens mirrored those in KEYNOTE-590 and CheckMate 648. Efficacy, safety, and prognostic factors were assessed. Prognostic factors were identified using multivariable Cox regression, and a point-based risk scoring system was developed. Results: Among 87 patients, the objective response rate was 48.3%, and the disease control rate was 77.0%. Median progression-free survival (PFS) was 5.6 months (95% CI, 4.5–8.7), and the median overall survival (OS) was 13.1 months (95% CI, 10.6–not reached). Grade 3–4 treatment-related adverse events occurred in 51.7% of patients. Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2, elevated C-reactive protein, and lower programmed death-ligand 1 (PD-L1) combined positive score (CPS) were independently associated with worse PFS and OS. A prognostic risk score ranging from 0 to 5 based on these factors stratified patients into four prognostic groups with distinct survival outcomes. Median PFS ranged from not reached in the low-risk group to 2.1 months in the high-risk group. Stratifying PD-L1 CPS into three levels (<10, 10–49, ≥50) revealed a graded association between CPS and treatment outcomes, supporting the need for more nuanced PD-L1 evaluation beyond binary classification. Conclusions: First-line anti-PD-1 therapy combined with chemotherapy demonstrated favorable real-world outcomes in ESCC. The proposed prognostic scoring system may help personalize treatment strategies. Full article

Background: Tumor-associated microbiota are implicated in colorectal cancer (CRC). Formalin-fixed paraffin-embedded (FFPE) tumor tissue is widely available yet seldom profiled for microbiota. We tested whether quantitative and presence/absence signals of selected taxa in FFPE tumors associate with clinicopathological features. Methods: DNA from FFPE primary CRCs (n = 52) was assayed by a targeted PCR panel quantifying 30 bacterial taxa, Candida spp., and total bacterial load. Presence/absence combinations were selected by the Apriori algorithm with Fisher’s exact testing and 10,000-permutation empirical p-values. Quantitative features were modeled by LASSO logistic regression; discrimination of single taxa and combinations was evaluated by ROC/AUC. Results: In relative-abundance analyses, Fusobacterium nucleatum showed pro-metastatic value (AUC = 0.622). The best absolute-abundance model for metastasis combined F. nucleatum, Faecalibacterium prausnitzii, total bacterial load, and Akkermansia muciniphila (AUC = 0.739). Anti-metastatic directionality in relative-abundance models was driven by Acinetobacter spp.; the two-taxon set Eubacterium rectale + Acinetobacter spp. achieved AUC = 0.747. Conclusions: PCR-based profiling of FFPE CRC tumors is feasible and reveals hypothesis-generating patterns. Signals linking F. nucleatum to metastatic CRC and Acinetobacter spp. to non-metastatic disease merit validation in larger cohorts; tumor-tissue microbiome features may complement clinicopathological assessment. Full article

The red seaweed Jania rubens (J. rubens) is prevalent along the Lebanese coast and has drawn attention for its notable antineoplastic properties. Our previous data showed that its dichloromethane–methanol (DM) extract possesses antioxidant, cytotoxic, and anti-migratory effects on colon cancer cells. In the present study, a GC-MS analysis of DM extract identified a diverse profile of bioactive compounds, including flavonoids and pyrazole derivatives with antioxidant and anticancer activities. In vitro assays demonstrated that the DM extract exerts significant cytotoxic activity against various cancer cell lines, including colon, breast, and cervical types. Further investigation into the underlying molecular mechanisms revealed that the extract induces G2/M cell cycle arrest and reduces the expression of EMT (epithelial–mesenchymal transition) markers, N-cadherin and Twist. In addition, the extract showed anti-metastatic properties through its ability to decrease MMP-2 and MMP-9 activity. Mechanistically, DM caused a substantial reduction in Ten-Eleven Translocation (TET) enzymes TET-1, TET-2, and TET-3, which are essential DNA demethylation regulators, thus decreasing their enzymatic product 5-hydroxymethylcytosine (5-hmC). Interestingly, despite a significant increase in intracellular ROS (reactive oxygen species), suggesting a contribution to cytotoxicity, no substantial change in the biogenesis of promyelocytic leukemia nuclear bodies (PML-NBs) was detected. These findings demonstrate that J. rubens DM extract contains bioactive compounds with multiple anticancer effects, thus making it a promising candidate for developing new therapeutic agents. Full article

Background/Objectives: In spite of substantial treatment progress, cancer persists as a leading health challenge. With the slow advancement in developing new anticancer agents, drug repurposing provides a promising strategy to enhance cancer therapy. This study investigates the antiproliferative and antimetastatic properties of two 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, atorvastatin and rosuvastatin, which represent lipophilic and hydrophilic statins, respectively. Methods: Growth inhibition was evaluated in a panel of human cancer cells using the standard MTT assay. Apoptotic effects were determined through flow cytometry, caspase-3 activity assay, mitochondrial membrane potential assessment, and Hoechst/Propidium iodide fluorescent double staining. Migration and invasion assays were conducted using wound-healing and Boyden chamber assays, respectively. Results: Atorvastatin demonstrated more pronounced growth-inhibitory effects than rosuvastatin, with the IC₅₀ values in the range of 2.57–61.01 µM. Atorvastatin exhibited both biochemical and morphological indicators of apoptosis. Flow cytometry revealed cell cycle disruptions and increased sub-G1 apoptotic populations in HPV-positive oral squamous carcinoma cells (UPCI-SCC-154) and HPV-negative cervical cancer cells (C33A). Atorvastatin also significantly inhibited cell migration and invasion in the tested cell lines. Conclusions: Our results highlight the promising anticancer potential of atorvastatin in cervical cancer and oral squamous carcinoma cells. However, these findings are limited to in vitro models and warrant further in vivo validation. Full article

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and the lung is one of the most frequent metastatic sites for HCC. In this study, we aimed to identify a mild active substance in Morus alba L. that can inhibit the pulmonary metastasis of HCC and reduce the drug resistance of clinical therapies. Further deepen the understanding of the anti-cancer functions of the mulberry active substances. In this study, we have screened and identified a flavonoid compound extracted from the root bark of the Morus alba L. named Kuwanon A (KA). Our research demonstrated that KA directly targeted the YWHAB (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta) and mediated its dimer dissociation. Thereby inhibiting the MAPK pathway and affecting downstream biological functions, including cell cycle arrest and migration/invasion inhibition. The experiment results proved that KA could inhibit the proliferation and metastasis of highly metastatic HCC cells both in vitro and in vivo. Additionally, when KA was combined with the clinical drug sorafenib, it exhibited a synergistic effect in inhibiting HCC cell proliferation, migration, and invasion. In conclusion, KA demonstrated a favorable anti-tumor effect in HCC cells. Full article

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a key enzyme for the repair of stalled topoisomerase 1 (TOP1)-DNA complexes. Previously, we obtained HEK293A cells with homozygous knockout of the TDP1 gene by the CRISPR/Cas9 method and used them as a cell model to study the mechanisms of anticancer therapy and to investigate the effect of TDP1 gene knockout on gene expression changes in the human HEK293A cell line by transcriptome analysis. In this study, we investigated the effect of a TDP1 inhibitor ((R,E)-2-acetyl-6-(2-(2-(4-bromobenzyliden) hydrazinyl) thiazol-4-yl)-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d] furan-1(9bH)-one, OL9-119, an usnic acid derivative), capable of potentiating the antitumor effect of topotecan, as well as its combination with topotecan, on the transcriptome of wild-type and TDP1 knockout HEK293A cells. OL9-119 was found to be able to reduce cell motility by decreasing the expression of a number of genes, which may explain the antimetastatic effect of this compound. Differentially expressed genes (DEGs) related to electron transport, mitochondrial function, and protein folding were also identified under TDP1 inhibitor treatment. Full article

Neuroendocrine neoplasms (NENs) represent a small and heterogeneous group of tumors that share a common phenotype, originating from cells within the endocrine and nervous systems. Metallodrugs have had a significant impact on the treatment of NENs, as platinum-based chemotherapy is the first-line therapy approved for managing these types of tumors. Currently, medicinal inorganic chemistry is investigating new metal-based drugs to mitigate the side effects of existing agents, including cisplatin and its derivative compounds. Among the emerging alternatives to platinum-based drugs, ruthenium-based complexes garnered attention as potential chemotherapeutics due to their notable antineoplastic and antimetastatic activity. This review focuses on the promising antitumor effects of certain Ru compounds in NEN therapy, emphasizing their potential in NEN treatment through interaction with new potential targets. Among these, IT-139 (also known as KP-1339 or NKP-1339), which has already entered clinical trials, and other new Ru compounds are highlighted. Full article