Yanis Boumber

Introduction. Histone methyltransferase NSD1 is often inactivated in head and neck squamous cell carcinoma. Loss of NSD1 is associated with improved prognosis in HPV (human papilloma virus) negative cancer. However, data on the signaling pathways regulated by NSD1 are limited. Aim. Validation and systemic assessment of reproducibility of the NSD1-Akt/mTORC1 axis based on integrative analysis of open transcriptomic and proteomic data from cell lines and samples of head and neck squamous cell carcinoma. Materials and methods. Systemic analysis was performed of the connection between NSD1 and Akt/mTORC1 signaling pathway using open transcriptomic and proteomic data (panel of squamous cell carcinoma cell lines on the DepMap portal and clinical cohorts from the The Cancer Genome Atlas (TCGA)). Pathway activity was evaluated using ssGSEA/GSEA (single-sample Gene Set Enrichment Analysis), proteomic activity – using protein expression data obtained with Reverse Phase Protein Array (RPPA), statistical significance – using standard correlation and nonparametric tests. Results. In the cell line panel, elevated NSD1 expression correlated with stronger PI3K/AKT/mTOR transcription signature and increased phosphorylation of the key pathway components according to RPPA data. Similar correlation was observed in patient tumor samples. Data on isogenic cell lines with NSD1 knockout demonstrated decreased expression of mTORC1 target genes. Conclusion. Reproducible correlation between NSD1 level and Akt/mTORC1 signaling pathway activity in head and neck cancer was established. However, additional confirmation of the NSD1 role in regulation of the Akt/mTORC1 pathways requires in vitro and in vivo investigation of expression and phosphorylation of protein components of this cascade, as well as functional experiments to evaluate proliferation, survival and drug sensitivity of head and neck cancer cells. Clinical significance of the established correlation in the context of disease progression requires further verification.

In this review, we describe the concept of the glymphatic system as a glial-dependent clearance pathway in the brain. The hypothesis of the glymphatic system function suggests that dural lymphatic vessels absorb the cerebrospinal fluid and brain interstitial fluid via the glymphatic system and transport fluid into deep cervical lymph nodes. We present the accumulated data of various studies confirming the possible interconnection among the brain interstitial fluid, cerebrospinal fluid, and the glymphatic system. Anatomical features are discussed here together with a possible variety of glymphatic system functions, including the removal of waste products, transport of substances, and immune function. The glymphatic system is hypothesized to be involved in pathogenesis of many diseases, including Alzheimer's disease, stroke, and Parkinson’s disease. We also discuss the role of the glymphatic system in pathophysiology and the complications of brain tumors. Meningeal lymphatics is thoroughly analyzed as well. Finally, we propose new treatment approaches to brain tumors, Parkinson’s disease, and stroke using cervical lymph nodes and backward fluid flow in the meningeal lymphatic vessels.

Lung cancer remains the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of all lung cancers, is a biologically diverse disease characterized by a wide range of molecular alterations. Among these, HER2 (human epidermal growth factor receptor 2, or Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2)), a gene more commonly associated with breast cancer, has emerged as an important oncogenic driver in NSCLC, particularly within the adenocarcinoma subtype. HER2 alterations are notably more prevalent among non-smokers, with estimates suggesting that up to 50–80% of patients with HER2 mutations or amplifications have no smoking history. In our comprehensive review, we outline the molecular biology of HER2 in NSCLC, including distinctions between HER2 mutations, amplification, and overexpression, and we delve into the diverse diagnostic complexities. We also review NCCN guidelines and the performance of newer FDA-approved testing assays (such as Guardant360 and FoundationOne) in detecting HER2 alterations and circulating tumor DNA (ctDNA) as a tool for treatment response monitoring. Furthermore, we present updated clinical trial data for published HER2-targeted agents and explore ongoing clinical trials examining combinatorial therapies and next-generation HER2-targeted agents such as zongertinib, A166, ARX788, SHRA1811, and others. Given the rapid evolution in this field, our review offers a timely and comprehensive synthesis of the current state and future directions for HER2-altered NSCLC.

The acid-catalyzed reaction of benzo[e(g)] derivatives of 2,3,3-trimethylindolenines with o-chloranil leads to new 2-(benzo[e(g)]indolin-2-yl)-5,6,7-trichloro-1,3-tropolones and 2-(benzo[e(g)]indolin-2-yl)-4,5,6,7-tetrachloro-1,3-tropolones. Based on the results of PBE0/6-311+G(d,p) calculations, the structural and energetic characteristics of the tautomeric forms of the obtained 1,3-tropolones were determined. The structure of 2-(3,3-dimethyl-3H-benzo[g]indolin-2-yl)-5,6,7-trichloro-1,3-tropolone was determined by X-ray diffraction analysis. The compounds obtained are capable of switching emission at 420–440 nm and 476–530 nm upon successive exposure to CN⁻ and Hg²⁺ ions in an acetonitrile solution. 2-(1,1-Dimethyl-1H-benzo[e]indolin-2-yl)-5,6,7-trichloro-1,3-tropolone exhibited high in vitro cytotoxic activity against A431 skin cancer and H1299 lung cancer cell lines.

PURPOSE: Preclinical studies demonstrated that dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways delay the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs), and in trials with first-generation EGFR TKIs, the combination of EGFR VEGF pathway inhibitors prolonged progression-free survival (PFS). METHODS: The RAMOSE trial (ClinicalTrials.gov identifier: NCT03909334 , HCRN LUN-18-335) is a randomized, open-label multicenter phase II study comparing osimertinib with ramucirumab (arm A) to osimertinib (arm B) for initial treatment of metastatic EGFR -mutant non–small cell lung cancer (NSCLC) with 2:1 random assignment. The primary end point is PFS for evaluable patients; secondary end points include objective response rates (ORRs), disease control rate (DCR), overall survival, and safety. The stratification criteria were EGFR mutation type and the presence of CNS metastasis. RESULTS: At data cutoff on August 29, 2023, 160 patients consented, 147 patients received treatment, and 139 patients were evaluable with at least one scan. In this preplanned interim analysis, the median follow-up was 16.6 months. Among the evaluable patients, 57 PFS events occurred. The median PFS was 24.8 (A) versus 15.6 (B) months (hazard ratio, 0.55 [95% CI, 0.32 to 0.93]; log-rank P = .023), 12-month PFS rate was 76.7% (A) versus 61.9% (B; P = .026). No significant difference was observed in the ORRs and DCRs between arms. Any-grade (G) adverse events (AEs) occurred in 100% (A) and 98% (B) of patients, with no G5 treatment-related AE (TRAE), one G4 TRAE (hyponatremia, A), and 53% (A) versus 41% (B) G3 TRAEs. AE-related discontinuation occurred in 13 patients (9.7% in A and 8.7% in B). The safety profile was in line with known safety of each drug. CONCLUSION: Ramucirumab plus osimertinib significantly prolonged PFS compared with osimertinib alone in patients with TKI-naïve EGFR -mutant NSCLC. The combination is safe and well tolerated.

Lung cancer is one of the most common types of cancer worldwide. Non-small cell lung cancer (NSCLC), typically caused by KRAS and TP53 driver mutations, represents the majority of all new lung cancer diagnoses. Overexpression of the RNA-binding protein (RBP) Musashi-2 (MSI2) has been associated with NSCLC progression. To investigate the role of MSI2 in NSCLC development, we compared the tumorigenesis in mice with lung-specific Kras -activating mutation and Trp53 deletion, with and without Msi2 deletion (KPM2 versus KP mice). KPM2 mice showed decreased lung tumorigenesis in comparison with KP mice. In addition, KPM2 lung tumors showed evidence of decreased proliferation, but increased DNA damage, marked by increased levels of phH2AX (S139) and phCHK1 (S345), but decreased total and activated ATM. Using cell lines from KP and KPM2 tumors, and human NSCLC cell lines, we found that MSI2 directly binds ATM mRNA and regulates its translation. MSI2 depletion impaired DNA damage response (DDR) signaling and sensitized human and murine NSCLC cells to treatment with PARP inhibitors in vitro and in vivo. Taken together, we conclude that MSI2 supports NSCLC tumorigenesis, in part, by supporting repair of DNA damage by controlling expression of DDR proteins. These results suggest that targeting MSI2 may be a promising strategy for lung cancers treated with DNA-damaging agents.

Head and neck squamous cell carcinoma (HNSCC) ranks among the most prevalent global cancers. Despite advancements in treatments, the five-year survival rate remains at approximately 66%. The histone methyltransferase NSD1, known for its role in catalyzing histone H3 lysine 36 di-methylation (H3K36me²), emerges as a potential oncogenic factor in HNSCC. Our study, employing Reverse Phase Protein Array (RPPA) analysis and subsequent validation, reveals that PIP4K2B is a key downstream target of NSD1. Notably, PIP4K2B depletion in HNSCC induces downregulation of the mTOR pathway, resulting in diminished cell growth in vitro. Our investigation highlights a direct, positive regulatory role of NSD1 on PIP4K2B gene transcription through an H3K36me2-dependent mechanism. Importantly, the impact of PIP4K2B appears to be context-dependent, with overexpression rescuing cell growth in laryngeal HNSCC cells but not in tongue/hypopharynx cells. In conclusion, our findings implicate PIP4K2B as a novel NSD1-dependent protein in HNSCC, suggesting its potential significance for laryngeal cancer cell survival. This insight contributes to our understanding of the molecular landscape in HNSCC and establishes PIP4KB as a promising target for drug development.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Despite advances in therapeutic management and immunotherapy, the 5-year survival rate for head and neck cancer remains at ~66% of all diagnosed cases. A better definition of drivers of HPV-negative HNSCC that are targetable points of tumor vulnerability could lead to significant clinical advances. NSD1 is a histone methyltransferase that catalyzes histone H3 lysine 36 di-methylation (H3K36me ² ); mutations inactivating NSD1 have been linked to improved outcomes in HNSCC. In this study, we show that NSD1 induces H3K36me ² levels in HNSCC and that the depletion of NSD1 reduces HNSCC of cell growth in vitro and in vivo. We also find that NSD1 strongly promotes activation of the Akt/mTORC1 signaling pathway. NSD1 depletion in HNSCC induces an autophagic gene program activation, causes accumulation of the p62 and LC3B-II proteins, and decreases the autophagic signaling protein ULK1 at both protein and mRNA levels. Reflecting these signaling defects, the knockdown of NSD1 disrupts autophagic flux in HNSCC cells. Taken together, these data identify positive regulation of Akt/mTORC1 signaling and autophagy as novel NSD1 functions in HNSCC, suggesting that NSD1 may be of value as a therapeutic target in this cancer.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Despite advances in therapeutic management and immunotherapy, the five-year survival rate for head and neck cancer remains at ∼66% of all diagnosed cases. A better definition of drivers of HPV-negative HNSCC that are targetable points of tumor vulnerability could lead to significant clinical advances. NSD1 is a histone methyltransferase which catalyzes histone H3 lysine 36 di-methylation (H3K36me ² ); mutations inactivating NSD1 have been linked to improved outcomes in HNSCC. In this study, we show that NSD1 induces H3K36me ² levels in HNSCC, and that the depletion of NSD1 reduces HNSCC of cell growth in vitro and in vivo . We also find that NSD1 strongly promotes activation of the Akt/mTORC1 signaling pathway. NSD1 depletion in HNSCC induces an autophagic gene program activation, causes accumulation of the p62 and LC3B-II proteins, and decreases the autophagic signaling protein ULK1 at both protein and mRNA levels. Reflecting these signaling defects, knockdown of NSD1 disrupts autophagic flux in HNSCC cells. Taken together, these data identify positive regulation of Akt/mTORC1 signaling and autophagy as novel NSD1 functions in HNSCC, suggesting that NSD1 may be of value as a therapeutic target in this cancer.