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AXL, a member of the TAM receptor family, has emerged as a potential target for advanced-stage human malignancies. It is frequently overexpressed in different cancers and plays a significant role in various tumor-promoting pathways, including cancer cell proliferation, invasion, metastasis, epithelial–mesenchymal transition (EMT), angiogenesis, stemness, DNA damage response, acquired therapeutic resistance, immunosuppression, and inflammatory responses. Beyond oncology, AXL also facilitates viral infections, including SARS-CoV-2 and Zika highlighting its importance in both cancer and virology. In preclinical models, small-molecule kinase inhibitors targeting AXL have shown promising anti-tumorigenic potential. This review primarily focuses on the induction, regulation and biological functions of AXL in mediating these tumor-promoting pathways. We discuss a range of therapeutic strategies, including recently developed small-molecule tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and antibody–drug conjugates (ADCs), anti-AXL-CAR, and combination therapies. These interventions are being examined in both preclinical and clinical studies, offering the potential for improved drug sensitivity and therapeutic efficacy. We further discuss the mechanisms of acquired therapeutic resistance, particularly the crosstalk between AXL and other critical receptor tyrosine kinases (RTKs) such as c-MET, EGFR, HER2/HER3, VEGFR, PDGFR, and FLT3. Finally, we highlight key research areas that require further exploration to enhance AXL-mediated therapeutic approaches for improved clinical outcomes.

Hypertension (HTN) is a major health concern that leads to cardiovascular disease and premature death. Assessing HTN knowledge, attitude, and practice (KAP) is crucial for controlling HTN. This study aimed to determine HTN KAP among hypertensive patients residing in Lebanon. This cross-sectional study involved 342 hypertensive patients. A questionnaire form was used to collect data related to patients' characteristics. SPSS was used to determine KAP scores, descriptive statistics, and correlations. Data from HTN patients was analyzed of whom 98.2% were Lebanese and 51.2% were males. The median age was 59.15 ± 13.55 years old. A proportion of 40.4% had HTN duration for at least 10 years and 67.3% had HTN family history. Patients had fair HTN knowledge and practice, but good attitude toward HTN. Only 45.3% regularly checked their blood pressure. Positive correlations were observed between HTN attitude and each of knowledge and practice. HTN knowledge and attitude were associated with many studied factors, whereas no relationship was found regarding practice. Hypertensive patients had fair levels of knowledge and practice, and a good level of attitude concerning their disease. We provided a model for predictors of HTN KAP scores that will allow the development of efficient campaigns related to HTN.

Background & Objective: Cardiovascular diseases (CVD) are the leading cause of death globally. Assessing CVD knowledge, attitude, and practice (KAP) is necessary to spread awareness about CVD in Lebanon, their corresponding risk factors, and behaviors in which individuals can avoid or minimize the possibility of developing a CVD.Subjects & Methods:This was a case-control alytical study that targeted 921 CVD and non-CVD subjects. A questionire form was used to collect data related to patients’ demographics, socioeconomic status, habits, medical and family history, KAP towards CVD, and source of information. Data was alyzed using SPSS v.25.Results: Data from 921 participants were distributed over the CVD group (52.6% males aged 58.3 ± 13.7 years [n = 460]) and the non-CVD group (47.7% males aged 36.3 ± 15.4 years [n = 461]). CVD patients were significantly older than non-CVD subjects (p < 0.001). All three KAP scores of both groups were of poor to fair levels. Both CVD knowledge and attitude mean scores in CVD patients (26.6 ± 5.2 over 40 [66.50%] and 63.3 ± 10.2 over 85 [74.47%], respectively) were significantly higher than the ones of non-CVD subjects (23.5 ± 7.9 over 40 [58.75%] and 61.4 ± 12.4 over 85 [72.74%], respectively, p < 0.001). However, the CVD mean practice score was significantly lower in CVD patients (6.0 ± 1.7 over 9 [66.67%]) than the one of non-CVD subjects (6.3 ± 2.2 over 9 [70.00%] p < 0.001). Mostly, educatiol level (p < 0.001), governorate (p < 0.01), and smoking (p < 0.001) were predictors of KAP CVD in both groups.Conclusion:With an overall limited knowledge, attitude, and practice toward CVDs, the Lebanese population (with CVD or non-CVD) needs targeted tiol campaigns about CVD according to the identified predictors of CVD KAP to prevent and to alleviate the complications due to CVDs.

Epigenetic dysregulation, including accumulation of Histone H3 lysine 27 acetylation (H3K27ac), is a hallmark of pVHL-deficient clear cell Renal Cell Carcinomas (ccRCCs). Using an in vivo positive selection ORF screen in poorly tumorigenic pVHL-proficient cells and mechanistic studies in pVHL-deficient cells, we discovered that the aspartate (Asp) and glutamate (Glu) transporter, SLC1A1/EAAT3, is a metabolic dependency in ccRCC. pVHL loss promotes Hypoxia Inducible Factor (HIF)-independent SLC1A1 expression via H3K27ac dysregulation. SLC1A1 inactivation, genetically or pharmacologically, depletes Asp/Glu-derived metabolites (e.g., Tricarboxylic acid cycle and nucleotide intermediates), impedes ccRCC growth, and sensitizes ccRCCs to anti-metabolite drugs (e.g., glutaminase blockers). In human tumors, higher SLC1A1 expression is associated with reduced immune infiltration, oncogenic metabolic programs, and advanced stage/metastatic disease. Finally, in ccRCC animal models, SLC1A1 inactivation diminishes lung metastasis and the outgrowth of established renal tumors. Altogether, our studies credential SLC1A1 as an actionable, HIF-independent, metabolic dependency in pVHL-deficient ccRCCs. Clear cell renal cell carcinoma (ccRCC) bears the hallmark loss of VHL but remains incurable. Here, the authors identify the SLC1A1 dicarboxylic amino acid transporter as an actionable, oncogenic, HIF-independent, metabolic dependency in VHL-deficient ccRCCs.

Background The Arab region comprises 22 countries located in the Middle East and North Africa, sharing cultural and linguistic ties. Arab countries have continued to lag in terms of biomedical research compared to other nations for several past decades. Cancer is a major public health concern, being the second leading cause of death globally. Given that high research activity on cancer reflects positively on screening programs, awareness, and clinical practice, this article aimed to examine the activity and trend of cancer research in the Arab world between 2005 and 2019. Methods Between 2005 and 2019, the number of cancer-related articles published by each Arab country, and regarding 27 different types, was assessed using the PubMed database. Numbers were normalized with respect to each country’s average population and average Gross Domestic Product (GDP). Results Arab countries contributed to 1.52% of total cancer publications. The number of cancer publications has steadily grown since 2005, with the last 7 years alone witnessing 75.69% of the total Arab cancer-related publications. In terms of publications per million persons, Qatar ranked first (393.74 per million persons), while in terms of publications per national GDP, Egypt ranked first (464.27 per billion US dollars). Breast, liver, and colorectal cancers had the highest numbers of all Arab cancer-related publications, while testicular, vulvar, and gallbladder cancers had the least. Conclusions This paper pools information and insight for scientists, clinicians, funders, and decision-makers on the actualities and developments of cancer research in the Arab world. Addressing the barriers facing cancer research remains a cornerstone in the plan to improve the Arab world’s output and contribution to the field of oncology.

Background Telomerase reverse transcriptase (TERT) gene promoter mutations have been explored, as biomarkers of improved survival for patients with cancer receiving immune checkpoint inhibitors. We sought to investigate their prevalence by race and sex across different cancer types to inform patient selection in clinical trials. Results In this observational study, 31 925 patients with cancer underwent next-generation sequencing of their tumors with 88% (27 970) patients self-reported being Whites, 7.1% (2273) Asians, and 5.3% (1682) Blacks. Examining the distribution of TERT promoter mutations by race, White patients with melanoma harbored more TERT promoter mutations than Asian and Black patients (OR = 25.83; 95%CI, 6.84-217.42; P < .001). In contrast, Asian patients with head and neck cancer (HNC) harbored more TERT promoter mutations compared to White patients (OR = 2.47; 95%CI, 1.39-4.37; P = .004). In addition, the distribution of TERT promoter mutations differed by sex. Males were enriched for TERT gene promoter mutations compared to females with melanoma (OR = 1.82; 95%CI, 1.53-2.16; P < .001), cancer of unknown primary (OR = 1.96; 95%CI, 1.43-2.69; P < .001), hepatobiliary (OR = 3.89; 95%CI, 2.65-5.69; P < .001), and thyroid cancers (OR = 1.42; 95%CI, 1.10-1.84; P = .0087), while females were more enriched for TERT promoter mutations compared to males for HNC (OR = 0.56; 95%CI, 0.39-0.81; P = .0021). Conclusions The prevalence of TERT gene promoter mutations varies among patients with cancer based on race and sex. These findings inform our understanding of cancer biology and can assist in the design of future clinical trials that leverage drugs targeting TERT promoter dependencies. TERT gene promoter mutations have been explored as biomarkers of improved survival for patients with cancer receiving immune checkpoint inhibitors. This article reports their prevalence by race and sex across different cancer types to inform patient selection in clinical trials.

This commentary focuses on the article by Correa et al on the association of circulating tumor DNA with patient prognosis in renal cell carcinoma.

Abstract Background Immunotherapy combinations have emerged as the standard of care for patients with advanced renal cell carcinoma (RCC). While the combination of first-line (1 L) nivolumab and ipilimumab has demonstrated long-term durability with 90-month progression-free survival (PFS) of 23%, primary progressive disease (PD) occurs in up to 20% of patients. There is an urgent clinical need to identify negative selection markers for patients unlikely to respond to nivolumab-ipilimumab therapy. Methods We used Tempus Lens to select records for 106 patients with RCC who received 1 L ipilimumab-nivolumab treatment from the Tempus multi-modal database. Eligible patients had tumor samples collected within one year of treatment initiation and were processed using xT (DNA-seq) and xR (RNA-seq) assays. Treatment response was investigator-assessed within 90 days of therapy start and categorized as progressive disease (PD) versus non-PD, which includes stable disease, partial response, or complete response. RNA-seq data were normalized, log2-transformed, and batch-corrected and used to measure checkpoint and angiogenic gene expression (Transcripts per million, TPM). Immunologic phenotype was assessed by TMB (mt/Mb), MSI status, PD-L1 (IHC, 22c3); immune infiltration was estimated by quanTIseq (RNA). Results Of the 106 patients, 55 experienced PD as the best response. The cohort was predominantly male (73%) and white (86%), with a median age at diagnosis of 59 years. Clinical characteristics were similar between treatment response categories, including rates of clear cell RCC (82% vs. 76%, P = .480) and primary nephrectomy (47% vs. 53%, P = .560). Patients with primary PD were more likely to have liver metastases (20% vs. 5.9%, P = .032). There was no significant difference in PD-L1 (IHC) expression between groups (P = .542). However, patients with primary PD exhibited significantly lower gene expression of CTLA4, TIGIT, and PD-1 as well as lower proportions of immune cells (Table 1). We observed a trend toward lower LAG3 expression and TMB in the PD group. Strong positive correlations were demonstrated between LAG3 expression and other checkpoint genes (all P < .002). No significant differences were found in angiogenic gene expression or somatic tumor alterations between response groups. Conclusions In patients with advanced RCC treated with 1 L nivolumab-ipilimumab, we identified distinct transcriptomic patterns of primary resistance characterized by lower expression of immune checkpoint genes. These findings suggest that tumors with reduced checkpoint pathway activity may be less responsive to dual checkpoint inhibition, possibly reflecting an immune-cold microenvironment with limited T-cell infiltration and activation. Future prospective validation of these findings, including IHC, could inform precision medicine strategies for patients with advanced RCC.

Abstract Background ccRCC is frequently driven by VHL loss, leading to HIF-2α stabilization and upregulation of downstream targets such as carbonic anhydrase 9 (CA9). While CA9 is a well-established diagnostic marker of HIF pathway activation, its prognostic and predictive roles remain unclear. Emerging evidence suggests that high CA9 and HIF-2α expression may be associated with improved outcomes in ccRCC. With the recent approval of the HIF-2α inhibitor belzutifan, understanding whether these markers predict treatment response is critical for guiding biomarker-driven therapy. Methods Next-generation sequencing of DNA (592-gene panel or whole exome) and RNA (whole transcriptome) were performed on ccRCC specimens through Caris Life Sciences to comprehensively characterize genomic and transcriptomic alterations. Expression levels of CA9 and HIF-2α were quantified based on RNA transcripts per million (TPM) and categorized as High or Low using the >75th vs < 25th percentile cutoff. Overall survival (OS) was defined as the time from initial diagnosis to death or last known follow-up. Time on treatment (TOT) was defined as the duration from the start of systemic therapy to treatment discontinuation. Results A total of 764 ccRCC specimens were analyzed. Of these, 433 (56.7%) were derived from primary kidney tumors, while the remaining samples were from metastatic sites, including lung (n = 71, 9.3%), bone (n = 70, 9.2%), endocrine (n = 43, 5.6%), liver (n = 23, 3%), lymph node (n = 23, 3%), CNS (n = 19, 2.5%), GI (n = 4, 0.5%) and other sites (n = 78, 10.2%). VHL alterations occurred in 82% (626/764) ccRCC tumors. The median age was 63. CA9 and HIF-2α expression levels were relatively higher in primary kidney tumors compared to metastatic sites. Expression levels of CA9 and HIF-2α were comparable across racial and ethnic subgroups. High CA9 expression (Q4 vs Q1) was associated with improved OS (mOS: 95 vs 42 months; HR 0.55, P = .005). Similarly, high HIF-2α expression (Q4 vs Q1) correlated with longer survival (mOS: 54.8 vs 38.3 months; HR 0.56, P < .001). Among belzutifan-treated patients (n = 80), CA9 expression was not associated with OS (mOS: NE vs 17.3, p : 0.851) or TOT of belzutifan (mTOT: 3.49 vs 2.34, p: 0.175). HIF-2α expression was not associated with OS (mOS: 16.2 vs 13.4, p : 0.89) or TOT of belzutifan among VHL mutant patients (2.96 vs 2.96; p: 0.91). There were limited VHL wild-type ccRCC patients (n = 9) treated with belzutifan in our cohort. Conclusions This comprehensive analysis of 764 ccRCC specimens demonstrates that VHL alterations are present in the majority of ccRCC tumors. CA9 and HIF-2α expression were consistent across racial and ethnic groups but showed higher expression in primary tumors compared to metastatic sites. High expression of both CA9 and HIF-2α were associated with significantly improved overall survival in the general ccRCC population. However, neither CA9 nor HIF-2α expression levels predicted response to belzutifan therapy. These findings enhance our understanding of HIF pathway biology in ccRCC and provide important context for the potential clinical application of CA9 PET imaging and HIF-2α inhibitor therapy in diverse patient populations.

Abstract Background c-Met, a receptor tyrosine kinase (RTK), is overexpressed in renal cell carcinoma (RCC) and correlates with a decreased survival rate. Upon binding to its specific ligand, Hepatocyte Growth Factor (HGF), c-Met activates pro-tumorigenic signaling pathways. Cabozantinib (Cabo) inhibits c-Met and a few other RTKs, including AXL, and is approved for the treatment of patients with advanced-stage RCC. AXL and its ligand, GAS6, are overexpressed in RCC and are also markers of poor prognosis. The pro-tumorigenic role of AXL and its potential crosstalk with c-Met in renal cancer need to be thoroughly investigated. Methods We generated a Cabo-resistant (CaboR) cell line from wild-type Cabo-sensitive (CaboS) Caki-1 clear-cell RCC cells, and CRISPR/Cas9-mediated AXL knock-out cells (AXL-KO) from 786-O clear-cell RCC cells. Chromatin immunoprecipitation and sequencing (ChIP-seq) was performed to profile H3K27ac, a histone post-translational modification associated with active promoters and enhancers, in CaboR and CaboS cell lines. We also performed RNA sequencing (RNA-seq) on CaboR and CaboS and evaluated differentially expressed genes and enriched pathways using gene set enrichment analysis (GSEA). Transcriptional profiles of control clones and AXL-KO cells were also compared to identify the effect of AXL-KO on pro-tumorigenic signaling. We utilized an AXL-specific small molecule inhibitor, TP-0903, in combination with Cabo to validate our data. Finally, we studied how AXL silencing or inhibition may affect resistance to Cabo. Results Our findings revealed that AXL forms a complex with c-Met and may have a significant crosstalk which can be involved in therapeutic resistance. We found that prolonged treatment with c-Met inhibitors Cabo, Crizotinib, and PF-4217903, induced c-Met and AXL overexpression in RCC cells. Interestingly, c-Met inhibitor(s)-induced overexpressed c-Met can also be increasingly phosphorylated (at low concentrations) in the presence of HGF, which may cause enhanced downstream tumor-promoting signaling. We found that silencing AXL can prevent this c-Met-inhibitors-mediated c-Met overexpression. Moreover, we found marked activation of the promoters and enhancers of several transcription factors, including ETV1, HOXA9, and FOXK1, in CaboR cells compared to CaboS cells. In the CaboR cells, genes involved in oxidative phosphorylation, progression through the division cycle, DNA replication, the NRF2 pathway, and DNA repair were upregulated, whereas genes associated with glycolysis, angiogenesis, hypoxia, and the Met pathway were downregulated (Figure 1). Finally, silencing AXL (using siRNA) or inhibiting AXL (using TP0903) in CaboR cells, induced significant apoptosis. Conclusions Together, our data suggest that CaboR cells have a distinct epigenomic and transcriptomic profile, and that targeting AXL along with c-Met inhibition can be beneficial in preventing acquired therapeutic resistance in RCC.