Search Results (388)

Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), is a chronic, relapsing inflammatory condition that significantly impairs the patient’s quality of life. While biologics have transformed disease management, a substantial number of patients remain unresponsive or lose efficacy over time. Tofacitinib (TOFA), an oral Janus kinase (JAK) inhibitor, introduces a novel therapeutic class of small-molecule drugs with a unique oral administration route, offering enhanced patient convenience and broader accessibility compared to parenterally administered biologics. As the first oral treatment approved for moderate to severe UC in years, TOFA acts by modulating the JAK/STAT pathway, influencing critical inflammatory mediators such as IL-6, IL-17, and IFN-γ. However, response rates are variable and appear dose-dependent, with up to 60% of patients showing inadequate therapeutic outcomes. This review represents the first comprehensive synthesis focused specifically on biomarkers of TOFA response in UC. Drawing on multi-omics data—epigenomics, transcriptomics, proteomics, and cellular profiling, we highlight emerging predictors of responsiveness, including CpG methylation signatures (e.g., LRPAP1 and FGFR2), transcriptomic regulators (e.g., REG3A and CLDN3), immune and epithelial cell shifts, and the cationic transporter MATE1. TOFA demonstrates a dual mechanism by modulating immune responses while supporting epithelial barrier restoration. Despite being promising, TOFA’s dose-dependent efficacy and interpatient variability underscore the critical need for non-invasive, predictive biomarkers to guide personalized treatment. As the first review of its kind, this work establishes a basis for precision medicine approaches to optimize the clinical utility of TOFA in UC management. Full article

Gain-of-function gene alterations in rearranged during transfection (RET), a receptor tyrosine kinase, are observed in both sporadic and hereditary medullary thyroid cancers (MTCs) and pheochromocytomas and paragangliomas (PPGLs). Several tyrosine kinase inhibitors (TKIs) that target RET have been proven to be effective on MTCs and PCCs. Recently, TKIs, namely, sunitinib and selpercatinib, which were clinically used to target PPGLs, have been reported to decrease catecholamine levels without reducing tumor size. Our clinical case of metastatic medullary thyroid cancer, which is associated with RET mutations undergoing treatment with vandetanib, also suggests that vandetanib can decrease catecholamine levels. Therefore, we investigated the effect of vandetanib, a representative multi-targeted TKI for RET-related MTC, on cell proliferation and catecholamine synthesis in rat pheochromocytoma PC12 cells. Vandetanib reduced viable cells in a concentration-dependent manner. The dopamine and noradrenaline levels of the cell lysate were reduced in a concentration-dependent manner. They also decreased more prominently at lower concentrations of vandetanib compared to the inhibition of cell proliferation. The RNA knockdown study of Ret revealed that this inhibitory effect on catecholamine synthesis is mainly mediated by the suppression of RET signaling. Next, we focused on two signaling pathways downstream of RET, namely, ERK and AKT signaling. Treatment with vandetanib reduced both ERK and AKT phosphorylation in PC12 cells. Moreover, both an MEK inhibitor U0126 and a PI3K/AKT inhibitor LY294002 suppressed catecholamine synthesis without decreasing viable cells. This study in rat pheochromocytoma PC12 cells reveals the direct inhibitory effects of vandetanib on catecholamine synthesis via the suppression of RET-ERK and RET-AKT signaling. Full article

Background: Medullary thyroid carcinoma (MTC) has a high rate of local and distant metastases. In particular, the RET protooncogene appears to be the predominant driver mutation for oncogenesis. The German S3 thyroid carcinoma guidelines recommend molecular genetic analysis of the tumour without specifying the site of the tissue sampling. Whether there is difference in RET protooncogene between the primary tumour, lymph node, and distant metastasis has not yet been investigated. However, differences could be important with regard to biopsy localization, and also, thus, the choice of single- or multi-tyrosine-kinase-inhibitor therapy. Methods: In a case of sporadic MTC, Cancer Hotspot panel diagnostics were performed on the primary tumour, lymph node metastasis, and distant metastasis. Mutations were classified using different gene databases, and the different stages of metastasis were compared. Results: RET protooncogene (chr10:43609933, c.1886_1891delTGTGCG, p.Leu629_Asp631delinsHis) was found to be present in the MTC tissue of the primary tumour, lymph node, and distant metastasis in the Cancer Hotspot Panel diagnostic, while the other investigated therapy-relevant mutational profiles were not consistently found. Conclusions: Further longitudinal studies in larger patient cohorts are required to elucidate the role of the RET protooncogene in the metastatic progression of MTC and to determine its impact on the selection of biopsy sites and the subsequent decision-making regarding single- versus multi-tyrosine kinase inhibitor therapy. Full article

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) are pivotal regulators of the cell cycle, whose dysregulation is closely linked to cancer progression. While synthetic CDK4/6 inhibitors such as Palbociclib and Ribociclib are clinically effective, their use is limited by significant adverse effects. Methods: In this study, the aqueous root extract of Thottea siliquosa, a traditionally used medicinal plant, was evaluated for its potential as a natural CDK4/6 inhibitor. Phytochemical profiling using GC-MS identified bioactive compounds, which were subsequently subjected to molecular docking, ADME prediction, and in vitro cell-based assays using HCT116 and L929 cells. Results: The docking results revealed that Isocorydine (−7.4 kcal/mol for CDK4 and −7.2 kcal/mol for CDK6) and Thunbergol (−6.5 kcal/mol for CDK4 and −7.0 kcal/mol for CDK6) exhibited promising binding affinities comparable to standard CDK inhibitors, Palbociclib (−7.2, −8.3 kcal/mol) and Ribociclib (−7.1, −8.1 kcal/mol). Among the other tested natural compounds, Squalene (−7.1 kcal/mol for CDK4) and 2-palmitoylglycerol (−5.2 kcal/mol for CDK4, −4.9 kcal/mol for CDK6) demonstrated moderate binding affinities. ADME analysis confirmed favorable drug-like properties with minimal toxicity alerts. The extract displayed dose-dependent cytotoxicity with an IC₅₀ of 140 μg/mL and reduced cell migration in HCT116 cells, indicating potential anti-proliferative effects. These findings suggest that T. siliquosa root extract, through synergistic phytochemical interactions, holds promise as a multi-targeted, plant-based therapeutic candidate for CDK4/6-associated cancers, warranting further in vitro and in vivo validation. Full article

Systemic mastocytosis (SM) is a rare and heterogeneous disorder characterized by clonal proliferation and accumulation of neoplastic mast cells in one or more organs, most commonly the bone marrow, liver, spleen, and skin. Among its clinical variants, aggressive SM (ASM) presents organ damage and debilitating symptoms due to extensive mast cell infiltration. The management of ASM remains challenging, primarily because treatment must address both symptom control and disease progression. Background/Objectives: Recent therapeutic approaches have focused on tyrosine kinase inhibitors (TKIs) that target the oncogenic KIT driver mutation, predominantly the D816V mutation, which is implicated in mast cell proliferation. We report a case series of four patients diagnosed with ASM to highlight the real-world experience in the management of ASM. All patients had confirmed KIT D816V mutations and presented with signs of advanced organ dysfunction, such as marked hepatosplenomegaly, cytopenia, and significant bone marrow infiltration. First-line therapies, including cytoreductive agents or other TKIs were used. Responses varied in these patients, and ultimately, they were initiated on or transitioned to midostaurin, a multikinase TKI. Results: All four patients, after the initiation of midostaurin, presented clinical and biological improvement—at least a clinical improvement response according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment & European Competence Network on Mastocytosis (IWG-MRT-ECNM) criteria. These findings highlight the benefits of KIT inhibition in managing ASM, especially for patients with inadequate responses to traditional therapies. The impact of midostaurin on organ function, mast cell burden, and symptom control emphasizes the importance of the timely integration of TKIs into therapeutic protocols. However, optimal treatment duration, long-term safety, and the development of acquired resistance remain critical questions that warrant further studies. Larger prospective trials are needed to better delineate the prognostic factors associated with sustained response, refine patient selection, and explore combination strategies that may enhance therapeutic efficacy. Conclusions: The patients presented in this case series benefited from midostaurin therapy, showing either a clinical improvement or partial response according to the IWG-MRT-ECNM criteria. Our case series illustrates that KIT inhibitors can offer meaningful clinical benefit in ASM, reinforcing their position as an emerging cornerstone option in ASM management. Full article

Background/Objectives: RAF pathway aberrations are one of the hallmarks of lung cancer. Sorafenib is a multi-kinase inhibitor targeting the RAF pathway and is FDA-approved for several cancers, yet its efficacy in lung cancer is controversial. Previous clinical research showed that a ARAF p.S214C mutation exhibited exceptional responsiveness to sorafenib in lung adenocarcinoma. Methods: Considering this promising clinical potential, the oncogenic potential and sorafenib response of the ARAF p.S214C mutation were investigated using lung cancer models. ARAF p.S214C mutant, ARAF wild-type (WT), and EGFP control genes were ectopically expressed in lung adenocarcinoma cell lines retroviral transduction. In vitro and in vivo sorafenib sensitivity studies were performed, followed by transcriptomics and proteomics analyses. Results: Compared to the ARAF-WT and EGFP-engineered cells, the ARAF p.S214C-engineered cells activated Raf-MEK-ERK signaling and exhibited enhanced oncogenic potential in terms of in vitro cell proliferation, colony and spheroid formation, migration, and invasion abilities, as well as in vivo tumorigenicity. The ARAF p.S214C-engineered cells also displayed heightened sensitivity to sorafenib in vitro and in vivo. RNA sequencing and reverse-phase protein array analyses demonstrated elevated expression of genes and proteins associated with tumor aggressiveness in the ARAF p.S214C mutants, and its sorafenib sensitivity was likely moderated through inhibition of the cell cycle and DNA replication. The ERK and PI3K signaling pathways were also significantly deregulated in the ARAF p.S214C mutants regardless of sorafenib treatment. Conclusions: This study demonstrates the oncogenicity and sorafenib sensitivity of the ARAF p.S214C mutation in lung cancer cells, which may serve as a biomarker for predicting the sorafenib response in lung cancer patients. Importantly, investigating the gene–drug sensitivity pairs in clinically exceptional responders may guide and accelerate personalized cancer therapies based on specific tumor mutations. Full article

Background/Objectives: Non-small-cell lung cancer (NSCLC) frequently metastasizes to the brain, significantly impacting patient prognosis and quality of life. Anlotinib, a novel tyrosine kinase inhibitor, has shown promise in treating NSCLC with brain metastasis. So, we aimed to evaluate the clinical efficacy of anlotinib and various types of radiotherapy combinations used to treat NSCLC patients with brain metastasis regarding overall survival and the treatment of internal and external lesions. Methods: A comprehensive literature search was conducted in the databases PubMed, Scopus, WoS, MedLine, and Cochrane Library up to April 2024. Studies assessing the efficacy of anlotinib combined with whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or other radiotherapy modalities in NSCLC patients with brain metastasis were included. The primary outcomes were (a) the efficacy of anlotinib and radiotherapy on the intracranial lesions and OS and (b) the effectiveness of combined anlotinib and radiotherapy versus radiotherapy alone in NSCLC patients with brain metastasis. The secondary outcome was the efficacy of anlotinib and radiotherapy on extracranial progression. We used a combination of keywords and MeSH terms including ‘non-small cell lung cancer’ OR ‘NSCLC’, ‘brain metastases’, ‘anlotinib’, ‘radiotherapy’, ‘radiation therapy’, and ‘combined treatment’, among others. Boolean operators (AND, OR) were applied as appropriate to optimize the search strategy across databases. Results: Nine studies met the inclusion criteria, comprising 210 patients in the combination group and 228 patients in the radiotherapy alone group. The combination of anlotinib with radiotherapy showed a significant improvement in iPFS compared to radiotherapy alone, with a pooled risk ratio (RR) for iORR of 1.18 (95% CI: 1.00–1.39) and a pooled SMD for OS of 0.03 (95% CI: −0.29, 0.36). Radiotherapy combined with anlotinib also demonstrated enhanced intracranial and extracranial control rates. Conclusions: Anlotinib combined with radiotherapy, especially WBRT, offers a promising treatment strategy for NSCLC patients with brain metastasis, improving intracranial control. Further large-scale randomized controlled trials are needed to confirm these findings and optimize treatment protocols. Full article

Programmed Death-Ligand 1 (PD-L1) is a major target for immunotherapy using checkpoint inhibitors (CPIs), particularly in lung cancer treatment. Tumoral PD-L1 expression has been recognized as a natural predictor of CPI response. This predictive relationship is primarily due to its upregulation by interferon-gamma, which is released by immune cells (mainly T lymphocytes and natural killer cells) in proximity to tumor cells, driving an immune resistance mechanism. However, PD-L1 expression is modulated at multiple levels, including oncogenic signaling pathways, and transcriptional and post-transcriptional regulations, potentially leading to false positive predictions. Conversely, variable glycosylation of PD-L1 may compromise the accuracy of immunohistochemical measurements, resulting in false negative predictive data. In addition, PD-L1 expression demonstrates relative instability throughout treatment courses (e.g., chemotherapy and tyrosine kinase inhibitors), further limiting its clinical utility. In this review, we focused on the molecular mechanisms governing PD-L1 expression with a special emphasis on lung cancer. We also discussed biomarker strategies for optimizing patient selection for checkpoint inhibitor therapy where multimodal/multi-omics meta-biomarker approaches are emerging. Such comprehensive PD-L1-enriched biomarker strategies require evaluation through large-scale prospective studies, particularly in lung cancer, where numerous competing predictive candidates exist for CPI response. Full article

Background: BCR-ABL inhibitors such as imatinib and nilotinib exhibit multi-kinase activity that extends beyond oncology, offering significant potential for drug repurposing. Objectives: This study aims to systematically evaluate and prioritize the repurposing potential of BCR-ABL inhibitors, particularly imatinib and nilotinib. Methods: An integrated pharmacoinformatics framework was applied to analyze seven BCR-ABL inhibitors. Structural clustering, cheminformatics analysis, and transcriptomic profiling using the Connectivity Map were employed to evaluate structural relationships, target profiles, and gene expression signatures associated with non-oncology indications. Results: Structurally, imatinib and nilotinib clustered closely, while HY-11007 exhibited distinct features. Nilotinib’s high selectivity correlated with strong transcriptional effects in neurodegeneration-related pathways (e.g., HSP90 and LYN), whereas imatinib’s broader kinase profile (PDGFR and c-KIT) was linked to fibrosis and metabolic regulation. Connectivity Map analysis identified more than 30 non-cancer indications, including known off-target uses (e.g., imatinib for pulmonary hypertension) and novel hypotheses (e.g., nilotinib for Alzheimer’s via HSPA5 modulation). A substantial portion of these predictions aligned with the existing literature, underscoring the translational relevance of the approach. Conclusions: These findings highlight the importance of integrating structure–activity relationships and transcriptomic signatures to guide rational repurposing. We propose prioritizing nilotinib for CNS disorders and imatinib for systemic fibrotic diseases, supporting their advancement into preclinical and clinical evaluation. More broadly, this framework offers a versatile platform for uncovering hidden therapeutic potential across other drug classes with complex polypharmacology. Full article

Treatment with endocrine therapy (ET) in combination with CDK4/6 inhibitors has improved the outcome of patients with hormone receptor (HR)+/HER2- advanced breast cancer (ABC), but most patients eventually experience disease progression. Since the PI3K-AKT-mTOR (PAM), estrogen receptor (ER), and cyclin-dependent kinase (CDK) pathways are interdependent drivers of HR+/HER2- breast cancer (BC), the simultaneous inhibition of these pathways is expected to enhance anti-tumor control. Here we investigated the molecular and cellular effects of gedatolisib, a multi-target kinase inhibitor of the PAM pathway currently being evaluated in Phase 3 clinical trials, combined with fulvestrant and/or palbociclib in BC cell models. We found that the gedatolisib/fulvestrant/palbociclib triplet inhibited BC cell growth significantly more than the single agents or the palbociclib/fulvestrant doublet, both in vitro and vivo. Specifically, the triplet combination counteracted adaptive responses associated with single drug treatment, such as the reactivation of the CDK-RB-E2F pathway after palbociclib treatment, and inhibited multiple cellular functions, such as cell cycle progression, cell survival, protein synthesis, and glucose metabolism. The triplet combination was effective in treatment-naïve BC cell lines as well as in cell lines adapted to palbociclib and/or fulvestrant, regardless of PIK3CA/PTEN genetic alterations. Our findings provide a mechanistic rationale for conducting clinical studies evaluating gedatolisib in combination with CDK4/6 inhibitors and ET in HR+/HER2- ABC. Full article

Background: Advanced adrenocortical carcinoma (ACC) remains a challenging malignancy with limited therapeutic options. Multi-kinase inhibitors (MKIs), either alone or in combination with immuno-oncology (IO) agents, have been investigated in recent single-arm clinical trials and retrospective series. Methods: We conducted a systematic review and single-arm meta-analysis of studies evaluating MKIs in advanced ACC. Objective response rate (ORR) and disease control rate (DCR) were pooled using random-effects models for single-arm proportions. Overall survival (OS) and progression-free survival (PFS) were summarized descriptively due to limited variance data. Subgroup analyses compared MKI monotherapy versus MKI + IO combinations, and meta-regression was performed to assess the impact of prior mitotane exposure. Results: Eleven studies (n = 208 patients) were included. The pooled ORR was 21% (95%CI, 11–36%), and the DCR was approximately 57%. Subgroup analysis revealed a higher ORR with MKI + IO regimens (26%; 95%CI, 12–48%) compared to MKI monotherapy (15%; 95%CI, 3–47%). Median OS ranged from 5.4 to 30.6 months, and PFS from 2.8 to 13.3 months, both favouring MKI + IO combinations. Meta-regression identified prior mitotane exposure as a significant predictor of ORR (p = 0.0279), particularly within the MKI + IO subgroup. Conclusions: MKI-based regimens, especially when combined with IO, demonstrate promising efficacy in advanced ACC, a disease with few established second-line options. While limited by the non-comparative design of available studies, these findings support further investigation in prospective, randomized clinical trials. Full article

Cellular senescence is a fundamental mechanism in aging, marked by irreversible growth arrest and diverse functional changes, including, but not limited to, the development of a senescence-associated secretory phenotype (SASP). While transient senescence contributes to beneficial processes such as tissue repair and tumor suppression, the persistent accumulation of senescent cells is implicated in tissue dysfunction, chronic inflammation, and age-related diseases. Notably, the SASP can exert both pro-inflammatory and immunosuppressive effects, depending on cell type, tissue context, and temporal dynamics, particularly in early stages where it may be profibrotic and immunomodulatory. Recent advances in senotherapeutics have led to two principal strategies for targeting senescent cells: senolytics, which selectively induce their apoptosis, and senomorphics, which modulate deleterious aspects of the senescence phenotype, including the SASP, without removing the cells. This review critically examines the molecular mechanisms, therapeutic agents, and clinical potential of both approaches in the context of anti-aging interventions. We discuss major classes of senolytics, such as tyrosine kinase inhibitors, BCL-2 family inhibitors, and natural polyphenols, alongside senomorphics including mTOR and JAK inhibitors, rapalogs, and epigenetic modulators. Additionally, we explore the biological heterogeneity of senescent cells, challenges in developing specific biomarkers, and the dualistic role of senescence in physiological versus pathological states. The review also highlights emerging tools, such as targeted delivery systems, multi-omics integration, and AI-assisted drug discovery, which are advancing precision geroscience and shaping future anti-aging strategies. Full article

Dermatofibrosarcoma protuberans (DFSP) is a rare sarcoma, characterized by a COL1A1-PDGFB fusion. Imatinib, a multi-target tyrosine kinase inhibitor, is a standard treatment of DFSP. However, resistance emerges in 10–50% of cases. There is an urgent need for predictive biomarkers to refine the patient selection and improve therapeutic outcomes. We aimed to identify predictive biomarkers for imatinib response and explored a pharmacokinomic approach using in vitro assays with patient-derived DFSP cell lines. Four DFSP cell lines that we established were analyzed for tyrosine kinase activities on PamChip, a three-dimensional peptide array, in the presence and absence of imatinib, along with an imatinib-sensitive cell line, GIST-T1, as a positive control. Drug screening was also performed using 60 FDA-approved tyrosine kinase inhibitors, including imatinib. The kinomic profiles were compared with the kinase inhibitor screening results to identify predictive druggable targets. Drug sensitivity was associated with increased activity of PDGFRB, as indicated by the PamChip assay and Western blotting. Furthermore, imatinib sensitivity correlated with the activity of three kinases: FER, ITK, and VEGFR1, suggesting their potential as potential predictive biomarkers. Our cell-based pharmacokinomic approach using patient-derived DFSP cell lines would facilitate the identification of resistant cases to imatinib and guide alternative therapeutic strategies. Full article

Thyroid cancer (TC) remains a prevalent malignancy, with over 820,000 global cases diagnosed in 2022. Differentiated thyroid carcinoma (DTC), primarily papillary and follicular types, accounts for most cases and has a favorable prognosis with total thyroidectomy and radioiodine (RAI) ablation. However, 5–15% of patients develop RAI-refractory (RAI-R) disease, leading to a significantly poorer outcome. For RAI-R patients, treatment decisions depend on disease progression. Active surveillance is suitable for indolent cases, while symptomatic or progressive disease requires systemic therapy. Multikinase inhibitors (MKIs) such as lenvatinib and sorafenib serve as first-line options, with cabozantinib recently approved for resistant cases. Additionally, novel targeted therapies, including RET and NTRK inhibitors, and immune checkpoint inhibitors, are under investigation, offering a personalized approach. A key challenge is determining the optimal timing for systemic therapy, balancing progression-free survival (PFS) benefits against MKI-related toxicities, which significantly impact quality of life (QoL). Molecular testing can identify actionable mutations, guiding therapy selection. Clinical guidelines (ATA, ESMO) recommend initiating treatment based on disease progression and patient condition, integrating strategies such as active surveillance, surgery, and radiotherapy when appropriate. Despite advances, systemic therapies carry significant adverse events (e.g., hypertension, fatigue, gastrointestinal toxicity), necessitating careful monitoring to prevent dose reductions or interruptions. A multidisciplinary approach is essential to optimize patient outcomes and maintain QoL. As targeted therapies continue to evolve, further research is needed to refine treatment sequencing and improve outcomes for RAI-R TC. This review synthesizes current evidence to guide clinical decision-making. Full article

Childhood neuroblastoma (NB) is a malignant tumour that is a member of a class of embryonic tumours that have their origins in sympathoadrenal progenitor cells. There are five stages in the clinical NB staging system: 1, 2A, 2B, 3, 4S, and 4. For those diagnosed with stage 4 neuroblastoma (NBS4), the treatment options are limited with a survival rate of between 40 and 50%. Since 1975, more than 15 targets have been identified in the search for a treatment for high-risk NBS4. This article is concerned with the search for a multi-target drug treatment for high-risk NBS4 and focuses on four possible treatment targets that research has identified as having a role in the development of NBS4 and includes the inhibitors Histone Deacetylase (HDAC), Bromodomain (BRD), Hedgehog (HH), and Tropomyosin Kinase (TRK). Computer-aided drug design and molecular modelling have greatly assisted drug discovery in medicinal chemistry. Computational methods such as molecular docking, homology modelling, molecular dynamics, and quantitative structure–activity relationships (QSAR) are frequently used as part of the process for finding new therapeutic drug targets. Relying on these techniques, the authors describe a medicinal chemistry strategy that successfully identified eight compounds (inhibitors) that were thought to be potential inhibitors for each of the four targets listed above. Results revealed that all four targets BRD, HDAC, HH and TRK receptors binding sites share similar amino acid sequencing that ranges from 80 to 100%, offering the possibility of further testing for multi-target drug use. Two additional targets were also tested as part of this work, Retinoic Acid (RA) and c-Src (Csk), which showed similarity (of the binding pocket) across their receptors of 80–100% but lower than 80% for the other four targets. The work for these two targets is the subject of a paper currently in progress. Full article