Search Results (185)

Background/Objectives: Brain metastases (BM) are a major challenge in the treatment of non-small cell lung cancer (NSCLC), particularly among patients with anaplastic lymphoma kinase rearrangements (ALK+ NSCLC), where incidence can reach up to 60% during the course of the disease. This study used in silico systems biology and artificial intelligence-based modeling to investigate the mechanistic effects of brigatinib, a second-generation ALK inhibitor, on metastatic processes in both primary tumors (PT) and established BM. Methods: We applied the Therapeutic Performance Mapping System (TPMS) technology, which integrates systems biology and artificial intelligence, to simulate the impact of brigatinib on metastasis-associated pathways in PT and BM of ALK+ NSCLC patients. Results: In these simulations, brigatinib was predicted to modulate a broad set of proteins implicated in metastasis in both PT and BM, acting mainly through IGF1R, EGFR, FLT3, and ROS1, in addition to its known target ALK. Conclusions: These results suggest brigatinib’s potential to impact key pathways involved in metastatic progression and intracranial disease control. Overall, this study provides insights into brigatinib’s multifaceted role in targeting metastatic processes in ALK+ NSCLC, underscoring its potential benefits in both PT and BM. Nonetheless, further experimental and clinical studies would confirm our results and the potential of in silico models reported here. Full article

Background: Emerging evidence suggests that biological sex shapes glioma biology and therapeutic response. Methods: We performed a sex-stratified analysis of CGGA (Chinese Glioma Genome Atlas) RNA sequencing data comparing low-grade glioma (LGG) with high-grade glioma (HGG) and glioblastoma (GBM). Using the 3PodR framework, we integrated differential expression analysis with Gene Set Enrichment Analysis (GSEA), EnrichR, leading-edge analysis, and iLINCS drug repurposing. Results: These comparisons provide a proxy for biological processes underlying malignant transformation. In LGG vs. HGG, 973 significantly differentially expressed genes (DEGs) were identified in females and 1236 in males, with 15.5% and 33.5% unique to each sex, respectively. In LGG vs. GBM, 2011 DEGs were identified in females and 2537 in males, with 12.6% and 30.7% being unique. Gene-level contrasts included GLI1 upregulation in males and downregulation in females, GCGR upregulation in males, MYOD1 upregulation in females, and HIST1H2BH downregulation in males. Additional top DEGs included PRLHR, DGKK, DNMBP-AS1, HOXA9, CTB-1I21.1, RP11-47I22.1, HPSE2, SAA1, DLK1, H19, PLA2G2A, and PI3. In both sexes, LGG–HGG and LGG–GBM grade comparisons converged on neuronal and synaptic programs, with enrichment of glutamatergic receptor genes and postsynaptic modules, including GRIN2B, GRIN2A, GRIN2C, GRIN1, and CHRNA7. In contrast, collateral pathways diverged by sex: females showed downregulation of mitotic and chromosome-segregation programs, whereas males showed reduction of extracellular matrix and immune-interaction pathways. Perturbagen analysis nominated signature-reversing compounds across sexes, including histone deacetylase inhibitors, Aurora kinase inhibitors, microtubule-targeting agents such as vindesine, and multi-kinase inhibitors targeting VEGFR, PDGFR, FLT3, PI3K, and MTOR. Conclusions: Glioma grade comparisons reveal a shared neuronal–synaptic program accompanied by sex-specific transcriptional remodeling. These findings support sex-aware therapeutic strategies that pair modulation of neuron–glioma coupling with chromatin- or receptor tyrosine kinase/angiogenic-targeted agents, and they nominate biomarkers such as GLI1, MYOD1, GCGR, PRLHR, and HIST1H2BH for near-term validation. Full article

Kinases, which make up 20% of the druggable genome, are thought to be essential signaling enzymes. Protein phosphorylation is induced by protein kinases. Proliferation, the cell cycle, apoptosis, motility, growth, differentiation, and other biological processes are all regulated by kinases. Their dysregulation disrupts several cellular functions, leading to a variety of illnesses, the most important of which is cancer. As a result, kinases are thought to be crucial targets in a number of malignancies and other diseases. Researchers from all over the world are hard at work developing inhibitors using various chemical structures. The scaffolds of imidazole and benzimidazole provide a versatile structure for a variety of physiologically active substances. Moreover, they serve as specialized scaffolding for the creation of target-specific pharmaceuticals to address various diseases. This article seeks to illustrate the application of imidazole and benzimidazole frameworks in the formulation of inhibitors that target various tyrosine kinases, including fibroblast growth factor receptors (FGFRs), c-Met kinase, epidermal growth factor receptors (EGFRs), vascular endothelial growth factor receptors (VEGFRs), and FMS-like tyrosine kinase 3 (FLT3), from 2020 to the present. The major structure–activity correlations (SARs) of imidazole and benzimidazole derivatives were examined, and, also, a docking study highlighted the varied interactions occurring inside the active site of tyrosine protein kinases. The objective of this effort is to consolidate the fundamental structural information necessary for the synthesis of imidazole- or benzimidazole-based tyrosine kinase inhibitors with enhanced efficacy. Full article

Blood cancer is characterized by the uncontrolled growth of blood cells in the bone marrow or in the lymphatic system. Chemotherapy is still considered the first line of treatment in several types of blood cancer despite its adverse effects. Recent advances in understanding the pathology and genomic changes in these cancers have led to the discovery of novel drug targets and the development of new therapeutic agents. In this review, we will discuss the mechanisms of action and clinical utility of several classes of targeted therapy used in blood cancers, including inhibitors of different types of tyrosine kinase enzymes (BCR-ABL, FLT3 and BTK), BCL-2 inhibitors, phosphoinositide 3-kinase inhibitors, nuclear export inhibitors, immune therapies (monoclonal antibodies, radioimmunoconjugates, chimeric antigen receptor T-cells, immune checkpoint inhibitors, and bispecific antibodies), and proteasome-dependent drugs (proteasome inhibitors and proteolysis targeting chimeras). Further advances in identifying distinct molecular subgroups in blood cancers will offer more opportunities for novel targeted therapies and more personalized medicine approaches. Full article

FMS-like tyrosine kinase 3 (FLT3) is a crucial regulator of normal hematopoiesis, with high expression in hematopoietic stem and progenitor cells. Beyond its role in stem cell survival and proliferation, FLT3 signaling is essential for immune regulation, particularly dendritic cell differentiation and NK cell expansion. In acute myeloid leukemia (AML), FLT3 mutations—most commonly internal tandem duplications (FLT3-ITD) and tyrosine kinase domain (FLT3-TKD) substitutions—are among the most frequent genetic alterations, driving constitutive activation of proliferative and antiapoptotic pathways and conferring adverse prognosis. The clinical development of FLT3 inhibitors has been a decades-long endeavor. Early multikinase agents established proof-of-concept but were hampered by off-target effects and incomplete efficacy. The subsequent generation of potent and selective inhibitors has transformed outcomes, culminating in FDA approvals of midostaurin, quizartinib, and gilteritinib. Together with allogeneic transplantation, these agents have reshaped the treatment paradigm for FLT3-mutant AML, converting a historically high-risk subset into one with realistic prospects for long-term survival. Despite these advances, challenges remain. Resistance emerges through cell-intrinsic mechanisms such as acquisition of secondary TKD or RAS pathway mutations, metabolic reprogramming, and antiapoptotic shifts, as well as cell-extrinsic mechanisms mediated by the bone marrow microenvironment, including cytokine support, stromal CYP3A4 metabolism, and retinoid inactivation. These pathways sustain measurable residual disease (MRD), the key predictor of relapse. Rational combination strategies and MRD-directed approaches are therefore essential to fully realize the curative potential of FLT3 inhibition. Full article

FMS-like tyrosine kinase 3 (FLT3) mutations in acute myeloid leukemia (AML) are associated with an increased risk of relapse and a poor prognosis. Several FLT3 inhibitors that have been developed demonstrated efficacy against the FLT3 tyrosine kinase domain and/or internal tandem duplication mutations. Nevertheless, remission rates for these agents remain in the range of 30~40% of patients, attributed to both primary and secondary mechanisms of resistance, with relapse rates varying from ~30 to 50%. The mechanisms underlying resistance to FLT3 inhibitors have been characterized, offering valuable insights that can guide the development of clinical trials aimed at discovering novel FLT3 tyrosine kinase inhibitors (TKIs) that can overcome resistance. Additionally, elucidating resistance signaling pathways may facilitate the identification of other TKIs, rational combination therapies or multiple targeted TKIs to address alternative pathways, potentially helping overcome resistance in AML patients with refractory clones. Full article

Objectives: To determine the prescribing prevalence of epidermal growth factor receptor (EGFR)- and anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients in Greece and examine patterns of first-line tyrosine kinase inhibitor (TKI) utilization and associated treatment costs using nationwide real-world data. Methods: A retrospective analysis of the national e-prescription database was performed, identifying patients initiating first-line treatment (FLT) for EGFR- or ALK-positive NSCLC between 1 January 2020 and 31 December 2022. Demographic characteristics, prescribing prevalence data, drug utilization patterns, total annual drug expenditures, and per patient treatment costs were assessed. All statistical analyses were performed using the statistical software SPSS-v.29. Results: Overall, 1188 EGFR-positive (mean age of 70.93 ± 11.6) and 246 (mean age of 64.26 ± 12.6) ALK-positive NSCLC patients initiated FLT during the three-year study period. EGFR mutations were slightly more common in females (53%), peaking in the 70–79 age group (35%). ALK mutations were also more common among females (52%), particularly within the 60–79 age group. In EGFR-positive patients, osimertinib usage markedly increased from 41% in 2020 to 63% in 2022, primarily displacing afatinib (from 32% to 22%) and erlotinib (from 24% to 14%), with gefitinib prescriptions falling below 2%. Among ALK-positive patients, crizotinib utilization declined significantly from 60% to 16%, whereas alectinib increased to 59% by 2022. Annual EGFR-related total drug expenditures remained stable (€11.5 million in 2020 vs. €11.9 million in 2022), driven primarily by increasing osimertinib usage. Similarly, ALK-related annual drug expenditures showed stability, with costs predominantly attributed to rising alectinib utilization. Conclusions: This nationwide analysis highlights the rapid adoption of second- and third-generation TKIs for EGFR- and ALK-positive NSCLC in Greece, reflecting evolving clinical practice patterns. Although the target patient populations are relatively small, the associated economic burden is considerable. To ensure long-term sustainability of the Greek healthcare system, policymakers should critically assess the cost-effectiveness of these innovative therapies and align resource allocation with value-based care principles. Full article

Background: FLT3 mutations, including internal tandem duplication (ITD) and tyrosine kinase domain (TKD) point mutations, represent common genetic alterations in acute myeloid leukemia (AML), with FLT3-ITD associated with poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs), such as quizartinib (Quiz) and gilteritinib, have improved clinical outcomes, secondary TKD mutations, particularly the gatekeeper mutation F691L, confer significant resistance. We previously demonstrated that chlorpromazine (CPZ), an antipsychotic drug, inhibits clathrin-mediated endocytosis and selectively suppresses the growth of cancer cells harboring mutant receptor tyrosine kinases. Methods: In this study, we examined the efficacy of CPZ in overcoming TKI resistance using Ba/F3 cells expressing FLT3-ITD or FLT3-ITD/F692L, the murine analog of F691L. Results: Quiz inhibited proliferation of FLT3-ITD cells but was ineffective against FLT3-ITD/F692L cells. CPZ suppressed growth in both cell types. Co-treatment with CPZ and Quiz exhibited synergistic effects in FLT3-ITD cells, but not in FLT3-ITD/F692L cells. CPZ reduced STAT5 phosphorylation and modulated downstream signaling in FLT3-ITD cells, while only partially affecting STAT5 in FLT3-ITD/F692L cells. Expression of constitutively active STAT5 partially rescued CPZ-induced growth inhibition. Conclusions: These findings suggest that STAT5 suppression is a key mechanism of CPZ’s antileukemic activity and support its potential as a therapeutic strategy for FLT3-ITD-positive AML. Full article

The development of molecular profiling approaches for AML patients such as whole genome sequencing, whole exome sequencing and transcriptomic sequencing have greatly contributed to better understanding of leukemia development, progression and treatment responsiveness/resistance. These studies have generated a new knowledge about driver events operating in AML that can be translated into clinics, thus favoring the mutations; using this approach, more than 50% of older AML patients display molecular alterations, such as IDH1, IDH2, FLT3 (FLT3-TKD and FLT3-ITD), NPM1 and KMT2A rearrangements that can be targeted by specific drugs. Preclinical and clinical studies have supported the use of drugs targeting these molecular alterations as first-line therapy in association with induction chemotherapy in chemotherapy-fit patients or with a hypomethylating agent in association with a Bcl-2 inhibitor (Venetoclax) in chemotherapy-unfit patients. These studies have shown promising results that need to be confirmed through randomized clinical studies specifically involving the enrollment of older AML patients. Full article

Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) that is involved in cell survival, proliferation, and differentiation of haematopoietic progenitors of lymphoid and myeloid lineages. Oncogenic mutations in the FLT3 gene, resulting in constitutively active FLT3 variants, are frequently found in patients with acute myeloid leukaemia (AML). In particular, patients expressing FLT3 ITD (internal tandem duplications of the juxtamembrane domain of FLT3) correlate with poor patient survival. Targeting FLT3-mutated leukaemic stem cells is therefore a key to the efficient treatment of patients with relapsed/refractory AML. The efficacy of approved tyrosine kinase inhibitors is regularly compromised by various resistance pathways or secondary mutations. Based on the current molecular understanding of aberrant signal transduction pathways and cell transformation, novel alternative treatment approaches can be exploited for therapeutic purposes. In particular, new insights into the regulation of the activity of counteracting protein tyrosine phosphatases (PTPs), the aberrant biogenesis and activation of mutant FLT3 proteins, as well as common factors controlling cell transformation are attractive avenues. This review summarises the current knowledge about the regulation of the oncogenic activities of mutant FLT3 proteins and discusses possible options for alternative treatments. Full article

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by the clonal proliferation of myeloid precursors and rapid progression. Historically consisting of intensive chemotherapy, AML management has evolved significantly due to advances in molecular diagnostics and risk stratification. This review discusses current therapeutic paradigms in AML, emphasizing the growing role of personalized medicine across age and risk groups. For younger, fit patients, intensive regimens such as the “7 + 3” protocol remain the standard, often enhanced by targeted agents like FMS-like tyrosine kinase 3 (FLT3) and IDH inhibitors. Older or unfit individuals benefit from low-intensity treatments such as hypomethylating agents combined with venetoclax, now considered a frontline standard of care. The use of liposomal chemotherapy (CPX-351), measurable residual disease (MRD) monitoring, and maintenance therapy further refine post-remission strategies. Emerging therapies, including menin inhibitors, antibody–drug conjugates, and immunotherapies like CAR-T cells and vaccines, offer additional options, especially in relapsed/refractory settings. This comprehensive review outlines the current landscape and future directions in AML therapy, emphasizing the transition toward individualized, mutation-driven treatment strategies. Full article

Background/Objectives: Acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) mutations carries a poor prognosis. While FLT3 inhibitors like midostaurin show benefits in combination with chemotherapy, the role of allelic ratio (AR), NPM1 mutation status, and hematopoietic stem cell transplantation (HSCT) remains uncertain. Real-world data can help refine prognostic classification and treatment strategies. Methods: We retrospectively analyzed 37 fit patients with FLT3-ITD AML treated with standard “7+3” chemotherapy, with and without midostaurin, between 2013 and 2022. Patients were stratified by FLT3-ITD AR, NPM1 status, and treatment approach. Outcomes assessed included complete remission (CR), disease-free survival (DFS), and overall survival (OS). Results: Overall, 67.6% achieved CR/CRi. Response rates did not differ significantly by AR (low vs. high: 66.7% vs. 69.2%) or midostaurin use (72.6% vs. 60%; p = 0.49). NPM1 mutations were associated with improved DFS (10.3 vs. 3 months, p = 0.036) but not OS. HSCT, performed in 54.1% of patients, mainly in first remission (CR1), significantly prolonged DFS (not reached vs. 5.3 months, p = 0.005) and remained an independent predictor in multivariate analysis (HR: 0.160, p = 0.039). OS (median 15.1 months) did not vary significantly across subgroups. Among patients achieving CR1, OS was significantly longer in those who underwent HSCT after midostaurin-based induction compared to those not transplanted (median OS not reached vs. 12.8 months; 95% CI, 6.9–18.7; p = 0.045), whereas no significant benefit was observed after standard induction. In a landmark analysis restricted to patients transplanted in CR1, those who had received midostaurin-based induction showed a trend toward improved OS compared to those treated with standard induction (median OS not reached vs. 11.5 months; 95% CI, 0.5–25.0; p = 0.086). Conclusions: This real-life study supports the importance of NPM1 mutations and HSCT in CR1, especially in the midostaurin era, for improving DFS in FLT3-ITD AML. These findings support updated guidelines for reducing the prognostic weight of AR and highlight the need for improved post-remission strategies in this setting. Full article

The internal tandem duplication mutation of FMS-like tyrosine kinase 3 (FLT3-ITD) is associated with high recurrence and mortality rates in acute myeloid leukemia (AML), making it a critical target for anti-AML therapies. Plinabulin is a diketopiperazines derivative that exhibits extensive anti-cancer potency by targeting β-tubulin. We designed and synthesized a novel FLT3 inhibitor, namely 5-3, based on the structure of plinabulin and evaluated its effect on FLT3-ITD mutant AML cells. The results indicated that 5-3 potently and selectively inhibits the growth of mutant FLT3-expressingleukemia cells, and had no effect on FLT3 wide-type cancer cells, suggesting the antiproliferative activity of 5-3 depends highly on FLT3-ITD expression. Mechanically, 5-3 significantly suppressed the phosphorylation of FLT3 signaling pathway, including STAT5, Erk and Akt. Moreover, the efficiency of compound 5-3 is not associated with Plinabulin’s typical target, β-tubulin. In conclusion, the study identified diketopiperazine derivative as a novel FLT3-ITD selective inhibitor. These results demonstrated that 5-3 might be a drug candidate for the treatment of FLT3-ITD-positive AML. Full article

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with a poor prognosis. Activating mutations in the FLT3 gene occur in approximately 30% of AML cases, with internal tandem duplications in the juxtamembrane domain (FLT3-ITD; 75%) and mutations in the tyrosine kinase domain (FLT3-TKD; 25%). FLT3-ITD mutations are linked to poor prognosis and offer significant clinical predictive value, whereas the implications of FLT3-TKD mutations are less understood. The Hedgehog–Gli pathway is an established therapeutic target in AML, and emerging evidence suggests crosstalk between FLT3-ITD signaling and Gli expression regulation via non-canonical mechanisms. Post-translational modifications involving myristic and palmitic acids regulate various cellular processes, but their role in AML remains poorly defined. In this study, we investigated the role of fatty acid synthase (FASN), which synthesizes myristic and palmitic acids and catalyzes palmitoyl-acyltransferation, in regulating FLT3-ITD-Gli signaling. FASN knockdown using shRNA and the FASN inhibitor TVB-3166 was performed in FLT3-ITD-mutated AML cell lines (MOLM13, MV411) and Baf3-FLT3-ITD cells. The impact of FASN inhibition was assessed through Western blot and kinome profiling, while biological implications were evaluated by measuring cell viability and proliferation. FASN inhibition resulted in reduced levels of phospho-Akt (pAkt) and phospho-S6 kinase (pS6) and decreased expression of Hedgehog–Gli1, confirming non-canonical regulation of Gli by FLT3-ITD signaling. Combining TVB-3166 with the Gli inhibitor GANT61 significantly reduced the survival of MOLM13 and MV411 cells. Full article

Background: FLT3 mutation testing is a key ancillary molecular assay for diagnosing and managing patients with acute myeloid leukemia (AML), including assessing the utility of FLT3 inhibitors during induction chemotherapy. FLT3 PCR utilizing fluorescently labeled primers and capillary electrophoresis readout is the most used technique for the rapid detection of FLT3 internal tandem duplications (ITDs) (including very small ITDs) and tyrosine kinase domain (TKD) mutations. However, capillary electrophoresis (CE) is a relatively lengthy and technically demanding result readout mode that could potentially be replaced by faster alternatives. Methods: Here, we describe the validation of a modified FLT3 PCR assay that uses the Agilent 4200 TapeStation platform for result readouts. This platform generates quantifiable electropherograms and gel images in under two minutes and at a low cost. We validated its ability to detect FLT3-ITD and -TKD mutations using 22 and 18 previously tested patient samples, respectively. Results: The TapeStation 4200 instrument is 100% sensitive, specific, and highly reproducible for post-PCR fragment analysis in detecting FLT3-ITD (greater than 15 bp in size) and TKD mutations in AML patients. Its results are nearly 100% concordant with those obtained from our previously validated NGS and PAGE methods. However, the limitation of this readout mode is its inability to reliably detect FLT3-ITDs smaller than 15 bp in size. Conclusions: Given the widespread use of TapeStation instruments in molecular diagnostics laboratories as part of next-generation sequencing (NGS) workflows, this modified assay is well-suited as a companion test for rapid NGS platforms to detect larger FLT3-ITDs, which are NGS often miscalledor under-called by the NGS bioinformatics algorithms. However, it is not suitable for use as a standalone assay, as it is unable to reliably detect very short FLT3-ITDs. Full article