A narrative review summarizes the major signaling pathways implicated in GBM pathogenesis, including EGFR, PI3K/AKT/mTOR, Wnt, and TGF-β signaling, while also discussing emerging therapeutic targets such as FGFR3–TACC3 fusions, regorafenib, and natural killer cell-based immunotherapy.
Abstract
Abstract Background: Glioblastoma multiforme (GBM) is the most aggressive primary malignant brain tumor in adults and remains associated with poor survival despite advances in surgery, radiotherapy, and chemotherapy. Increasing evidence suggests that IDH-wildtype glioblastoma progression is driven by complex interactions between dysregulated molecular signaling pathways, intratumoral heterogeneity, glioma stem cells, and immune suppression within the tumor microenvironment. Objective: This narrative review summarizes the major signaling pathways implicated in GBM pathogenesis, including EGFR, PI3K/AKT/mTOR, Wnt, and TGF-β signaling, while also discussing emerging therapeutic targets such as FGFR3–TACC3 fusions, regorafenib, and natural killer cell-based immunotherapy. Results The review further examines mechanisms underlying treatment resistance and the limitations of current targeted therapies. Although many pathway-directed treatments have demonstrated promising preclinical activity, clinical translation remains challenging because of compensatory signaling, blood–brain barrier limitations, and molecular heterogeneity. Conclusion: Future progress will likely depend on biomarker-driven patient stratification, improved CNS drug delivery, and rational combination therapies capable of simultaneously targeting multiple tumor-promoting mechanisms.
ABSTRACT Purpose Glioblastoma (GBM), the most aggressive and common primary brain tumor in adults, has a poor prognosis, rapid growth, and resistance to treatment. Abnormal activation of signaling pathways like PI3K/AKT/mTOR, MAPK/ERK, JAK/STAT, Wnt/β‐catenin, NF‐κB, and Notch facilitates uncontrolled proliferation, angiogenesis, invasion, and immune evasion. Conventional treatments are insufficient in modifying complex networks, necessitating the urgent need for novel multitargeted treatments. Natural compounds are increasingly being considered as potential treatments for GBM due to their ability to control multiple oncogenic pathways simultaneously and their lower toxicity compared to synthetic medicines. This review provides an integrated and translational perspective on GBM, differing from past reviews that focused on the anticancer effects of individual phytochemicals or specific signaling pathways. We discussed the relationship between natural compounds and key oncogenic signaling networks, focusing on GBM pathogenesis, blood–brain barrier penetration, nanotechnology‐assisted delivery, and strategies combining standard therapies. Furthermore, this review critically distinguished in vitro, in vivo, and clinical evidence, focusing on bioavailability challenges, ongoing clinical trials, and future opportunities in precision oncology. Method To ensure the inclusion of the most appropriate articles in this review, an in‐depth search was carried out on prominent medical, biological, and chemical databases, including Scopus, PubMed, and Web of Science. The search strategy employed combinations of Medical Subject Headings and Boolean operators, focusing on terms related to glioblastoma, natural compounds, and various molecular mechanisms involved in drug delivery, clinical trials, and diagnosis. Finding These natural compounds demonstrated potential in preclinical GBM models for inducing apoptosis, suppressing angiogenesis, modulating oxidative stress, and enhancing chemosensitivity. Additionally, some natural compounds can cross the blood–brain barrier, thereby increasing their translational significance. The use of molecular diagnostics, including biomarkers, genetic profiling, and advanced imaging, has significantly improved early identification and patient stratification. Specific compounds with strong translational potential, such as curcumin, resveratrol, EGCG, quercetin, berberine, and luteolin, are highlighted along with their main molecular targets and therapeutic effects. The integration of natural compounds into precision‐based therapy approaches has been made possible. Conclusion Future research aims to combine molecular diagnostics with phytochemical therapies, validate clinical trial outcomes, and enhance bioavailability with nanotechnology delivery systems. The combination of natural compounds shows potential for creating safe, effective, and pathway‐specific treatments for GBM.
Mehrukh Zehravi, Md Abul Hassan, Md. Al Amin et al.· Brain and Behavior· 0 citations
This comprehensive review highlights BMBC resistance mechanisms, drawing from preclinical models, clinical studies, and genomic analyses, and highlights the potential for personalized, multi-targeted approaches to improve patient outcomes in BMBC.
Paromita Sarker, Shreyas S Rao· Biochimica et biophysica act...· 0 citations
The therapeutic landscape of targeted therapies in glioblastomas is summarized, spanning major target classes including receptor tyrosine kinases, intracellular signalling proteins, cell-cycle dysregulation and synthetic-lethal vulnerabilities and emerging strategies targeting genome integrity and telomeres, epigenetic modulators, and tumour-neural circuitry are examined.
E. Aquilanti, M. Touat, P. French et al.· Nature Reviews Clinical Onco...· 0 citations
The integration of TME-targeted and individualized therapeutic strategies may offer promising prospects toward achieving durable clinical outcomes in breast cancer treatment.
P. Shankar, Gowthamarajan Kuppusamy, Apsara Unni et al.· Current Cancer Therapy Revie...· 0 citations
A comprehensive overview of emerging and targeted therapeutic strategies in colorectal cancer, with emphasis on their molecular basis and clinical relevance, highlights a shift toward precision oncology for improved management of colorectal cancer.
Debgopal Ganguly, Ananta Choudhury, H. Deka et al.· Clinical and Translational O...· 0 citations
Acute myeloid leukemia (AML) and related myeloid malignancies remain clinically challenging despite recent advances in molecular profiling and targeted therapy. Although recurrent oncogenic drivers have improved disease classification and informed therapeutic development, durable disease control remains limited by signaling plasticity and therapeutic resistance of heterogeneous malignant stem and progenitor populations. These limitations drive continued interest in signaling dependencies that investigate oncogenic inputs across genetically diverse myeloid disease states. The p90 ribosomal S6 kinase (RSK) family has emerged as one such candidate. Positioned as a downstream convergence of MAPK/ERK and PI3K/PDK-1 signaling, RSK regulates proliferation, survival, translational control, inflammatory signaling, and cellular stress adaptation, all processes directly relevant to malignant progression. Growing evidence supports aberrant RSK activation in AML, functional dependency in FLT3-mutant AML and myeloproliferative neoplasms/myelofibrosis, and increasing translational interest in selective pharmacologic inhibition. Early preclinical studies demonstrate anti-leukemic activity through both genetic and pharmacologic targeting, while emerging clinical development of RSK inhibitors in solid tumors supports therapeutic feasibility. Here, we review the biologic role of RSK signaling in myeloid malignancies and discuss the therapeutic opportunities and challenges associated with targeting this signaling axis.
G. Traber, S. Dunn, Kathleen M. Sakamoto· Frontiers in Cell and Develo...· 0 citations
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