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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Sprache: Englisch
Nanomaterials in Glioblastoma Research, Diagnosis, and Therapy offers a comprehensive exploration of how nanotechnology is revolutionizing the fight against glioblastoma (GBM), one of the deadliest and most treatment-resistant brain cancers. The book covers the molecular and epigenetic mechanisms underlying GBM, laying the foundation for innovative strategies in diagnosis and therapy. It highlights cutting-edge advances, including nanomaterial-based biosensors for early diagnosis, biomaterials to enhance immunotherapy, and novel therapeutic approaches like gold nanoparticles, cold plasma, and combinational nanomedicine. The book also addresses critical challenges such as overcoming the blood-brain barrier through oral delivery nanostructures and provides future perspectives on clinical applications.
Key Features:
- Insights into GBM genetics, epigenetics, and molecular pathways.
- Applications of nanomaterials in drug delivery, imaging, and immunotherapy.
- Detailed coverage of advanced diagnostics and therapeutic strategies.
- Future directions and challenges in nanotechnology-based GBM treatment.
Readership:
This essential resource is ideal for researchers, oncologists, nanotechnology specialists, and graduate students seeking innovative solutions to advance GBM diagnosis and therapy.
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Seitenzahl: 264
Veröffentlichungsjahr: 2025
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FOREWORD
It gives me immense pleasure to introduce to you the groundbreaking book, "Nanomaterials in Glioblastoma Research, Diagnosis and Therapy." This comprehensive work delves into the transformative potential of nanotechnology in addressing the challenges of glioblastoma, a highly aggressive form of brain cancer that continues to pose significant obstacles to researchers and medical practitioners.
Despite advancements in conventional therapies, the prognosis for glioblastoma patients remains bleak. However, the advent of nanomaterials has ushered in a new era of hope and possibility for both diagnosis and treatment. Within the pages of this meticulously crafted volume, leading experts and researchers in the field have collaborated to explore the remarkable potential of nanomaterials in eradicating glioblastoma.
Covering a wide array of topics, including the synthesis and characterization of nanomaterials, their applications in targeted drug delivery, imaging techniques, and emerging nanotherapeutic strategies, this book offers a comprehensive overview of the latest advancements in the field.
Nanomaterials provide a multifaceted approach that holds promise for personalized medicine in glioblastoma treatment. By precisely tailoring nanoparticles to deliver therapeutic agents with spatial and temporal control, nanotechnology is revolutionizing the fight against this devastating disease. Furthermore, the use of nanomaterials enables novel diagnostic techniques, facilitating early detection and more accurate monitoring of disease progression.
As you embark on this enlightening journey through the pages of "Nanomaterials in Glioblastoma Research, Diagnosis and Therapy," you will witness how the convergence of nanotechnology and neuro-oncology has the potential to reshape the future of glioblastoma management. The authors' expertise and dedication shine through in their compelling narratives, presenting cutting-edge research findings and visionary predictions.
This volume aims not only to inform researchers, clinicians, and students in the field but also to inspire interdisciplinary collaborations, fostering the translation of scientific discoveries into impactful clinical applications. By fostering a deeper understanding and appreciation for the immense possibilities offered by nanotechnology, we aim to expedite the development of more effective and safer therapies, ultimately leading to improved outcomes and a brighter future for glioblastoma patients worldwide.
I express my deepest gratitude to all the esteemed contributors who have shared their knowledge and insights, driving the advancement of nanomaterials in glioblastoma research. My heartfelt appreciation also goes to the dedicated teams working tirelessly in laboratories and hospitals, united by the common goal of finding a cure for this formidable disease.
May this landmark publication serve as a guiding light, paving the way for transformative advancements and opening new avenues for hope and healing in the battle against glioblastoma.
Preface
Welcome to "Nanomaterials in Glioblastoma Research, Diagnosis and Therapy"! In this groundbreaking book, we explore the unprecedented potential of nanotechnology in revolutionizing the field of glioblastoma research, diagnosis, and therapy. Glioblastoma, the most aggressive form of brain cancer, has posed significant challenges to clinicians, researchers, and patients alike for decades. Current treatment options often fall short of providing effective and long-lasting solutions. However, with the advent of nanotechnology, a new era of possibilities has dawned upon us.
The integration of nanomaterials into glioblastoma research has allowed for remarkable advancements in detection, imaging, drug delivery, and therapy. Nanotechnology offers precise control over the targeted delivery of therapeutics, enabling the enhancement of treatment efficacy while minimizing side effects. Moreover, nanomaterials possess unique physicochemical properties that can be harnessed for improved diagnostics and monitoring of glioblastoma progression. This book brings together leading experts in the field, who have made significant contributions to the development and application of nanomaterials in glioblastoma research and therapy. Each chapter explores the latest discoveries, methodologies, and breakthroughs, providing a comprehensive overview of the current state of the art in nanotechnology for glioblastoma.
We begin by delving into the fundamental principles of nanomaterials, their synthesis, and characterization techniques. Subsequently, we delve into the utilization of nanomaterials for imaging glioblastoma, from traditional imaging modalities to cutting-edge molecular imaging and theranostics approaches. The subsequent sections delve into the innovative applications of nanomaterials in targeted drug delivery, gene therapy, immunotherapy, and hyperthermia. Each chapter uncovers the immense potential of nanotechnology in enhancing the efficacy of therapeutic interventions while minimizing the adverse effects on healthy brain tissue.
Finally, we explore emerging trends and future directions in nanomaterials research, highlighting the ongoing efforts to translate these advancements from the laboratory bench to the clinical setting. We also address the challenges and ethical considerations surrounding the use of nanomaterials in glioblastoma research and therapy. "Nanomaterials in Glioblastoma Research, Diagnosis and Therapy" aims to serve as a comprehensive resource for scientists, clinicians, and students interested in the intersection of nanotechnology and glioblastoma. We hope that the knowledge shared within these pages will spark curiosity, drive innovation, and ultimately contribute to the development of effective treatments for this devastating disease. We would like to express our gratitude to the contributing authors for their invaluable insights and expertise, as well as the diligent efforts of the editorial team in bringing this book to fruition. May this collective endeavor pave the way toward a brighter future for glioblastoma patients through the power of nanomaterials.
Acknowledgements
We would like to express our deepest gratitude and appreciation to all those who have contributed to the completion of this book, "Nanomaterials in Glioblastoma Research, Diagnosis and Therapy".
First and foremost, we are immensely thankful to the researchers, scientists, and experts in the field of nanomaterials and glioblastoma who have tirelessly dedicated their time, efforts, and knowledge to share their invaluable insights and advancements. Your expertise has undeniably enriched the content of this book and shed light on the intricate relationship between nanomaterials and glioblastoma. We extend our sincere appreciation to the individuals who have supported and encouraged us throughout this journey. To our colleagues, mentors, and friends who have provided guidance, constructive feedback, and encouragement, we are indebted to your unwavering belief in our work.
We offer our heartfelt gratitude to the editorial team who has worked tirelessly to shape this book into its final form. Your meticulous attention to detail and commitment to excellence have immensely contributed to the quality and coherence of this work. We would also like to thank the reviewers and experts who critically evaluated the manuscript, offering valuable suggestions and observations that have undoubtedly improved its overall quality.
Finally, we express our deepest gratitude to our families for their unwavering love, support, and understanding throughout the course of this project. Your patience and encouragement have been invaluable, and we are forever grateful.
This book would not have been possible without the collective efforts of these individuals. We humbly acknowledge and appreciate the contributions of all those who have played a part, however big or small, in bringing this book to fruition.
Thank you
Molecular Genetics of Glioblastoma (GBM)
Nura Brimo,Emir Baki Denkbas,Beyzanur CakarAbstract
Glioblastoma (GBM) is a highly malignant brain tumor with complex genetic alterations. This chapter provides an overview of the molecular genetics of GBM, including the genetic alterations that contribute to its pathogenesis, the molecular subtypes of GBM, and potential therapeutic targets for GBM treatment. The genetic alterations in GBM involve multiple signaling pathways, including the receptor tyrosine kinase (RTK) pathway, the p53 pathway, the RB pathway, and the PI3K/AKT/mTOR pathway. GBM is also characterized by molecular subtypes that have distinct genetic alterations and clinical features. Potential therapeutic targets for GBM treatment include RTK inhibitors, PI3K/AKT/mTOR inhibitors, and histone deacetylase inhibitors. However, the development of effective therapies for GBM is challenging due to its genetic heterogeneity and the presence of the blood-brain barrier. Understanding the molecular genetics of GBM is crucial for the development of effective therapies and improving patient outcomes.
INTRODUCTION
Glioblastoma (GBM) represents one of the most aggressive and lethal types of brain tumors, characterized by an extremely poor prognosis. This malignancy is defined by complex genetic alterations, encompassing a wide range of mutations, amplifications, deletions, and chromosomal rearrangements. The intricate molecular genetics underlying GBM are essential for informing the development of more effective therapeutic interventions against this formidable disease. Key genetic alterations in GBM are seen across multiple signaling pathways, notably the receptor tyrosine kinase (RTK) pathway, the p53 pathway, the RB pathway, and the PI3K/AKT/mTOR pathway, all of which play crucial roles in regulating cell proliferation, survival, and differentiation. Disruptions in these pathways significantly contribute to the pathogenesis and progression of GBM [1]. Furthermore, GBM encompasses several molecular subtypes, including the classical, mesenchymal, proneural, and neural variants. Each subtype exhibits unique genetic profiles and clinical characteristics, presenting distinct challenges and opportunities for targeted therapeutic strategies. Potential treatment options for GBM focus on inhibiting critical pathways and molecular targets, such as
RTK inhibitors, PI3K/AKT/mTOR inhibitors, and histone deacetylase inhibitors. Nevertheless, developing effective therapies remains a substantial challenge due to the genetic heterogeneity of GBM and the protective barrier posed by the blood-brain interface, which restricts drug delivery to the tumor site [2, 3].
This chapter aims to provide a comprehensive overview of the molecular genetics of GBM, focusing on the genetic alterations that drive its pathogenesis, the defining characteristics of its molecular subtypes, and the potential therapeutic targets under investigation. Additionally, we will explore the ongoing challenges in creating effective treatments for GBM and outline prospective research directions that may yield new insights and advancements in the fight against this devastating disease.
GENETIC ALTERATIONS IN GLIOBLASTOMA
Glioblastoma (GBM) is distinguished by its complex genetic landscape, which includes a variety of mutations, amplifications, deletions, and chromosomal rearrangements. These genetic changes affect several critical signaling pathways, such as the receptor tyrosine kinase (RTK) pathway, the p53 pathway, the RB pathway, and the PI3K/AKT/mTOR pathway. The dysregulation of these pathways plays a fundamental role in GBM pathogenesis, fostering tumor growth and resistance to apoptosis.
One of the most frequently altered pathways in GBM is the RTK pathway, with mutations in the epidermal growth factor receptor (EGFR) gene being among the most common genetic modifications observed. These EGFR mutations can result in the constant activation of the RTK pathway, thereby enhancing cell proliferation and survival. Beyond EGFR, other RTKs, such as the platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR), also exhibit genetic alterations, including gene amplification, which further drives the dysregulation of this pathway [4].
The p53 pathway is another key pathway frequently disrupted in GBM. The p53 protein acts as a tumor suppressor, regulating cell proliferation and DNA repair mechanisms. Mutations in the TP53 gene, leading to a loss of p53 function, are common in GBM and contribute to uncontrolled cell growth and diminished DNA repair. Additional alterations within the p53 pathway include the amplification of the MDM2 gene, which negatively modulates p53 activity, and mutations in the CDKN2A gene, which encodes p16^INK4a, a crucial negative regulator of the RB pathway [5]. Similarly, the RB pathway is commonly disrupted in GBM, with mutations in the RB1 gene frequently observed. Loss of RB function promotes unchecked cell proliferation and impairs cellular differentiation. Other genetic changes in this pathway include the amplification of the CDK4 gene, which encodes cyclin-dependent kinase 4, a positive regulator of the RB pathway, further contributing to GBM pathogenesis [6].
The PI3K/AKT/mTOR pathway, essential for regulating cell growth, metabolism, and survival, is also frequently altered in GBM. Mutations in genes such as PIK3CA and PTEN are prevalent in this pathway. Dysregulation within this pathway drives increased cell proliferation and survival while inhibiting apoptosis. Additional genetic changes in the PI3K/AKT/mTOR pathway include amplification of the AKT3 gene and mutations in TSC1 and TSC2, which act as negative regulators of mTOR signaling.
In summary, genetic alterations in key pathways—including the RTK, p53, RB, and PI3K/AKT/mTOR pathways—are integral to the development and progression of GBM. A deeper understanding of these genetic changes is essential for the development of targeted therapies that may more effectively combat this aggressive form of cancer.
Receptor Tyrosine Kinase (RTK) Pathway
The receptor tyrosine kinase (RTK) pathway plays a crucial role in cellular processes, and its dysregulation is frequently observed in glioblastoma (GBM), a highly aggressive brain tumor characterized by its rapid proliferation and resistance to therapy. RTKs are transmembrane proteins that facilitate cellular communication by binding to specific extracellular ligands, which trigger the activation of downstream intracellular signaling cascades. These cascades regulate fundamental cellular processes, including proliferation, survival, and differentiation, which are critical for maintaining normal cellular function. However, when the RTK pathway is dysregulated, as is often the case in GBM, it can drive uncontrolled cell growth and invasive behavior typical of this malignancy. The aberrant activation of the RTK pathway in GBM not only contributes to tumorigenesis but also complicates therapeutic intervention strategies [5].
Among the various alterations within the RTK pathway, mutations or amplification of the epidermal growth factor receptor (EGFR) gene stands out as some of the most prevalent and impactful in GBM. Mutations in EGFR can lead to its constitutive activation, meaning that the RTK pathway remains persistently active even in the absence of external ligand binding. This constitutive activation results in the continuous promotion of cellular proliferation and enhanced cell survival, fostering an environment conducive to tumor growth and progression. Additionally, gene amplification—where multiple copies of the EGFR gene lead to overexpression of the EGFR protein—can further exacerbate RTK pathway activation. The net effect of these genetic modifications is an intensified signaling output that propels the aggressive nature of GBM. Besides EGFR, other RTKs, such as platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR), are also commonly altered in GBM, each contributing to the overall dysregulation of signaling pathways that support tumor growth and survival.
Given the central role of the RTK pathway in GBM, targeting this pathway has emerged as a potential therapeutic approach. Multiple RTK inhibitors have been developed with the goal of interrupting aberrant signaling within this pathway. For instance, drugs like erlotinib, gefitinib, and lapatinib have been designed to specifically inhibit EGFR, while other agents such as imatinib and sunitinib target PDGFR. Despite the theoretical promise of these drugs, clinical trials have generally shown limited efficacy. Several factors contribute to this limited success, including the substantial genetic heterogeneity inherent in GBM tumors and the presence of the blood-brain barrier (BBB), which restricts the penetration of therapeutic agents into the brain. The BBB is a highly selective barrier that protects the brain from potentially harmful substances in the bloodstream, but it also poses a significant challenge to the effective delivery of RTK inhibitors to the tumor site [2].
In light of these challenges, researchers have explored combination therapies as a potentially more effective strategy for targeting GBM. One promising avenue involves combining RTK inhibitors with agents targeting additional signaling pathways, such as the PI3K/AKT/mTOR pathway, which is frequently dysregulated alongside the RTK pathway in GBM. Preclinical studies have shown that such combination therapies may enhance therapeutic efficacy by simultaneously blocking multiple pathways that contribute to tumor survival and growth. This approach holds promise for overcoming some of the limitations posed by single-agent RTK inhibitors, particularly in addressing the complex network of signaling dysregulation characteristic of GBM.
In summary, the dysregulation of the RTK pathway represents a common and significant genetic alteration in GBM that is closely tied to the disease's pathogenesis. Targeting this pathway remains a key focus in the search for effective GBM therapies; however, the inherent genetic diversity of GBM tumors and the protective role of the BBB present substantial obstacles to achieving therapeutic success. Continued exploration of combination therapies and novel approaches to enhance drug delivery to the brain may ultimately yield more effective treatment options for patients with GBM [6].
p53 Pathway
The p53 pathway is a critical regulator of cellular functions and is frequently disrupted in glioblastoma (GBM), a highly malignant and aggressive brain tumor. At the heart of this pathway lies the p53 protein, often referred to as the “guardian of the genome” due to its essential role as a tumor suppressor. p53 is pivotal in maintaining cellular integrity through its regulation of cell proliferation, DNA repair, and apoptosis (programmed cell death). In healthy cells, p53 monitors genomic stability and responds to DNA damage or cellular stress by halting the cell cycle, facilitating DNA repair mechanisms, or, in cases of irreparable damage, initiating apoptosis to prevent the propagation of mutated cells. In GBM, however, the function of p53 is frequently compromised, which diminishes its capacity to act as a safeguard against tumorigenesis, thus contributing to the development, progression, and resistance of the tumor to standard therapies [7].
The primary mechanism of p53 pathway dysregulation in GBM is through mutations or deletions in the TP53 gene, which encodes the p53 protein. TP53 mutations are among the most common genetic alterations observed in GBM and often lead to a complete loss of p53 function. This loss of function permits unchecked cell proliferation and survival, as p53 can no longer enforce cell cycle arrest or apoptosis in response to DNA damage or oncogenic signals. Additionally, without functional p53, DNA repair processes are compromised, allowing mutations to accumulate and contributing to genomic instability—an essential characteristic of GBM progression. Beyond TP53 mutations, other genetic alterations within the p53 pathway further exacerbate its dysregulation. For example, amplification of the MDM2 gene is frequently observed in GBM. MDM2 encodes an oncoprotein that directly inhibits p53 activity by targeting it for proteasomal degradation. Overexpression of MDM2 reduces p53 levels in cells, even in cases where TP53 itself is not mutated, further impairing the cell’s ability to undergo apoptosis or cell cycle arrest. Another significant alteration involves mutations in the CDKN2A gene, which encodes the tumor suppressor protein p16INK4a. p16INK4a functions as a negative regulator of the RB (retinoblastoma) pathway, and its inactivation removes critical checkpoints on cell cycle progression, allowing cells to proliferate uncontrollably. These combined alterations within the p53 pathway highlight the multifaceted mechanisms through which GBM can evade regulatory controls and promote its own growth and survival [7, 8].
Given the central role of the p53 pathway in GBM pathogenesis, targeting this pathway represents a promising therapeutic strategy. Several small molecules have been developed to modulate components of the p53 pathway, offering potential avenues to restore its tumor-suppressive functions. Among these, PRIMA-1 and APR-246 are notable for their capacity to reactivate mutant p53, restoring its ability to initiate apoptosis and halt cell cycle progression in cancer cells with dysfunctional p53. Another molecule, nutlin-3a, operates by inhibiting the interaction between p53 and MDM2, thereby preventing p53 degradation and enabling the reactivation of its tumor-suppressive functions. These agents have demonstrated encouraging efficacy in preclinical studies, and some have advanced to clinical trials, showing potential as viable treatment options for patients with GBM. However, the complexity of GBM’s genetic landscape necessitates a more comprehensive approach.
In addition to single-agent therapies that target the p53 pathway, combination therapies that inhibit multiple dysregulated pathways in GBM are under investigation. One promising approach involves the use of p53-targeted therapies in conjunction with inhibitors of the PI3K/AKT/mTOR pathway, another signaling axis frequently altered in GBM. The PI3K/AKT/mTOR pathway regulates cell growth, survival, and metabolism, and its dysregulation in GBM further contributes to the tumor’s aggressive phenotype. By concurrently targeting both the p53 and PI3K/AKT/mTOR pathways, researchers aim to block multiple survival mechanisms simultaneously, thereby enhancing therapeutic efficacy. Preclinical studies of these combination strategies have shown promising results, suggesting that they may overcome some of the limitations associated with monotherapy in GBM [9].
In conclusion, alterations in the p53 pathway are a fundamental aspect of GBM’s molecular pathology, facilitating unchecked cell proliferation, reduced apoptosis, and impaired DNA repair mechanisms. Targeting the p53 pathway, either through reactivation of mutant p53 or inhibition of negative regulators like MDM2, offers a viable therapeutic strategy that has demonstrated promise in preclinical and early clinical studies. Given the complexity and heterogeneity of GBM, combination therapies that address multiple signaling pathways may represent the most effective approach to overcoming resistance and improving patient outcomes. Continued research into the molecular interactions within the p53 pathway and its interplay with other oncogenic pathways holds the potential to unlock new treatment options for this challenging and often treatment-resistant cancer [10].
RB Pathway
The retinoblastoma (RB) pathway is an essential regulatory mechanism that controls cell cycle progression and cellular differentiation, playing a particularly significant role in the pathology of glioblastoma (GBM). This pathway is frequently altered in GBM, with one of the most common genetic abnormalities being mutations or deletions in the RB1 gene, which encodes the RB protein, a critical tumor suppressor. The loss of RB function disrupts the pathway’s normal control over cell proliferation and differentiation, leading to unchecked cellular growth, prolonged survival, and impaired differentiation. These effects collectively contribute to the aggressive growth and resistance to treatment that characterize GBM [11].
The RB protein exerts its tumor-suppressive effects by inhibiting cell cycle progression through its interaction with E2F transcription factors. Under normal conditions, RB binds to and inactivates E2F transcription factors, effectively halting the cell cycle at the G1 phase. This inhibition prevents the transition from the G1 phase to the S phase, where DNA synthesis and replication occur. However, the RB protein’s suppressive role is modulated by phosphorylation events. When cyclin-dependent kinases (CDKs), specifically CDK4 and CDK6, phosphorylate the RB protein, RB undergoes a conformational change that leads to the release of E2F transcription factors. Once freed, E2F activates a suite of target genes necessary for cell cycle progression, driving the cell through the G1/S checkpoint and into DNA synthesis. This regulatory balance is essential for maintaining controlled cell proliferation.
In GBM, the dysregulation of the RB pathway often results from various genetic and molecular alterations. While mutations or deletions in the RB1 gene are direct means of inactivating the RB pathway, other alterations can achieve similar effects by influencing upstream and downstream components of the pathway. For instance, amplification of the CDK4 gene, which leads to the overexpression of CDK4, can cause excessive phosphorylation of RB, thereby reducing its inhibitory function on E2F and promoting continuous cell cycle progression. Additionally, alterations in other signaling molecules that interact with the RB pathway can contribute to its dysregulation, creating a permissive environment for unregulated cell proliferation and tumor growth [12].
Given the critical role of the RB pathway in GBM pathogenesis, targeting this pathway has emerged as a promising therapeutic strategy. CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, have been developed to specifically inhibit the activity of cyclin-dependent kinases 4 and 6. By blocking these kinases, CDK4/6 inhibitors prevent the phosphorylation of the RB protein, maintaining its binding to E2F transcription factors and effectively enforcing cell cycle arrest. This action can induce apoptosis and limit the proliferation of GBM cells, slowing down tumor progression. CDK4/6 inhibitors have shown considerable promise in both preclinical studies and clinical trials, with ongoing research examining their efficacy as monotherapies or in combination with other treatments to enhance therapeutic outcomes.
The complexity of GBM's molecular landscape suggests that targeting a single pathway, such as the RB pathway, may not be sufficient to achieve substantial and lasting therapeutic effects. Consequently, researchers have explored combination therapies that simultaneously target multiple pathways commonly dysregulated in GBM. For example, the PI3K/AKT/mTOR pathway, which is heavily involved in promoting cell survival and growth, is frequently altered in GBM. Preclinical studies have shown that combining CDK4/6 inhibitors targeting the RB pathway with inhibitors of the PI3K/AKT/mTOR pathway can produce synergistic effects, enhancing the anti-tumor response and potentially overcoming some of the resistance mechanisms that limit the efficacy of monotherapy approaches [13, 14].
In summary, alterations in the RB pathway are integral to the pathogenesis of GBM, as they remove critical cell cycle checkpoints and promote unregulated proliferation. Therapeutic strategies targeting the RB pathway, particularly through CDK4/6 inhibition, have shown promise in early studies and are actively being investigated in clinical trials. Given the genetic heterogeneity of GBM, combination therapies that address multiple dysregulated pathways, such as the RB and PI3K/AKT/mTOR pathways, may offer a more effective approach to managing this challenging and aggressive cancer.
PI3K/AKT/mTOR Pathway
The PI3K/AKT/mTOR pathway is a fundamental signaling cascade that regulates essential cellular processes such as growth, survival, and metabolism. This pathway is especially relevant in the context of glioblastoma (GBM), one of the most aggressive forms of brain cancer, where its dysregulation is a prevalent feature. Alterations in this pathway contribute to the malignant behavior of GBM, including rapid cell proliferation, resistance to apoptosis, and enhanced metabolic activity. Dysregulation of the PI3K/AKT/mTOR pathway in GBM commonly arises from mutations or amplifications of genes encoding its key components, which can directly activate the pathway or lead to a loss of regulatory control [15].
