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Keywords = hedgehog pathway inhibitors

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17 pages, 902 KiB  
Review
Cancer Stem Cells in Melanoma: Drivers of Tumor Plasticity and Emerging Therapeutic Strategies
by Adrian-Horațiu Sabău, Andreea-Cătălina Tinca, Raluca Niculescu, Iuliu Gabriel Cocuz, Andreea Raluca Cozac-Szöke, Bianca Andreea Lazar, Diana Maria Chiorean, Corina Eugenia Budin and Ovidiu Simion Cotoi
Int. J. Mol. Sci. 2025, 26(15), 7419; https://doi.org/10.3390/ijms26157419 - 1 Aug 2025
Viewed by 162
Abstract
Cutaneous malignant melanoma is an extraordinarily aggressive and heterogeneous cancer that contains a small subpopulation of tumor stem cells (CSCs) responsible for tumor initiation, metastasis, and recurrence. Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack [...] Read more.
Cutaneous malignant melanoma is an extraordinarily aggressive and heterogeneous cancer that contains a small subpopulation of tumor stem cells (CSCs) responsible for tumor initiation, metastasis, and recurrence. Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack of specific markers (CD271, ABCB5, ALDH, Nanog) and the ability of cells to dynamically change their phenotype. Phenotype-maintaining signaling pathways (Wnt/β-catenin, Notch, Hedgehog, HIF-1) promote self-renewal, treatment resistance, and epithelial–mesenchymal transitions. Tumor plasticity reflects the ability of differentiated cells to acquire stem-like traits and phenotypic flexibility under stress conditions. The interaction of CSCs with the tumor microenvironment accelerates disease progression: they induce the formation of cancer-associated fibroblasts (CAFs) and neo-angiogenesis, extracellular matrix remodeling, and recruitment of immunosuppressive cells, facilitating immune evasion. Emerging therapeutic strategies include immunotherapy (immune checkpoint inhibitors), epigenetic inhibitors, and nanotechnologies (targeted nanoparticles) for delivery of chemotherapeutic agents. Understanding the role of CSCs and tumor plasticity paves the way for more effective innovative therapies against melanoma. Full article
(This article belongs to the Special Issue Mechanisms of Resistance to Melanoma Immunotherapy)
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21 pages, 5292 KiB  
Article
Downregulation of S6 Kinase and Hedgehog–Gli1 by Inhibition of Fatty Acid Synthase in AML with FLT3-ITD Mutation
by Maxim Kebenko, Ruimeng Zhuang, Konstantin Hoffer, Anna Worthmann, Stefan Horn, Malte Kriegs, Jan Vorwerk, Nikolas von Bubnoff, Cyrus Khandanpour, Niklas Gebauer, Sivahari Prasad Gorantla, Walter Fiedler, Carsten Bokemeyer and Manfred Jücker
Int. J. Mol. Sci. 2025, 26(12), 5721; https://doi.org/10.3390/ijms26125721 - 14 Jun 2025
Viewed by 571
Abstract
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 [...] Read more.
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
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10 pages, 241 KiB  
Review
Advanced Basal Cell Carcinoma: A Narrative Review on Current Systemic Treatments and the Neoadjuvant Approach
by Andrea Paradisi, Maria Mannino, Francesco Brunetti, Enrico Bocchino, Alessandro Di Stefani and Ketty Peris
J. Pers. Med. 2025, 15(6), 226; https://doi.org/10.3390/jpm15060226 - 1 Jun 2025
Cited by 1 | Viewed by 756
Abstract
Background/Objectives: Systemic therapy with hedgehog pathway inhibitors (HHIs) and anti-programmed cell death protein 1 (PD-1) antibodies represent the first- and second-line treatment options for advanced basal cell carcinoma (aBCC), respectively. A shift in the treatment paradigms toward the neoadjuvant approach is gaining increasing [...] Read more.
Background/Objectives: Systemic therapy with hedgehog pathway inhibitors (HHIs) and anti-programmed cell death protein 1 (PD-1) antibodies represent the first- and second-line treatment options for advanced basal cell carcinoma (aBCC), respectively. A shift in the treatment paradigms toward the neoadjuvant approach is gaining increasing interest in aBCC management, whereby prior systemic therapy followed by surgery is likely to yield more favorable outcomes. The aim of this narrative review is to summarize the current evidence on systemic treatment options and the neoadjuvant approach for aBCC management. Methods: We performed a non-systematic review of the literature based on PubMed as search engine. Results: The pivotal phase II trials ERIVANCE and BOLT investigated the efficacy and safety profile of vismodegib and sonidegib, respectively, with reported objective response rates (ORRs) of 60.3% and 56% in laBCC patients, respectively. The pivotal phase II trial NCT03132636 investigated the efficacy and safety profile of cemiplimab in patients who progressed or were intolerant to prior HHI therapy, with an ORR of 32.1% in laBCC patients. Real-life studies confirmed the effectiveness and safety profile of HHI and anti-PD-1 immunotherapy. Several phase I/II clinical trials are currently investigating HHIs and immune-checkpoint inhibitors in the neoadjuvant setting followed by surgery for aBCC patients, with the aim of providing more favorable treatment outcomes, especially when upfront surgery would result in functional and/or aesthetic sequelae. Conclusions: Advanced BCC treatment is challenging, and the neoadjuvant approach followed by surgery is expected to reduce surgical complexity, increase tissue preservation, and improve patients’ satisfaction. Full article
(This article belongs to the Special Issue Dermatology: Molecular Mechanisms, Diagnosis and Therapeutic Targets)
10 pages, 413 KiB  
Article
Clinical and Histological Predictors of Advanced Basal Cell Carcinoma Recurrence After Complete Response to Hedgehog Pathway Inhibitors: A Retrospective Multicenter Observational Study
by Maria Mannino, Massimiliano Scalvenzi, Alessandro Di Stefani, Claudia Costa, Piergiacomo Calzavara-Pinton, Maria Concetta Fargnoli, Alfredo Piccerillo, Enrico Bocchino, Iris Zalaudek, Paolo Antonio Ascierto, Pietro Quaglino, Paola Queirolo, Emi Dika, Vincenzo De Giorgi, Elvira Moscarella, Luca Bianchi, Caterina Longo, Carmen Cantisani, Alessia Villani, Ketty Peris and Collaboratorsadd Show full author list remove Hide full author list
Cancers 2025, 17(11), 1840; https://doi.org/10.3390/cancers17111840 - 30 May 2025
Viewed by 610
Abstract
Background/Objectives: Long-term outcome data of locally advanced basal cell carcinoma patients who achieve complete response (CR) on hedgehog pathway inhibitors (HHIs) are lacking, highlighting a gap in the identification of the predictors of tumor recurrence. We aimed to investigate the [...] Read more.
Background/Objectives: Long-term outcome data of locally advanced basal cell carcinoma patients who achieve complete response (CR) on hedgehog pathway inhibitors (HHIs) are lacking, highlighting a gap in the identification of the predictors of tumor recurrence. We aimed to investigate the clinical and histological factors associated with locally advanced BCC recurrence after CR on HHIs. Patients and methods: We performed a retrospective multicenter observational study at 14 Italian tertiary referral centers (1 January 2016–1 March 2024). Univariate logistic regression was used to investigate the association between locally advanced BCC recurrence and clinical and histological features. Kaplan–Meier analysis was used to estimate relapse-free survival (RFS). Results: A total of 106 locally advanced BCC patients were enrolled, of whom 14/106 (13.2%) experienced relapse after a median follow-up of 12 months (range: 1–70 months). Low-risk locally advanced BCC histological subtypes (superficial and nodular) were associated with a decreased probability of locally advanced BCC recurrence (odds ratio [OR]: 0.15, 95% CI: 0.04–0.51; p: 0.003); a longer time to CR predicted locally advanced BCC relapse (OR: 1.07, 95% CI: 1.01–1.15; p: 0.04). Accordingly, locally advanced BCC histology and time to CR significantly impacted RFS probability. Conclusions: Specific locally advanced BCC histological subtypes and time to CR predict tumor recurrence after CR on HHIs. Full article
(This article belongs to the Special Issue Advances in Skin Cancer: Diagnosis, Treatment and Prognosis)
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23 pages, 7972 KiB  
Article
Short Tandem Repeat (STR) Somatic Mutation in Non-Melanoma Skin Cancer (NMSC): Association with Transcriptomic Profile and Potential Implications for Therapy
by Muhammad G. Kibriya, Armando Almazan, Maria Argos, Tariqul Islam, Christopher R. Shea, Habibul Ahsan and Farzana Jasmine
Cancers 2025, 17(10), 1669; https://doi.org/10.3390/cancers17101669 - 15 May 2025
Viewed by 681
Abstract
Background: Studies on somatic mutations in cancer typically report single-nucleotide variants in coding regions, while mutations in short tandem repeats (STRs) are usually overlooked. Homopolymeric regions, a subset of STRs, are stretches of DNA where only a single nucleotide is repeated multiple times [...] Read more.
Background: Studies on somatic mutations in cancer typically report single-nucleotide variants in coding regions, while mutations in short tandem repeats (STRs) are usually overlooked. Homopolymeric regions, a subset of STRs, are stretches of DNA where only a single nucleotide is repeated multiple times (e.g., AAAAA or TTTTT). Only recently have mutations in such STR regions been seen in colorectal cancer, where microsatellite instability (MSI) is common. In non-melanoma skin cancer (NMSC), MSI is rare. In this study, we focus on somatic mutations in such homopolymeric regions in NMSC and their functional implications. Methods: We performed targeted DNA sequencing (paired tissue and blood from the same individual), using more than 400 cancer-related genes from 32 NMSC patients as cases and non-lesional skin tissue from 16 independent individuals as controls. Results: We identified NMSC-associated STR somatic mutations. These are associated with the dysregulation of DNA damage and repair mechanisms. In artificial intelligence (AI) predictive modeling, these markers could successfully differentiate basal cell carcinoma (BCC) and non-lesional skin tissue. To our knowledge, we present the first study focusing on STR somatic mutations in multiple cancer-related genes in NMSC found only in tumor tissue and not in non-lesional skin tissue. Some of them (APC, BRAF) are associated with more pronounced dysregulation of relevant gene pathways (hedgehog, Notch signaling, and Wnt signaling). Conclusions: Our findings suggest that this STR somatic mutation status might potentially be used to select BCC patients who could benefit from certain precision therapy including hedgehog inhibitors, gamma-secretase inhibitors, anti-Vasuclar endothelial growth factor (VEGF), proteasome inhibitors, and immune check-point inhibitors. Full article
(This article belongs to the Special Issue Advances in Genetic and Molecular Approaches to Skin Cancer)
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14 pages, 2258 KiB  
Article
Plasma Protein Binding, Biostability, Metabolite Profiling, and CYP450 Phenotype of TPB15 Across Different Species: A Novel Smoothened Inhibitor for TNBC Therapy
by Dingsheng Wen, Boyu Chen, Mingtong Deng, Shaoyu Wu and Shuilin Xie
Pharmaceutics 2025, 17(4), 423; https://doi.org/10.3390/pharmaceutics17040423 - 26 Mar 2025
Viewed by 535
Abstract
Background/Objectives: Triple-negative breast cancer (TNBC) is a major cause of cancer-related deaths among women. The Hedgehog (Hh) signaling pathway plays a critical role in tumor development, and targeting this pathway may provide new therapeutic opportunities for TNBC. TPB15 is a novel smoothened [...] Read more.
Background/Objectives: Triple-negative breast cancer (TNBC) is a major cause of cancer-related deaths among women. The Hedgehog (Hh) signaling pathway plays a critical role in tumor development, and targeting this pathway may provide new therapeutic opportunities for TNBC. TPB15 is a novel smoothened inhibitor of the Hh pathway, showing promising tumor reduction and low-toxicity properties in vivo/vitro. This study aims to evaluate TPB15’s protein binding rates, metabolic stability, and metabolism across different species, including mice, rats, dogs, monkeys, and humans. Methods: TPB15 was synthesized, and its pharmacokinetic profile was assessed. Plasma protein binding was determined using ultrafiltration across multiple species. Stability studies were conducted in plasma and liver microsomes from each species. Additionally, metabolic enzymes in human liver microsomes were characterized with selective CYP450 inhibitors, and high-resolution mass spectrometry was employed to identify metabolites. Results: Plasma protein binding of TPB15 was consistent across species, ranging from 81.5% to 82.4% in humans and rats. After 120 min, TPB15 remained stable in plasma, with retention rates of 97.2–98.3%. The elimination half-life (t1/2) varied from 88 min in monkeys to 630 min in dogs. In human liver microsomes, metabolism was significantly inhibited by sulfaphenazole and ketoconazole, indicating the involvement of CYP3A4 and CYP2C9 enzymes. TPB15 underwent phase I metabolism, producing a major metabolite with a molecular weight of 468.9. Conclusions: TPB15 demonstrates stable pharmacokinetic properties across species, with consistent protein binding and significant variability in half-life. The observed differences in metabolism are primarily attributed to CYP2C9 and CYP3A4, offering valuable insights into its drug development potential. Full article
(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)
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10 pages, 2441 KiB  
Case Report
Recurrent Metastatic Basal Cell Carcinomas of the Face in a Patient with Gorlin–Goltz Syndrome
by Petko Petrov, Dobromira Shopova, Georgi Goranov, Atanaska Dinkova, Nina Stoyanova and Nikolay Yanev
Curr. Oncol. 2025, 32(4), 193; https://doi.org/10.3390/curroncol32040193 - 26 Mar 2025
Viewed by 629
Abstract
Gorlin–Goltz syndrome, also known as nevoid basal cell carcinoma syndrome (NBCCS), is a rare, inherited autosomal dominant disorder primarily caused by mutations in the PTCH1 gene, which regulates the Hedgehog signaling pathway. This genetic defect leads to the uncontrolled proliferation of basal cells, [...] Read more.
Gorlin–Goltz syndrome, also known as nevoid basal cell carcinoma syndrome (NBCCS), is a rare, inherited autosomal dominant disorder primarily caused by mutations in the PTCH1 gene, which regulates the Hedgehog signaling pathway. This genetic defect leads to the uncontrolled proliferation of basal cells, resulting in the formation of multiple basal cell carcinomas (BCCs) and odontogenic keratocysts (OKCs). This study aims to present a complex clinical case of a patient with Gorlin–Goltz syndrome who developed multiple recurrent metastatic basal cell carcinomas on the facial region, detailing the multidisciplinary treatment strategies employed and the challenges encountered during the management of the disease. The patient, diagnosed with a pathogenic PTCH1 gene mutation, underwent a series of treatment interventions over several years. These included multiple surgical excisions aimed at tumor removal, diverse radiotherapy approaches for residual or inoperable lesions, and systemic targeted therapy with Hedgehog pathway inhibitors to control tumor progression. The recurrent and aggressive nature of the basal cell carcinomas resulted in extensive facial tissue loss, posing significant challenges for radical tumor excision and subsequent reconstructive procedures. Multimodal therapeutic strategies, including Mohs micrographic surgery for precise tumor clearance and targeted systemic therapy with vismodegib, were implemented. However, the aggressive progression of lesions required ongoing surgical interventions, highlighting the limitations of current treatment modalities in achieving long-term disease control. This case underscores the critical need for a comprehensive, multidisciplinary approach to managing Gorlin–Goltz syndrome. Successful management requires close collaboration between dermatologists, oncologists, maxillofacial surgeons, and plastic surgeons to balance effective tumor control with optimal functional and aesthetic outcomes. The integration of advanced surgical techniques and targeted molecular therapies shows promise in improving patient outcomes. Nonetheless, early diagnosis, rigorous follow-up, and patient education remain essential components in minimizing disease progression and enhancing the quality of life for affected individuals. Full article
(This article belongs to the Section Head and Neck Oncology)
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14 pages, 2289 KiB  
Review
Basal Cell Carcinoma: An Old Friend with Multiple Faces
by Maria Chiara Sergi, Francesca Ambrogio, Mario Della Mura, Joana Sorino and Gerardo Cazzato
Cancers 2025, 17(6), 993; https://doi.org/10.3390/cancers17060993 - 15 Mar 2025
Viewed by 1415
Abstract
BCC is the most prevalent form of skin cancer, characterized by diverse clinical and pathological subtypes ranging from indolent to highly aggressive forms. While the majority of BCC cases are treated effectively with surgery or local therapies, locally advanced BCC (laBCC) and metastatic [...] Read more.
BCC is the most prevalent form of skin cancer, characterized by diverse clinical and pathological subtypes ranging from indolent to highly aggressive forms. While the majority of BCC cases are treated effectively with surgery or local therapies, locally advanced BCC (laBCC) and metastatic BCC (mBCC) pose significant therapeutic challenges. Recent advances in HHIs and immunotherapy have transformed the treatment landscape in such cases. However, resistance and intolerance to these treatments necessitate alternative approaches, including chemotherapy. Platinum-based agents such as cisplatin and carboplatin have shown limited efficacy but remain viable options in rapidly progressive cases. Among the therapeutic innovations to be explored, further lines of immunotherapy as well as combination therapies involving immunotherapy and targeted therapy have been proposed. This review synthesizes the current understanding about BCC subtypes, risk stratification, and emerging treatments, with a particular focus on laBCC and mBCC. Full article
(This article belongs to the Special Issue Advances in Skin Cancer: Diagnosis, Treatment and Prognosis)
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19 pages, 769 KiB  
Review
Meningioma: Novel Diagnostic and Therapeutic Approaches
by Carlen A. Yuen, Michelle Zheng, Max A. Saint-Germain and David O. Kamson
Biomedicines 2025, 13(3), 659; https://doi.org/10.3390/biomedicines13030659 - 7 Mar 2025
Cited by 2 | Viewed by 2490
Abstract
Background/Objectives: Meningiomas are the most common intracranial tumors. Surgery and radiation therapy are the cornerstones of treatment and no standard of care therapy exists for refractory meningiomas. This manuscript aims to provide a comprehensive review of novel diagnostic and therapeutic approaches against [...] Read more.
Background/Objectives: Meningiomas are the most common intracranial tumors. Surgery and radiation therapy are the cornerstones of treatment and no standard of care therapy exists for refractory meningiomas. This manuscript aims to provide a comprehensive review of novel diagnostic and therapeutic approaches against these tumors. Methods: A search for the existing literature on systemic therapies for meningiomas was performed on PubMed and a search for presently accruing clinical trials was performed on ClinicalTrials.gov. Results: Systemic treatments, including chemotherapy, somatostatin analogs, anti-hormone therapy, and anti-angiogenic therapy, have been extensively studied with marginal success. Targeted therapies are actively being studied for the treatment of meningiomas, including focal adhesion kinase (FAK), sonic hedgehog signaling pathway, phosphoinositide-3-kinase (PI3K), and cyclin-dependent kinases (CDK) inhibitors. These driver mutations are present only in a subset of meningiomas. In stark contrast, somatostatin receptor 2 (SSTR2) is ubiquitously expressed in meningiomas and was formerly targeted with somatostatin analogs with modest success. Theranostic SSTR2-targeting via [68Ga]DOTATATE for PET imaging and β-emitting [177Lu]DOTATATE for the treatment of meningiomas are currently under active investigation. Conclusions: A nuanced approach is needed for the treatment of refractory meningiomas. Targeted therapies show promise. Full article
(This article belongs to the Special Issue Meningioma: Novel Diagnostic and Therapeutic Approaches)
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14 pages, 1484 KiB  
Article
Synthesis and Evaluation of Aromatic A-Ring 23-Oxavitamin D3 Analogues as Hedgehog Pathway Inhibitors
by Wang Chen, Feifan Lai and Jianghe Xu
Int. J. Mol. Sci. 2025, 26(4), 1631; https://doi.org/10.3390/ijms26041631 - 14 Feb 2025
Cited by 1 | Viewed by 584
Abstract
The Hedgehog (Hh) signaling pathway plays a crucial role in the initiation and progression of tumors, and Hh inhibitors have been used as potential chemotherapeutic agents for the treatment of basal cell carcinomas (BCCs). Vitamin D3 (VD3) and its derivatives [...] Read more.
The Hedgehog (Hh) signaling pathway plays a crucial role in the initiation and progression of tumors, and Hh inhibitors have been used as potential chemotherapeutic agents for the treatment of basal cell carcinomas (BCCs). Vitamin D3 (VD3) and its derivatives have been identified as potent Hh inhibitors. However, the selectivity of VD3 derivatives to vitamin D receptor (VDR) and the Hh signaling pathway still needs optimization. In this study, a series of aromatic A-ring mimics VD3 analogues that contain a C-23 oxygen atom or incorporate C-25 hydroxyl on side chains were designed and synthesized. These compounds were tested in various cell lines for anti-Hh activity, with analogues 3j and 4i identified as potent inhibitors. Mechanism studies showed their anti-Hh effects are mainly due to targeting Smoothened (Smo) without binding to the cyclopamine site. Structure-activity relationship (SAR) studies revealed that VD3-based inhibitors enhance anti-Hh activity by adding a hydroxyl group at C25 while reducing VDR activity by incorporating an oxygen atom into the side chain. Full article
(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)
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22 pages, 1936 KiB  
Review
Hedgehog and PI3K/Akt/mTOR Signaling Pathways Involvement in Leukemic Malignancies: Crosstalk and Role in Cell Death
by Mariaconcetta Sicurella, Marica De Chiara and Luca Maria Neri
Cells 2025, 14(4), 269; https://doi.org/10.3390/cells14040269 - 13 Feb 2025
Cited by 3 | Viewed by 1488
Abstract
The Hedgehog (Hh) and PI3K/Akt/mTOR signaling pathways play a pivotal role in driving the initiation and progression of various cancers, including hematologic malignancies such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). These [...] Read more.
The Hedgehog (Hh) and PI3K/Akt/mTOR signaling pathways play a pivotal role in driving the initiation and progression of various cancers, including hematologic malignancies such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). These pathways are often dysregulated in leukemia cells, leading to increased cell growth, survival, and drug resistance while also impairing mechanisms of cell death. In leukemia, the Hh pathway can be abnormally activated by genetic mutations. Additionally, the PI3K/Akt/mTOR pathway is frequently overactive due to genetic changes. A key aspect of these pathways is their interaction: activation of the PI3K/Akt pathway can trigger a non-canonical activation of the Hh pathway, which further promotes leukemia cell growth and survival. Targeted inhibitors of these pathways, such as Gli inhibitors and PI3K/mTOR inhibitors, have shown promise in preclinical and clinical studies. Full article
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13 pages, 275 KiB  
Review
Wnt Signaling Pathway in Tumor Biology
by Sabina Iluta, Madalina Nistor, Sanda Buruiana and Delia Dima
Genes 2024, 15(12), 1597; https://doi.org/10.3390/genes15121597 - 13 Dec 2024
Cited by 3 | Viewed by 1241
Abstract
Relapse and metastasis are the major challenges that stand in the way of cancer healing and survival, mainly attributed to cancer stem cells (CSCs). Their capabilities of self-renewal and tumorigenic potential leads to treatment resistance development. CSCs function through signaling pathways such as [...] Read more.
Relapse and metastasis are the major challenges that stand in the way of cancer healing and survival, mainly attributed to cancer stem cells (CSCs). Their capabilities of self-renewal and tumorigenic potential leads to treatment resistance development. CSCs function through signaling pathways such as the Wnt/β-catenin cascade. While commonly involved in embryogenesis and adult tissues homeostasis, the dysregulation of the Wnt pathway has direct correlations with tumorigenesis, metastasis, and drug resistance. The development of therapies that target CSCs and bulk tumors is both crucial and urgent. However, the extensive crosstalk present between Wnt and other signaling networks (Hedgehog and Notch) complicates the development of efficient long-term therapies with minimal side-effects on normal tissues. Despite the obstacles, the emergence of Wnt inhibitors and subsequent modulation of the signaling pathways would provide dynamic therapeutic approaches to impairing CSCs and reversing resistance mechanisms. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
29 pages, 2260 KiB  
Review
Hedgehog Signaling Pathway in Fibrosis and Targeted Therapies
by Yuchen Hu, Linrui Peng, Xinyu Zhuo, Chan Yang and Yuwei Zhang
Biomolecules 2024, 14(12), 1485; https://doi.org/10.3390/biom14121485 - 22 Nov 2024
Cited by 4 | Viewed by 2237
Abstract
Hedgehog (Hh) signaling is a well-established developmental pathway; it is crucial for early embryogenesis, cell differentiation, and damage-driven regeneration. It is being increasingly recognized that dysregulated Hh signaling is also involved in fibrotic diseases, which are characterized by excessive extracellular matrix deposition that [...] Read more.
Hedgehog (Hh) signaling is a well-established developmental pathway; it is crucial for early embryogenesis, cell differentiation, and damage-driven regeneration. It is being increasingly recognized that dysregulated Hh signaling is also involved in fibrotic diseases, which are characterized by excessive extracellular matrix deposition that compromises tissue architecture and function. As in-depth insights into the mechanisms of Hh signaling are obtained, its complex involvement in fibrosis is gradually being illuminated. Notably, some Hh-targeted inhibitors are currently under exploration in preclinical and clinical trials as a means to prevent fibrosis progression. In this review, we provide a concise overview of the biological mechanisms involved in Hh signaling. We summarize the latest advances in our understanding of the roles of Hh signaling in fibrogenesis across the liver, kidneys, airways, and lungs, as well as other tissues and organs, with an emphasis on both the shared features and, more critically, the distinct functional variations observed across these tissues and organs. We thus highlight the context dependence of Hh signaling, as well as discuss the current status and the challenges of Hh-targeted therapies for fibrosis. Full article
(This article belongs to the Section Molecular Medicine)
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11 pages, 1596 KiB  
Article
Hedgehog Pathway Is a Regulator of Stemness in HER2-Positive Trastuzumab-Resistant Breast Cancer
by Idris Er and Asiye Busra Boz Er
Int. J. Mol. Sci. 2024, 25(22), 12102; https://doi.org/10.3390/ijms252212102 - 11 Nov 2024
Cited by 3 | Viewed by 1295
Abstract
HER2 overexpression occurs in 20–30% of breast cancers and is associated with poor prognosis. Trastuzumab is a standard treatment for HER2-positive breast cancer; however, resistance develops in approximately 50% of patients within a year. The Hedgehog (Hh) signalling pathway, known for its role [...] Read more.
HER2 overexpression occurs in 20–30% of breast cancers and is associated with poor prognosis. Trastuzumab is a standard treatment for HER2-positive breast cancer; however, resistance develops in approximately 50% of patients within a year. The Hedgehog (Hh) signalling pathway, known for its role in maintaining stemness in various cancers, may contribute to trastuzumab resistance in HER2-positive breast cancer. This study aimed to investigate the role of Hedgehog signalling in maintaining stemness and contributing to trastuzumab resistance in HER2-positive breast cancer cell lines. Trastuzumab-resistant HER2-positive breast cancer cell lines, SKBR3 and HCC1954, were developed through continuous trastuzumab exposure. Cells were treated with GANT61 (Hh inhibitor, IC50:10 µM) or SAG21K (Hh activator, IC50:100 nM) for 24 h to evaluate the Hedgehog signalling response. Stemness marker expression (Nanog, Sox2, Bmi1, Oct4) was measured using qRT-PCR. The combination index (CI) of GANT61 with trastuzumab was calculated using CompuSyn software (version 1.0) to identify synergistic doses (CI < 1). The synergistic concentrations’ impact on stemness markers was assessed. Data were analysed using two-way ANOVA and Tukey’s post hoc test (p < 0.05). Trastuzumab-resistant cells exhibited increased Hedgehog signalling activity. Treatment with GANT61 significantly downregulated stemness marker expression, while SAG21K treatment led to their upregulation in both SKBR3-R and HCC1954-R cells. The combination of GANT61 and trastuzumab demonstrated a synergistic effect, markedly reducing the expression of stemness markers. These findings indicate that Hedgehog signalling plays a pivotal role in maintaining stemness in trastuzumab-resistant cells, and that the inhibition of this pathway may prevent tumour progression. Hedgehog signalling is crucial in regulating stemness in trastuzumab-resistant HER2-positive breast cancer. Targeting this pathway could overcome resistance and enhance trastuzumab efficacy. Further studies should explore the clinical potential of Hedgehog inhibitors in combination therapies. Full article
(This article belongs to the Special Issue Hormone Receptors and Signaling in Breast Cancer)
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15 pages, 716 KiB  
Review
Immunotherapy in Basal Cell Carcinoma
by Loredana Ungureanu, Alina Florentina Vasilovici, Salomea-Ruth Halmágyi, Ioana Irina Trufin, Adina Patricia Apostu, Manuela Prisecaru and Simona Corina Șenilă
J. Clin. Med. 2024, 13(19), 5730; https://doi.org/10.3390/jcm13195730 - 26 Sep 2024
Cited by 2 | Viewed by 2133
Abstract
Basal cell carcinoma (BCC) is the most frequent of all cancers, with an increasing incidence. The first line therapy is surgical excision, but topical therapies can be used in low-risk superficial BCCs, while the more advanced, unresectable, or metastatic BCCs benefit from systemic [...] Read more.
Basal cell carcinoma (BCC) is the most frequent of all cancers, with an increasing incidence. The first line therapy is surgical excision, but topical therapies can be used in low-risk superficial BCCs, while the more advanced, unresectable, or metastatic BCCs benefit from systemic therapies with hedgehog inhibitors and immunotherapy. The purpose of this review is to highlight local and systemic immunotherapies and their efficacy in the management of BCCs. Local therapies can be considered in superficial and low-risk nodular BCCs, with imiquimod frequently used for its antitumor and immunoregulatory properties. Imiquimod alone demonstrated higher histological clearance rates, but patients treated with imiquimod experienced more adverse events than ones treated with other therapies. Imiquimod can be used as an adjuvant before Mohs micrographic surgery and can also be combined with other local therapies, like curettage, electrodesiccation, cryosurgery, and photodynamic therapy, with some treatment methods yielding results comparable with the surgery. Interferons and Interleukin-2 were evaluated in a small number of studies with different results. Systemic immunotherapies with programmed death-ligand 1 (PD-L1) inhibitors showed inconsistent results in patients with advanced BCCs, being effective in some patients that progressed on or were intolerant to hedgehog pathway inhibitors (HHI). Full article
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