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23 pages, 2002 KiB  
Article
Precision Oncology Through Dialogue: AI-HOPE-RTK-RAS Integrates Clinical and Genomic Insights into RTK-RAS Alterations in Colorectal Cancer
by Ei-Wen Yang, Brigette Waldrup and Enrique Velazquez-Villarreal
Biomedicines 2025, 13(8), 1835; https://doi.org/10.3390/biomedicines13081835 - 28 Jul 2025
Viewed by 441
Abstract
Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of [...] Read more.
Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10−5). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. Full article
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12 pages, 1017 KiB  
Article
Forebrain-Specific B-raf Deficiency Reduces NMDA Current and Enhances Small-Conductance Ca2+-Activated K+ (SK) Current
by Cornelia Ruxanda, Christian Alzheimer and Fang Zheng
Int. J. Mol. Sci. 2025, 26(15), 7172; https://doi.org/10.3390/ijms26157172 - 25 Jul 2025
Viewed by 227
Abstract
B-raf (rapidly accelerated fibrosarcoma) is a crucial player within the ERK/MAPK signaling pathway. In the CNS, B-raf has been implicated in neuronal differentiation, long-term memory, and major depression. Mice with forebrain neuron-specific B-raf knockout show behavioral deficits in spatial learning tasks and impaired [...] Read more.
B-raf (rapidly accelerated fibrosarcoma) is a crucial player within the ERK/MAPK signaling pathway. In the CNS, B-raf has been implicated in neuronal differentiation, long-term memory, and major depression. Mice with forebrain neuron-specific B-raf knockout show behavioral deficits in spatial learning tasks and impaired hippocampal long-term potentiation (LTP). To elucidate the mechanism(s) underlying diminished synaptic plasticity in B-raf-deficient mice, we performed whole-cell recordings from CA1 pyramidal cells in hippocampal slices of control and B-raf mutant mice. We found that the NMDA/AMPA ratio of excitatory postsynaptic currents (EPSCs) at the Schaffer collateral—CA1 pyramidal cell synapses was significantly reduced in B-raf mutants, which would at least partially account for their impaired LTP. Interestingly, the reduced NMDA component of field postsynaptic potentials in mutant preparations was partially reinstated by blocking the apamin-sensitive small-conductance Ca2+-activated K+ (SK) channels, which have also been reported to modulate hippocampal LTP and learning tasks. To determine the impact of B-raf-dependent signaling on SK current, we isolated the apamin-sensitive tail current after a strong depolarizing event and found indeed a significantly bigger SK current in B-raf-deficient cells compared to controls, which is consistent with the reduced action potential firing and the stronger facilitating effect of apamin on CA1 somatic excitability in B-raf-mutant hippocampus. Our data suggest that B-raf signaling readjusts the delicate balance between NMDA receptors and SK channels to promote synaptic plasticity and facilitate hippocampal learning and memory. Full article
(This article belongs to the Special Issue Advances in Synaptic Transmission and Plasticity)
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26 pages, 1016 KiB  
Article
TIM-3/Galectin-9 Immune Axis in Colorectal Cancer in Relation to KRAS, NRAS, BRAF, PIK3CA, AKT1 Mutations, MSI Status, and the Cytokine Milieu
by Błażej Ochman, Anna Kot, Sylwia Mielcarska, Agnieszka Kula, Miriam Dawidowicz, Dorota Hudy, Monika Szrot, Jerzy Piecuch, Dariusz Waniczek, Zenon Czuba and Elżbieta Świętochowska
Int. J. Mol. Sci. 2025, 26(14), 6735; https://doi.org/10.3390/ijms26146735 - 14 Jul 2025
Viewed by 245
Abstract
In this study, we investigated the expression of TIM-3 and Galectin-9 (Gal-9) in colorectal cancer (CRC) and their associations with oncogenic mutations, MSI status, cytokine profiles, and transcriptional data. TIM-3 and Gal-9 protein levels were significantly increased in CRC tissues compared to matched [...] Read more.
In this study, we investigated the expression of TIM-3 and Galectin-9 (Gal-9) in colorectal cancer (CRC) and their associations with oncogenic mutations, MSI status, cytokine profiles, and transcriptional data. TIM-3 and Gal-9 protein levels were significantly increased in CRC tissues compared to matched non-tumor margins (p < 0.05 and p < 0.001, respectively). TIM-3 protein concentration was notably higher in PIK3CA-mutated tumors (p < 0.05), while no associations were found with KRAS, NRAS, BRAF, AKT1, or MSI status. Multiplex cytokine profiling revealed strong correlations between TIM-3 and Gal-9 levels and key immunomodulatory pathways, including IL-10, IL-17, and chemokine signaling. We also observed significant associations with cytokine subsets involved in protumor activity and immune regulation. Gene set enrichment analysis (GSEA) demonstrated that high TIM-3 and Gal-9 expression was associated with upregulation of cell cycle-related pathways, and downregulation of immune signatures, such as interferon responses and TNF-α/NFκB signaling. These findings suggest that increased TIM-3 and Gal-9 expression reflects a shift toward proliferative activity and immune suppression in the CRC tumor microenvironment, highlighting their potential as biomarkers of immunoevasive tumor phenotypes, especially in PIK3CA-mutant CRC tumors. Full article
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11 pages, 2928 KiB  
Communication
Resistance to MAPK Pathway Inhibition in BRAF-V600E Mutant Colorectal Cancer Can Be Overcome with Insulin Receptor/Insulin-like Growth Factor-1 Receptor Inhibitors
by Layla El Bouazzaoui, Daniëlle A. E. Raats, André Verheem, Inne H. M. Borel Rinkes, Hugo J. G. Snippert, Madelon M. Maurice and Onno Kranenburg
Organoids 2025, 4(2), 14; https://doi.org/10.3390/organoids4020014 - 12 Jun 2025
Viewed by 360
Abstract
The current treatment for refractory BRAF-V600E mutant metastatic colorectal cancer (mCRC) involves combined inhibition of BRAF and the epidermal growth factor receptor (EGFR). However, tumour responses are often short-lived due to a rebound in mitogen-activated protein kinase (MAPK) activity. In this study, [...] Read more.
The current treatment for refractory BRAF-V600E mutant metastatic colorectal cancer (mCRC) involves combined inhibition of BRAF and the epidermal growth factor receptor (EGFR). However, tumour responses are often short-lived due to a rebound in mitogen-activated protein kinase (MAPK) activity. In this study, we combined short-term cell viability assays with long-term regrowth assays following drug removal over a period of three weeks. This allowed assessment of regrowth after therapy discontinuation. We tested the effect of combined BRAF inhibition (encorafenib) and EGFR inhibition (afatinib) on BRAF-V600E mutant CRC patient-derived organoids (PDOs). Combined EGFR/BRAF inhibition initially caused a major reduction in PDO growth capacity in BRAF-V600E mutant PDOs. This was followed by rapid regrowth after drug removal, mirroring clinical outcomes. EGFR inhibition in BRAF-V600E mutant PDOs led to activation of the insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R). The IGF1R/IR inhibitor linsitinib prevented the rebound in MAPK activity following removal of afatinib and encorafenib, prevented regrowth of CRC PDOs, and improved the anti-tumour response in an in vivo model. PDO regrowth assays allow the identification of pathways driving tumour recurrence. IR/IGF1R-inhibition prevents regrowth following golden standard MAPK pathway-targeted therapy and provides a strategy to improve the treatment of BRAF-V600E mutant CRC Full article
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26 pages, 705 KiB  
Review
Recent Advances in Molecular Research and Treatment for Melanoma in Asian Populations
by Soichiro Kado and Mayumi Komine
Int. J. Mol. Sci. 2025, 26(11), 5370; https://doi.org/10.3390/ijms26115370 - 3 Jun 2025
Viewed by 1048
Abstract
Melanoma treatment comprised a few treatment choices with insufficient efficacy before the emergence of molecularly targeted medication and immune checkpoint inhibitors, which dramatically improved patient outcomes. B-Rapidly Accelerated Fibrosarcoma (BRAF) and Mitogen-Activated Protein Kinase (MAPK) Kinase (MEK) inhibitors significantly improved survival in BRAF [...] Read more.
Melanoma treatment comprised a few treatment choices with insufficient efficacy before the emergence of molecularly targeted medication and immune checkpoint inhibitors, which dramatically improved patient outcomes. B-Rapidly Accelerated Fibrosarcoma (BRAF) and Mitogen-Activated Protein Kinase (MAPK) Kinase (MEK) inhibitors significantly improved survival in BRAF-mutant melanoma and immune checkpoint inhibitors, such as anti-programmed cell death 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) agents, established new standards of care. Challenges remain, however, including the existence of resistance mechanisms and the reduced efficacy of immune-based therapies in Asian populations, particularly for acral and mucosal subtypes. This review highlights historical and current therapeutic advancements, discusses regional considerations, and explores emerging strategies aiming at globally optimizing melanoma management. Full article
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14 pages, 1875 KiB  
Case Report
Dramatic Responses to High-Dose Ipilimumab Plus Temozolomide After Progression on Standard- or Low-Dose Ipilimumab in Advanced Melanoma
by Julie Williamson, Muhammad Zaki Hidayatullah Fadlullah, Magdalena Kovacsovics-Bankowski, Berit Gibson, Umang Swami, Alyssa Erickson-Wayman, Debra Jamison, Dan Sageser, Joanne Jeter, Tawnya L. Bowles, Donald M. Cannon, Ben Haaland, Joyce D. Schroeder, David A. Nix, Aaron Atkinson, John Hyngstrom, Jordan McPherson, Aik-Choon Tan and Siwen Hu-Lieskovan
Curr. Oncol. 2025, 32(3), 144; https://doi.org/10.3390/curroncol32030144 - 28 Feb 2025
Viewed by 1159
Abstract
Patients with advanced melanoma who progress on standard-dose ipilimumab (Ipi) + nivolumab continue to have poor prognosis. Studies support a dose–response activity of Ipi, and one promising combination is Ipi 10 mg/kg (Ipi10) + temozolomide (TMZ). We performed a retrospective cohort analysis of [...] Read more.
Patients with advanced melanoma who progress on standard-dose ipilimumab (Ipi) + nivolumab continue to have poor prognosis. Studies support a dose–response activity of Ipi, and one promising combination is Ipi 10 mg/kg (Ipi10) + temozolomide (TMZ). We performed a retrospective cohort analysis of patients with advanced melanoma treated with Ipi10 + TMZ in the immunotherapy refractory/resistant setting (n = 6, all progressed after prior Ipi + nivolumab), using similar patients treated with Ipi3 + TMZ (n = 6) as comparison. Molecular profiling by whole-exome sequencing (WES) and RNA-sequencing (RNA-seq) of tumors harvested through one responder’s treatment was performed. With a median follow up of 119 days, patients treated with Ipi10 + TMZ had a statistically significant longer median progression-free survival of 144.5 days (range 27–219) vs. 44 (26–75) in Ipi 3 mg/kg (Ipi3) + TMZ, p = 0.04, and a trend of longer median overall survival of 154.5 days (27–537) vs. 89.5 (26–548). Two patients in the Ipi10 + TMZ cohort had a partial response, and both responders had BRAF V600E mutant melanoma. RNA-seq showed enrichment of inflammatory signatures, including interferon responses in metastases after Ipi10 + TMZ compared to the primary tumor, and downregulated negative immune regulators. Ipi10 + TMZ demonstrated efficacy, including dramatic responses in patients refractory to prior Ipi + anti-PD1. Molecular data suggest a potential threshold of Ipi dose for activation of sufficient anti-tumor immune response, and higher doses are required for some patients. Full article
(This article belongs to the Section Dermato-Oncology)
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18 pages, 3189 KiB  
Article
The Olive Oil Monophenolic Secoiridoid Ligstroside Aglycone Suppresses Melanoma Progression by Targeting the BRAF Signaling Pathway
by Md Ashiq Mahmud, Abu Bakar Siddique, Afsana Tajmim, Judy Ann King and Khalid A. El Sayed
Molecules 2025, 30(1), 139; https://doi.org/10.3390/molecules30010139 - 1 Jan 2025
Viewed by 1655
Abstract
Melanoma is among the most abundant malignancies in the US and worldwide. Ligstroside aglycone (LA) is a rare extra-virgin olive oil-derived monophenolic secoiridoid with diverse bioactivities. LA dose–response screening at the NCI 60 cancer cells panel identified the high sensitivity of the Malme-3M [...] Read more.
Melanoma is among the most abundant malignancies in the US and worldwide. Ligstroside aglycone (LA) is a rare extra-virgin olive oil-derived monophenolic secoiridoid with diverse bioactivities. LA dose–response screening at the NCI 60 cancer cells panel identified the high sensitivity of the Malme-3M cell line, which harbors a BRAF V600E mutation. Daily oral 10 mg/kg LA exhibited potent in vivo antitumor effects against Malme-3M cells xenograft in a nude mouse model by targeting the BRAF signaling pathway. A human Clariom S microarray analysis of the collected Malme- 3M tumors identified 571 dysregulated genes, with the downregulation of pathways critical for melanoma cells growth and survival. A Western blot analysis of the collected animal tumors further validated the downregulation of the mutated BRAF–MAPK axis, as well as the GPD1 and ELOVL6 expression levels. A histopathological analysis of Malme-3M tumor sections showed extensive focal tumor necrosis in treated mice. An immunofluorescence study of tumor sections showed notable reductions in proliferation marker ki67 and the vasculogenesis marker CD31 in treated tumors. These findings promote LA as a potential nutraceutical lead for the control of the BRAF V600E mutant melanoma. Full article
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11 pages, 3156 KiB  
Article
Real-World Data of Patients with BRAF V600E-Mutated Metastatic Colorectal Cancer Treated with Trifluridine/Tipiracil
by Javier Ros, Jose Maria Ucha, Eduardo Garcia-Galea, Pablo Gomez, Giulia Martini, Francesca Balconi, Raquel Comas, Vicente Alonso, Marta Rodriguez, Iosune Baraibar, Francesc Salva, Nadia Saoudi, Adriana Alcaraz, Ariadna Garcia, Josep Tabernero and Elena Elez
Cancers 2024, 16(24), 4140; https://doi.org/10.3390/cancers16244140 - 12 Dec 2024
Viewed by 1630
Abstract
Background: For patients with refractory metastatic colorectal cancer (mCRC), trifluridine/tipiracil (FTD–TPI) has been associated with a significant improvement in overall survival (OS). However, data are lacking regarding the activity of FTD–TPI in patients with BRAF-mutated mCRC. Methods: This retrospective, multicenter, international cohort [...] Read more.
Background: For patients with refractory metastatic colorectal cancer (mCRC), trifluridine/tipiracil (FTD–TPI) has been associated with a significant improvement in overall survival (OS). However, data are lacking regarding the activity of FTD–TPI in patients with BRAF-mutated mCRC. Methods: This retrospective, multicenter, international cohort included patients with BRAF-mutated mCRC treated with FTD–TPI in a real-life setting in Spain and Italy. Survival analysis was performed using Kaplan–Meier methods and Cox proportional hazard models and according to established prognostic groups: good prognosis characteristics (GPC; < 3 metastatic sites and time from metastases to FTD–TPI ≥ 18 months) and poor prognosis characteristics (PPC; ≥ 3 metastatic sites or time from metastases to FTD–TPI < 18 months). Results: In the 26 patients included, the median age was 61 years, 13 (50%) were female, and 20 (77%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Fourteen (56%) patients had right-sided tumors, six (23%) had microsatellite instability tumors, and thirteen (50%) had liver metastases. Median progression-free survival was 2.3 months (95% CI 2.0–3.2), and median OS (mOS) was 6.6 months (95% CI 4.4–12.0). mOS was 7.6 vs. 4.2 months (HR 1.64, 95% CI 0.65–4.10, p = 0.3) for GPC and PPC patients, respectively. Exploratory analyses identified ECOG as the only feature associated with survival. The most frequent grade 3–4 adverse events were neutropenia (8%), anemia (8%), and asthenia (4%). Conclusions: Patients with BRAF mutant mCRC achieved modest benefits with FTD–TPI; however, patients with GPC and ECOG 0 achieved longer OS compared with those with PPC or ECOG 1–2, thus warranting further exploration in prospective cohorts. Full article
(This article belongs to the Special Issue Developments in the Management of Gastrointestinal Malignancies)
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16 pages, 4631 KiB  
Article
Role of Annexin 7 (ANXA7) as a Tumor Suppressor and a Regulator of Drug Resistance in Thyroid Cancer
by Alakesh Bera, Surya Radhakrishnan, Narayanan Puthillathu, Madhan Subramanian, Nahbuma Gana, Eric Russ, Harvey B. Pollard and Meera Srivastava
Int. J. Mol. Sci. 2024, 25(23), 13217; https://doi.org/10.3390/ijms252313217 - 9 Dec 2024
Cited by 1 | Viewed by 1248
Abstract
Thyroid cancer is the most common endocrine malignancy in the United States, with an overall favorable prognosis. However, some patients experience poor outcomes due to the development of resistance to conventional therapies. Genetic alterations, including mutations in BRAF, Met, and p53, play critical [...] Read more.
Thyroid cancer is the most common endocrine malignancy in the United States, with an overall favorable prognosis. However, some patients experience poor outcomes due to the development of resistance to conventional therapies. Genetic alterations, including mutations in BRAF, Met, and p53, play critical roles in thyroid cancer progression, with the BRAF V600E mutation detected in over 60% of cases. This study investigates the tumor-suppressive role of Annexin A7 (ANXA7) in thyroid cancer, focusing on its potential impact on tumor behavior and therapeutic response. Our analysis, which included RNA sequencing and protein profiling, revealed reduced ANXA7 expression in thyroid cancer cells, particularly in those harboring the BRAF V600E mutation. Upon treatment with inhibitors targeting BRAF and MEK, ANXA7 expression increased, leading to reduced phosphorylation of ERK and activation of apoptotic pathways. Additionally, we identified the cyclin-dependent kinase inhibitor p21 as a key player in modulating resistance to BRAF inhibitors. Combination therapies aimed at concurrently increasing p21 and ANXA7 levels resulted in a marked enhancement of apoptosis. These findings suggest a previously uncharacterized regulatory network involving the ANXA7/p21/BRAF/MAPK/p53 axis, which may contribute to drug resistance in thyroid cancer. This study provides new insights into overcoming resistance to BRAF and MAPK inhibitors, with implications for treating thyroid cancer and potentially other BRAF-mutant tumors. Future efforts will focus on high-throughput screening approaches to explore ANXA7-targeted therapeutic strategies for thyroid cancer. Full article
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16 pages, 2870 KiB  
Article
Regorafenib Combined with BRAF/MEK Inhibitors for the Treatment of Refractory Melanoma Brain Metastases
by Iris Dirven, Eden Pierre, An-Sofie Vander Mijnsbrugge, Manon Vounckx, Jolien I. Kessels and Bart Neyns
Cancers 2024, 16(23), 4083; https://doi.org/10.3390/cancers16234083 - 5 Dec 2024
Cited by 3 | Viewed by 1767
Abstract
Background: There are no active treatment options for patients with progressive melanoma brain metastases (MBM) failing immune checkpoint blockade (ICB) and BRAF/MEK inhibitors (BRAF/MEKi). Regorafenib (REGO), an oral multi-kinase inhibitor (incl. RAF-dimer inhibition), can overcome adaptive resistance to BRAF/MEKi in preclinical models. Methods: [...] Read more.
Background: There are no active treatment options for patients with progressive melanoma brain metastases (MBM) failing immune checkpoint blockade (ICB) and BRAF/MEK inhibitors (BRAF/MEKi). Regorafenib (REGO), an oral multi-kinase inhibitor (incl. RAF-dimer inhibition), can overcome adaptive resistance to BRAF/MEKi in preclinical models. Methods: This is a single-center retrospective case series of patients with refractory MBM treated with REGO plus BRAF/MEKi (compassionate use). Results: A total of 22 patients were identified (18 BRAF-mutant, 4 NRASQ61-mutant; 19 with progressive MBM; 11 on corticosteroids). Thirteen BRAFV600-mutant patients were progressing on BRAF/MEKi at the time of REGO association. BRAF-mutant patients received REGO (40–80 mg once daily) combined with BRAF/MEKi, NRAS-mutant patients were treated with REGO + MEKi (+low-dose BRAFi to mitigate skin-toxicity). Grade 3 TRAE included arterial hypertension (n = 4) and maculopapular rash (n = 3). There were no G4/5 TRAE. In BRAF-mutant patients, overall and intracranial objective response rates (overall ORR and IC-ORR) were 11 and 29%, and overall and intracranial disease control rates (overall DCR and IC-DCR) were 44 and 59%, respectively. In NRAS-mutant patients overall ORR and IC-ORR were 0 and 25% and overall DCR and IC-DCR were 25 and 50%, respectively. The median PFS and OS were, respectively, 7.1 and 16.4 weeks in BRAF-mutant and 8.6 and 10.1 weeks in NRAS-mutant patients. Conclusions: In heavily pretreated patients with refractory MBM, REGO combined with BRAF/MEKi demonstrated promising anti-tumor activity with an acceptable safety profile. In BRAFV600-mutant melanoma patients, responses cannot solely be attributed to BRAF/MEKi rechallenge. Further investigation in a prospective trial is ongoing to increase understanding of the efficacy. Full article
(This article belongs to the Special Issue Melanoma: Clinical Trials and Translational Research)
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27 pages, 557 KiB  
Review
Braf-Mutant Melanomas: Biology and Therapy
by Elvira Pelosi, Germana Castelli and Ugo Testa
Curr. Oncol. 2024, 31(12), 7711-7737; https://doi.org/10.3390/curroncol31120568 - 3 Dec 2024
Cited by 3 | Viewed by 2282
Abstract
The incidence of melanoma, the most lethal form of skin cancer, has increased mainly due to ultraviolet exposure. The molecular characterization of melanomas has shown a high mutational burden led to the identification of some recurrent genetic alterations. BRAF gene is mutated in [...] Read more.
The incidence of melanoma, the most lethal form of skin cancer, has increased mainly due to ultraviolet exposure. The molecular characterization of melanomas has shown a high mutational burden led to the identification of some recurrent genetic alterations. BRAF gene is mutated in 40–50% of melanomas and its role in melanoma development is paramount. BRAF mutations confer constitutive activation of MAPK signalling. The large majority (about 90%) of BRAF mutations occur at amino acid 600; the majority are BRAFV600E mutations and less frequently BRAFv600K, V600D and V600M. The introduction of drugs that directly target BRAF-mutant protein (BRAF inhibitors) and of agents that stimulate immune response through targeting of immune check inhibitor consistently improved the survival of melanoma BRAFV600-mutant patients with unresectable/metastatic disease. In parallel, studies in melanoma stage II-III patients with resectable disease have shown that adjuvant therapy with ICIs and/or targeted therapy improves PFS and RFS, but not OS compared to placebo; however, neoadjuvant therapy plus adjuvant therapy improved therapeutic response compared to adjuvant therapy alone. Full article
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22 pages, 1521 KiB  
Review
Safety and Efficacy Analysis of Targeted and Immune Combination Therapy in Advanced Melanoma—A Systematic Review and Network Meta-Analysis
by Anna Sára Lengyel, Fanni Adél Meznerics, Noémi Ágnes Galajda, Noémi Gede, Tamás Kói, Alzahra Ahmed Mohammed, Petra Nikolett Péter, Alexandra IT Lakatos, Máté Krebs, Dezső Csupor, András Bánvölgyi, Péter Hegyi, Péter Holló and Lajos V. Kemény
Int. J. Mol. Sci. 2024, 25(23), 12821; https://doi.org/10.3390/ijms252312821 - 28 Nov 2024
Cited by 2 | Viewed by 1948
Abstract
The combinations of BRAF inhibitor-based targeted therapies with immune checkpoint inhibitors currently represent less common therapeutic approaches in advanced melanoma. The aim of this study was to assess the safety and efficacy of currently available melanoma treatments by conducting a systematic review and [...] Read more.
The combinations of BRAF inhibitor-based targeted therapies with immune checkpoint inhibitors currently represent less common therapeutic approaches in advanced melanoma. The aim of this study was to assess the safety and efficacy of currently available melanoma treatments by conducting a systematic review and network meta-analysis. Four databases were systematically searched for randomized clinical studies that included patients with advanced/metastatic melanoma receiving chemotherapy, immune checkpoint inhibitors, BRAF/MEK inhibitor therapy, or combinations thereof. The primary endpoints were treatment-related adverse events (TRAE), serious adverse events (SAE) of grade ≥ 3 adverse events, therapy discontinuation, progression-free survival (PFS), as well as objective response rate (ORR) and complete response rate (CRR). A total of 63 articles were eligible for our systematic review; 59 of them were included in the statistical analysis. A separate subgroup analysis was conducted to evaluate the efficacy outcomes, specifically in BRAF-positive patients. Triple combination therapy or triple therapy (inhibiting BRAF, MEK and PD1/PDL1 axis) showed significantly longer progression-free survival compared to BRAF + MEK combination therapies (HR = 0.76; 95% CI 0.64–0.9), but similar objective and complete response rates in BRAF-mutated melanoma. This safety analysis suggests that triple therapy is not inferior to combined immune checkpoint inhibitors (ICI) and BRAF/MEK therapies in terms of serious adverse events and therapy discontinuation rates. However, monotherapies and BRAF/MEK combinations showed notable advantage over triple therapy in terms of treatment-related adverse events. Combination strategies including BRAF/MEK-targeted therapies with ICI therapies are effective first-line options for advanced, BRAF-mutant melanoma; however, they are associated with more frequent side effects. Therefore, future RCTs are required to evaluate and identify high-risk subpopulations where triple therapy therapies should be considered. Full article
(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Skin Cancer)
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8 pages, 877 KiB  
Perspective
Adjuvant Radiation Therapy in Macroscopic Regional Nodal Melanoma
by Gerald B. Fogarty
Cancers 2024, 16(23), 3950; https://doi.org/10.3390/cancers16233950 - 25 Nov 2024
Viewed by 1062
Abstract
Adjuvant radiation therapy (ART) for macroscopic regional nodal cutaneous melanoma has evolved. A significant step was the discovery of targeted therapies, particularly towards V600E-mutated melanoma, and immunotherapy under its different kinds. Prior to this, the defining trial was the Australia and New Zealand [...] Read more.
Adjuvant radiation therapy (ART) for macroscopic regional nodal cutaneous melanoma has evolved. A significant step was the discovery of targeted therapies, particularly towards V600E-mutated melanoma, and immunotherapy under its different kinds. Prior to this, the defining trial was the Australia and New Zealand Melanoma Trials Group (ANZMTG) 01.02/Trans-Tasman Radiation Oncology Group (TROG) 02.01 phase III trial that showed that ART using three-dimensional conformal radiotherapy (3DCRT) decreased in-field recurrence by 50% (48 Gray (Gy) in 20 fractions). After the advent of systemic therapies, a trial of the combination targeted therapy of dabrafenib plus trametinib toward BRAF V600-mutant nodal cutaneous melanoma showed that all 35 patients achieved a pathological response. Radiotherapy (RT) was found to be safe to give with concurrent combination therapy. A retrospective immunotherapy study found that in 71 patients that received ART after a first recurrence, further in-field recurrence significantly decreased (p = 0.01). For those tumours that do recur in-field, there are now competing therapies like Talimogene laherparepvec or T-VEC. Generally, ART is now used at the first recurrence. The challenge now is to find which melanomas are truly radiosensitive if ART is to have any future role in this scenario. Full article
(This article belongs to the Special Issue Radiotherapy in Melanoma)
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8 pages, 1208 KiB  
Case Report
BRAF V600E-Mutant Acute Myeloid Leukemia: A Case Series and Literature Review of a Rare Entity
by Giby V. George, Andrew G. Evans and Audrey N. Jajosky
Genes 2024, 15(11), 1383; https://doi.org/10.3390/genes15111383 - 28 Oct 2024
Cited by 2 | Viewed by 2004
Abstract
Background: Although BRAF V600E mutations are common in solid tumors and select hematologic neoplasms, they are reported less frequently in myeloid malignancies. Of the cases of BRAF V600E-mutant acute myeloid leukemia (AML) that have been described, most display monocytic morphology and concurrent KMT2A [...] Read more.
Background: Although BRAF V600E mutations are common in solid tumors and select hematologic neoplasms, they are reported less frequently in myeloid malignancies. Of the cases of BRAF V600E-mutant acute myeloid leukemia (AML) that have been described, most display monocytic morphology and concurrent KMT2A rearrangement. Strikingly, all cases have been associated with poor survival. Case Presentation: Here, we report two cases of AML, one diagnosed in an elderly male with metastatic lung adenocarcinoma and hepatocellular carcinoma and the other diagnosed in a young boy previously treated for B-cell acute lymphoblastic leukemia. Peripheral blood NGS revealed oncogenic mutations in BRAF p.V600E (VAF = 33%), TET2 p.M508Cfs*25 (VAF = 48%), TET2 p.C211* (VAF = 49%), ZRSR2 p.R295* (VAF = 71%), BRAF p.N581S (VAF = 6%), and EZH2 c.118-2A>G, p.? (VAF = 4%) in case 1 and BRAF p.V600E (VAF = 1%) and KRAS p.G12A (VAF = 28%) in case 2. Cytogenetic workup revealed a complex karyotype in case 1 and an abnormal karyotype with non-clonal aberrations and KMT2A (MLL) rearrangement in case 2. Morphologically, both patients were found to have AML with monocytic features. The post-mortem examination of case 2 also revealed extensive solid organ infiltration, consistent with a monocytic leukemia. Both patients died within days of diagnosis, demonstrating the lethality of this molecular subgroup of AML. Conclusions: Our cases add to the literature, highlighting the poor prognosis of patients diagnosed with BRAF-mutant AML. Although it is uncertain whether the complex karyotype and somatic mutations observed in case 1 and KMT2A rearrangement and variants identified in case 2 may have either independently or cooperatively conferred a poor prognosis, we contend that additional comprehensive studies are needed to further understand the pathophysiology and prognosis of BRAF mutations in AML. We further posit whether patients with BRAF V600E-mutant AML may benefit from the combined use of BRAF inhibitors and/or RAS-pathway-targeting regimens, which are currently FDA-approved for the treatment of BRAF V600-mutant solid tumors and BRAF-mutant histiocytic neoplasms. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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15 pages, 1159 KiB  
Review
Evolution of Acquired Drug Resistance in BRAF-Mutant Melanoma
by Josué Ballesteros-Álvarez and Ana M. Blázquez-Medela
DNA 2024, 4(4), 355-369; https://doi.org/10.3390/dna4040025 - 12 Oct 2024
Viewed by 1392
Abstract
Melanoma is a highly aggressive type of skin cancer. Metastatic melanoma tumors have historically featured a particularly poor prognosis and have often been considered incurable. Recent advances in targeted therapeutic interventions have radically changed the landscape in metastatic melanoma management, significantly increasing the [...] Read more.
Melanoma is a highly aggressive type of skin cancer. Metastatic melanoma tumors have historically featured a particularly poor prognosis and have often been considered incurable. Recent advances in targeted therapeutic interventions have radically changed the landscape in metastatic melanoma management, significantly increasing the overall survival of patients. Hyperactive BRAF is the most common mutational event found in metastatic melanoma and its inhibition has proven to be a successful approach in a number of patients. Unfortunately, initial tumor retreat is followed by relapse in most cases, highlighting the elusiveness of finding a widely effective treatment. Melanoma tumors often carry a particularly high number of mutations in what is known as a high level of inter- and intra-patient tumor heterogeneity, driving resistance to treatment. The various mutations that are present in these tumors, in addition to impacting the root cause of the malignancy and the potential for therapeutic interventions, have also been known to arise during tumor clonal evolution leading to the establishment of drug resistance, a major issue in melanoma management. Full article
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