Trametinib for a child with refractory Rosai–Dorfman–Destombes disease harboring a novel somatic mutation in MAP2K1

International Journal of Hematology, Journal Year: 2024, Volume and Issue: 120(4), P. 520 - 524

Published: July 14, 2024

Language: Английский

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Target-Driven Tissue-Agnostic Drug Approvals—A New Path of Drug Development

Cancers, Journal Year: 2024, Volume and Issue: 16(14), P. 2529 - 2529

Published: July 13, 2024

The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation drug development process. conventional models are histology-based. On other hand, a new (or combination) focuses on targeting common genomic biomarker in multiple cancers, regardless histology. basket-like clinical trials with cohorts allow clinicians evaluate pan-cancer efficacy and toxicity. There currently eight tumor agnostic granted by Food Drug Administration (FDA). This includes two immune checkpoint inhibitors, five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was first FDA-approved treatment for unresectable or metastatic microsatellite instability-high (MSI-H) deficient mismatch repair (dMMR) solid tumors 2017. It later approved mutational burden-high (TMB-H) tumors, although TMB cut-off used still debated. Subsequently, 2021, another anti-PD-1 antibody, dostarlimab, also dMMR refractory setting. Patients fusion-positive cancers typically difficult treat due their rare prevalence distribution. Gene rearrangements fusions present variety tumors. Neurotrophic tyrosine kinase (NTRK) range pediatric adult varying frequency. Larotrectinib entrectinib were neurotrophic cancers. Similarly, selpercatinib rearranged during transfection (RET) FDA combination dabrafenib, B-Raf proto-oncogene serine/threonine (BRAF) inhibitor, plus trametinib, mitogen-activated protein (MEK) inhibitor patients 6 months older (except colorectal cancer) carrying BRAFV600E mutation. most recent approval fam-trastuzumab deruxtecan-nxki (T-Dxd) HER2-positive important identify expeditiously develop drugs potential provide benefit across types.

Language: Английский

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The effects of the combination therapy of chemotherapy drugs on the fluctuations of genes involved in the TLR signaling pathway in glioblastoma multiforme therapy

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 177, P. 117137 - 117137

Published: July 17, 2024

Language: Английский

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Functional genomics pipeline identifies CRL4 inhibition for the treatment of ovarian cancer

Clinical and Translational Medicine, Journal Year: 2025, Volume and Issue: 15(2)

Published: Jan. 24, 2025

Language: Английский

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Pan-Cancer Molecular Biomarkers: Practical Considerations for the Surgical Pathologist

Modern Pathology, Journal Year: 2025, Volume and Issue: unknown, P. 100752 - 100752

Published: March 1, 2025

Language: Английский

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Cardiovascular Toxicity in Patients Treated for Childhood Cancer: A Scientific Statement From the American Heart Association

Circulation, Journal Year: 2025, Volume and Issue: unknown

Published: March 19, 2025

The field of cardio-oncology has expanded over the past 2 decades to address ever-increasing issues related cardiovascular disease in patients with cancer and survivors. There is increasing recognition that nearly all treatments pose some short- or long-term risk for development pediatric may be especially vulnerable because young age at treatment expected long life span afterward. Anthracycline chemotherapy chest-directed radiotherapy are most well-studied cardiotoxic therapies, dose reduction, use cardioprotection anthracyclines, modern approaches have contributed improved outcomes Newer such as small-molecule inhibitors, antibody-based cytotoxic therapy, immunotherapy options previously difficult-to-treat cancers but also revealed new profiles. Application effective surveillance strategies survivors been a focus practitioners researchers, whereas prevention extant still developing. Incorporation an equitable manner appropriate transition from adult care will greatly influence health-related growing population childhood disease.

Language: Английский

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Unraveling BRAF alterations: molecular insights to circumvent therapeutic resistance across cancer types

Cancer Drug Resistance, Journal Year: 2025, Volume and Issue: unknown

Published: March 24, 2025

Aim: As intrinsic resistance - often driven by concurrent genomic alterations in tumor suppressor genes or oncogenes remains a major challenge oncology, this work aimed to comprehensively analyze BRAF somatic across cancer types and identify new potential therapeutic strategies overcome drug resistance. Methods: We conducted an extensive analysis of genomics, transcriptomics, clinical data retrieved from public repositories, including cBioPortal. Our comprehensive examined [point mutations, structural variants (SVs) copy number alteration] more than 217,000 samples 120 distinct primary metastatic sites both adult pediatric cohorts, focusing on mutual exclusivity co-occurrence mutations other suppressors. The also explores the association with survival, molecular features. Results: Analysis mutation frequencies revealed that BRAFV600E represents approximately 90% all alterations. While melanoma thyroid carcinoma show highest prevalence followed colorectal non-small cell lung terms absolute patients harboring worldwide, notably high were identified rare malignancies, hairy-cell leukemia, ganglioglioma, serous borderline ovarian tumors. profiling these tumors uncovered patterns co-occurring mutually exclusive genes, illuminating mechanisms suggesting novel combinations. Conclusion: Comprehensive is critical for optimizing targeted therapy overcoming -mutated cancers. identification provides opportunities rational combination therapies, emphasizing importance detailed developing effective treatment diverse types.

Language: Английский

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MAPK Signaling and Angiopoietin-2 Contribute to Endothelial Permeability in Capillary Malformations

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 5, 2025

Capillary malformations (CM) are slow-flow vascular abnormalities present at birth and predominantly manifest as cutaneous lesions. In the rare neurocutaneous disorder known Sturge Weber Syndrome (SWS), individuals exhibit CM not only on skin but also within leptomeninges of brain choroid eye. >90% caused by a somatic R183Q mutation in GNAQ, gene encoding Gαq - heterotrimeric G-protein subunit. The GNAQ is notably enriched endothelial cells (ECs) isolated from CM-affected regions. Here we show blood vessels leptomeningeal SWS lesions extravascular fibrin indicating compromised barrier. Longitudinal MRI one patient further suggests permeability. To explore this pathological phenotype, employed trans-endothelial electrical resistance (TEER) assay to measure permeability EC-EC barrier vitro . Human EC CRISPR edited create allele (EC-R183Q) exhibited reduced compared mock (EC-WT). We sought identify signaling molecules needed for formation. Knockdown angiopoietin-2 (ANGPT2), be significantly increased EC-R183Q CM, partially yet restored barrier, while an anti-ANGPT2 function blocking antibody did not. next tested MEK1,2 inhibitor (Trametinib) because MAPK mutation. inhibitors implicating involvement MAPK/ERK signaling. combination ANGPT2 knockdown Trametinib near EC-WT levels. additive impacts ANGPT inhibition indicate two operate separate pathways. summary, discovered that p.R183Q ECs formation, reflecting lesions, combined with effectively restores What known?: mutant Gαq-R183Q activates phospholipase β3, contributing angiopoietin-2, pro-angiogenic, proinflammatory molecule contributes permeability.Endothelial sufficient drive formation enlarged akin what observed CM. shRNA prevented vessel phenotype xenograft model.An EC-specific mouse model showed vessels, detected perfusion Evans Blue dye, integrity.What New Information Does This Article Contribute?: Reduced integrity confirmed Martius Scarlet staining longitudinal imaging brain. form weaker control ECs. weakened ECscan rescued inhibitor, YM254890, confirming consequence Gαq. Titration experiments modeling mosaic nature CMshow 5- 10% monolayer reduce or EC. Combining addition MEK Trametinib, seen wild type ECs.What translational message?: (SWS) involves atypical overgrowth skin, It associated facial (aka port wine birthmark), visible MRI, glaucoma. Theneurological sequalae involve seizures, cerebral atrophies calcification, intellectual disorders. Currently there no molecularly targeted therapies non-syndromic SWS. Our study shows pathway path target driven

Language: Английский

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Advances in Targeted and Systemic Therapy for Salivary Gland Carcinomas: Current Options and Future Directions

Current Oncology, Journal Year: 2025, Volume and Issue: 32(4), P. 232 - 232

Published: April 16, 2025

Salivary gland carcinomas (SGCs) represent a rare and heterogeneous group of malignancies accounting for 3–6% all head neck cancers. While surgical resection radiotherapy remain the standard locoregional control, systemic treatment is indicated recurrent or metastatic disease. Advances in molecular profiling have identified actionable targets such as NTRK gene fusions, HER2, immune checkpoint regulators, androgen receptors, RET receptors. These facilitated development targeted therapies, including TRK inhibitors, HER2-directed agents, receptor modulators, well emerging combinations immunotherapy chemotherapy. Despite these advancements, challenges resistance mechanisms limited therapeutic efficacy persist. Overall response rates relatively low across most reflecting persistent unmet clinical need. This review discusses current landscape options explores promising trials future directions to enhance outcomes patients with SGCs.

Language: Английский

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Paediatric Thyroid Carcinoma: The Genetic Revolution and Its Implications for Therapy and Outcomes

Cancers, Journal Year: 2025, Volume and Issue: 17(9), P. 1549 - 1549

Published: May 2, 2025

Background: The understanding of the molecular basis paediatric thyroid carcinoma has expanded rapidly in last decade. Most carcinomas are associated with de novo somatic gene alterations that confer distinct clinicopathological characteristics. In comparison to adults, less commonly point mutations and more fusions, which characterised by more-invasive disease. Cancer predisposition genes play an important role a small percentage tumours, family history recognition other syndromic features key identifying these patients. Molecular testing platforms for clinical use have been developed validated their is becoming established management indeterminate nodules, where they significantly reduce rates diagnostic lobectomy. Paediatric data limited than adult data, evolving. Methods: This review describes current knowledge carcinomas, evidence supporting practice, future directions research. Results Conclusions: A diagnosis enables molecularly targeted therapies children adolescents advanced or radioiodine-refractory There also great potential improve accuracy risk-stratification reducing surgical intervention complications without negatively impacting outcomes, support such approach emerging.

Language: Английский

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