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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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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Dabrafenib protects from cisplatin-induced hearing loss in a clinically relevant mouse model

JCI Insight, Journal Year: 2023, Volume and Issue: 8(24)

Published: Nov. 7, 2023

The widely used chemotherapy cisplatin causes permanent hearing loss in 40%-60% of patients with cancer. One drug, sodium thiosulfate, is approved by the FDA for use pediatric localized solid tumors preventing cisplatin-induced loss, but more drugs are desperately needed. Here, we tested dabrafenib, an FDA-approved BRAF kinase inhibitor and anticancer a clinically relevant multidose mouse model. protective effects given orally twice daily cisplatin, were determined functional tests cochlear outer hair cell counts. Toxicity drug cotreatment was evaluated, levels phosphorylated ERK measured. A dabrafenib dose 3 mg/kg BW, daily, mice, to be minimum effective dose, it equivalent one-tenth human cancer treatment. protection acquired, 20-25 dB at frequencies tested, both female male persisted 4 months after completion treatments. Moreover, exhibited good vivo therapeutic index (> 25), protected 2 strains, diminished weight loss. This study demonstrates that promising candidate from

Language: Английский

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Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 4094 - 4094

Published: April 7, 2024

Many tumors have well-defined vulnerabilities, thus potentially allowing highly specific and effective treatment. There is a spectrum of actionable genetic alterations which are shared across various tumor types and, therefore, can be targeted by given drug irrespective histology. Several agnostic drug-target matches already been approved for clinical use, e.g., immune therapy with microsatellite instability (MSI) and/or high mutation burden (TMB), NTRK1-3 RET inhibitors cancers carrying rearrangements in these kinases, dabrafenib plus trametinib BRAF V600E mutated malignancies. Multiple lines evidence suggest that this histology-independent approach also reasonable ALK ROS1 translocations, biallelic BRCA1/2 inactivation homologous recombination deficiency (HRD), strong HER2 amplification/overexpression coupled the absence other MAPK pathway-activating mutations, etc. On hand, some well-known targets not agnostic: example, PD-L1 expression predictive efficacy PD-L1/PD1 only but all cancer types. Unfortunately, individual probability finding druggable target relatively low, even use comprehensive next-generation sequencing (NGS) assays. Nevertheless, rapidly growing utilization NGS will significantly increase number patients unusual or exceptionally rare tumor-target combinations. Clinical trials may provide framework treatment attitudes, while decisions usually require case-by-case consideration deriving benefit from versus standard therapy, availability, associated costs, circumstances. The existing format data dissemination optimal medicine, as conventional scientific journals understandably biased towards publication positive findings discourage submission case reports. Despite limitations concerns, matching certainly feasible increasingly utilized future.

Language: Английский

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Target-Driven Tissue-Agnostic Drug Approvals; a New Path of Drug Development

Published: June 3, 2024

The regulatory approvals of tumor agnostic therapies have led to reevaluation the 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 8 granted by Food Drug Administration (FDA). This includes two immune checkpoint inhibitors, 5 targeted therapy agents. Pembrolizumab is an anti-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 mutational burden-high (TMB-H) tumors, although TMB cut-off used still debated. Subsequently, 2021, another 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 cancers. Similarly, selpercatinib Rearranged During Transfection (RET) combination dabrafenib, B-Raf Proto-Oncogene Serine/Threonine Kinase (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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