J Proteome Res. 2025 Sep 1. doi: 10.1021/acs.jproteome.5c00424. Online ahead of print.

ABSTRACT

Glioma is an aggressive brain tumor that requires challenging treatments. Tumor Treating Fields (TTFields), an FDA-approved therapy for glioblastoma (GBM), pleural mesothelioma, and platinum-refractory metastatic nonsmall cell lung cancer (in combination with PD-1/PD-L1 inhibitors or docetaxel), employs specific frequency electric fields to disrupt cell division and enhance treatment efficacy. However, their molecular mechanisms remain unclear. This study aimed to elucidate these mechanisms and optimize the therapeutic potential of TTFields through quantitative proteomics, phosphoproteomics, and glycoproteomics. Pathway analysis of the proteomics revealed that TTFields impact the cell cycle, DNA repair, autophagy, and DNA replication. Phosphoproteomic studies further demonstrated a marked decline in the activity of key kinases ABL1 and PDK1, while glycoproteomics highlighted disruptions in cell adhesion and ECM-receptor interactions. Notably, proteomic analysis identified an upregulation of PARP1 and BRD4 protein levels, suggesting a previously unrecognized resistance mechanism. Consistently, combining TTFields with inhibitors targeting these proteins significantly enhanced the treatment efficacy in U87 cells. Thus, this study uncovers comprehensive molecular mechanisms underlying TTFields' effects on GBM cells and supports the development of concomitant therapies to enhance treatment efficacy.

PMID:40889189 | DOI:10.1021/acs.jproteome.5c00424

Nat Commun. 2025 Jan 8;16(1):430. doi: 10.1038/s41467-024-55428-y.

ABSTRACT

The analysis of circulating tumour DNA (ctDNA) through minimally invasive liquid biopsies is promising for early multi-cancer detection and monitoring minimal residual disease. Most existing methods focus on targeted deep sequencing, but few integrate multiple data modalities. Here, we develop a methodology for ctDNA detection using deep (80x) whole-genome TET-Assisted Pyridine Borane Sequencing (TAPS), a less destructive approach than bisulphite sequencing, which permits the simultaneous analysis of genomic and methylomic data. We conduct a diagnostic accuracy study across multiple cancer types in symptomatic patients, achieving 94.9% sensitivity and 88.8% specificity. Matched tumour biopsies are used for validation, not for guiding the analysis, imitating an early detection scenario. Furthermore, in silico validation demonstrates strong discrimination (86% AUC) at ctDNA fractions as low as 0.7%. Additionally, we successfully track tumour burden and ctDNA shedding from precancerous lesions post-treatment without requiring matched tumour biopsies. This pipeline is ready for further clinical evaluation to extend cancer screening and improve patient triage and monitoring.

PMID:39779727 | PMC:PMC11711490 | DOI:10.1038/s41467-024-55428-y