Biology subjects

Fedeles, B. I.

Publications and source records attributed to Fedeles, B. I..

3 recordsLinked to original sources

bioRxiv2025

DNA adduct and mutational profiles reveal a threshold of cellular defenses against N-nitrosodimethylamine administered to mice in drinking water

N-Nitrosodimethylamine (NDMA) is classified as an animal and probable human carcinogen. Murine liver DNA adducts, mutations, MGMT and CYP2E1 were evaluated following chronic administration of NDMA in drinking water. In a dose-escalation study, 7-methylguanine (m7G) increased linearly with NDMA dose. O6-Methylguanine (m6G) remained near background for NDMA doses up to [~]1 ppm, beyond which its level, and corresponding mutations, rose steeply. An extended study was done with 5 ppm NDMA, in which adducts were measured at 3 weeks and mutations at 10 weeks. While the level of CYP2E1 was unchanged, MGMT gene transcription was induced in females at 10 weeks. Homologous recombination-mediated chromosomal rearrangements did not increase over background. Point mutations, however, were elevated substantially in both sexes. Mutational analysis over 96 trinucleotide contexts revealed predominantly GC[->]AT mutations in 5-purine-G-3 contexts in a pattern matching human COSMIC cancer mutational signature SBS11, with secondary features resembling SBS119 (AT[->]GC). Taken together, the data implicate m6G as the dominant mutagenic adduct under chronic dosing with NDMA. Furthermore, the genomic m6G level was identified at which its dedicated repair protein, MGMT, became saturated. The coordinated application of DNA adduct, mutational and biochemical analyses provides a new approach for early detection and cancer management. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/687536v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1e6ae72org.highwire.dtl.DTLVardef@1c6fad6org.highwire.dtl.DTLVardef@7e3716org.highwire.dtl.DTLVardef@52a87b_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

Systems analysis uncovers early temozolomide responses and peptide antigens in glioblastoma

Temozolomide (TMZ) is the standard treatment for nearly all glioblastoma (GBM) patients, as it is the only chemotherapy shown to extend overall survival. However, this benefit is limited to a few months, underscoring the need for combination strategies to improve its efficacy. While TMZ-induced DNA damage can both mediate cytotoxicity and promote resistance, DNA damage more broadly can also stimulate immune activation. To evaluate its immunomodulatory potential, we characterized the previously unexplored early, cell-intrinsic consequences of TMZ in GBM cells, spanning DNA damage, stress responses, and antigen presentation. A multi-omics approach combining RNA sequencing and quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) profiled changes in gene expression, nascent protein translation, steady-state protein levels, kinase-substrate phosphorylation patterns, and MHC-I peptide presentation in GBM cells within 72 hours of TMZ exposure. This analysis revealed rapid activation of DNA damage signaling and p53-associated stress pathways, alongside dynamic changes in protein synthesis and antigen presentation. A set of TMZ treatment-associated peptide antigens (TAPAs) was identified, including peptides derived from stress response proteins, phosphorylated MHC-I peptides, and those induced by other genotoxic treatments such as radiation. Several of these peptides were also detected in recurrent GBM patient tumors. Our findings suggest that TMZ not only triggers early adaptive and potentially resistance-associated stress programs but may also enhance the immune visibility of GBM cells. These data highlight potential windows for combination therapies with TMZ that bolster immune recognition of GBM, while the systems approach provides a framework to examine how genotoxic therapies across cancers alter tumor immunogenicity.

cancer biology↗

bioRxiv2024

Modulation of blood-tumor barrier transcriptional programs improves intra-tumoral drug delivery and potentiates chemotherapy in GBM

Glioblastoma (GBM) is the most common malignant primary brain tumor. GBM has an extremely poor prognosis and new treatments are badly needed. Efficient drug delivery to GBM is a major obstacle as the blood-brain barrier (BBB) prevents passage of the majority of cancer drugs into the brain. It is also recognized that the blood-brain tumor barrier (BTB) in the growing tumor represents a challenge. The BTB is heterogeneous and poorly characterized, but similar to the BBB it can prevent therapeutics from reaching effective intra-tumoral doses, dramatically hindering their potential. Here, we identified a 12-gene signature associated with the BTB, with functions related to vasculature development, morphogenesis and cell migration. We identified CDH5 as a core molecule in this set and confirmed its over-expression in GBM vasculature using spatial transcriptomics of GBM patient specimens. We found that the indirubin-derivative, 6-bromoindirubin acetoxime (BIA), could downregulate CDH5 and other BTB signature genes, causing endothelial barrier disruption in endothelial monolayers and BBB 3D spheroids in vitro. Treatment of tumor-bearing mice with BIA enabled increased intra-tumoral accumulation of the BBB non-penetrant chemotherapeutic drug cisplatin and potentiated cisplatin-mediated DNA damage by targeting DNA repair pathways. Finally, using an injectable BIA nanoparticle formulation, PPRX-1701, we significantly improved the efficacy of cisplatin in patient-derived GBM xenografts and prolonged their survival. Overall, our work reveals potential targets at the BTB for improved chemotherapy delivery and the bifunctional properties of BIA as a BTB modulator and potentiator of chemotherapy, supporting its further development.

cancer biology↗