Biology subjects

Moniz-Garcia, D.

Publications and source records attributed to Moniz-Garcia, D..

2 recordsLinked to original sources

bioRxiv2026

Functional genomics identifies therapeutic options, biomarkers, and resistance mechanisms for high-grade gliomas

High-grade gliomas (HGGs) are aggressive tumors with poor outcomes and limited treatment options. Here, we combined genomic and transcriptomic tumor profiling with drug testing in a patient-derived 3-dimensional culture model to identify individualized treatments and predictive biomarkers. Activity of single agents targeting frequently dysregulated glioma pathways was relatively poor ex vivo and generally reflected historical patient data. However, compounds targeting PI3K, epigenetic, and survival/senescence signaling were effective in some cases. Drug sensitivity correlated with transcriptional rather than genomic features and suggested heterogeneity as a resistance mechanism. Bromodomain and extraterminal domain inhibition was particularly effective in tumors enriched in the mesenchymal transcriptional subtype, promoted proneural transition, and was overcome by upregulated PI3K signaling. Notably, combinations were largely effective, with 6 strategies exhibiting stronger efficacy than corresponding single agents in most cases (58-77%). This study identifies HGG vulnerabilities and associated biomarkers, resistance mechanisms, and effective combination strategies that warrant further clinical validation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/701806v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@cdb75corg.highwire.dtl.DTLVardef@1c133e6org.highwire.dtl.DTLVardef@1365153org.highwire.dtl.DTLVardef@11543a4_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Microphysiological system modeling pericyte-induced temozolomide resistance in glioblastoma

Glioblastoma (GBM) is a malignancy with poor survival and high rates of chemoresistance. Temozolomide (TMZ), the standard-of-care chemotherapy for GBM patients, but GBM cells can be resistant to TMZ, resulting in limited clinical efficacy. Elucidating the complex mechanisms of TMZ chemoresistance in GBM requires novel in vitro models replicating the complex tumor microenvironment (TME). We present an multicellular 3D GBM model recapitulating the biomechanical characteristics of brain tissues and pericyte-mediated TMZ resistance. The composite hydrogel used to encapsulate GBM spheroids (U87, LN229, and PDM140), pericytes, or GBM spheroids with pericytes, mimics the rheological properties of brain tissues (G[~]800Pa and G"[~]100Pa). When untreated, the GBM models remain viable and proliferative for 14 days. PDM140 spheroids were most sensitive to TMZ (IC50=73M), followed by LN229 (IC50=278M) and U87 (IC50=446M). With pericytes, the viability of TMZ-treated GBM spheroids significantly increases by 22.7% for PDM140, 32.5% for LN229, and 22.1% for U87, confirming pericyte-induced GBM chemoresistance responses. The upregulation (380-fold) of C-C motif chemokine ligand 5 (CCL5) in pericytes upon TMZ treatment could explain the chemoresistance responses. This innovative brain-mimicking 3D GBM model represents a novel in vitro platform for testing the efficacy of TMZ and novel drugs targeting CCL5-mediated chemoresistance pathways in GBM.

bioengineering↗