Glioblastoma

P2, N=90, Active, not recruiting, Philogen S.p.A. | Recruiting --> Active, not recruiting

P1, N=94, Recruiting, Mayo Clinic | Trial completion date: Feb 2029 --> May 2029 | Trial primary completion date: Feb 2028 --> May 2028

We experimentally validated several actionable findings, including tepotinib to target the IRAK1/4-cholesterol pathway in glioblastoma, brigatinib to target the MARK2/3-Hippo pathway in pancreatic cancer and gilteritinib to overcome MET mutation-driven drug resistance and metastasis. To facilitate exploration of our data, we provide KIRHub, a web-based tool that allows identification of existing inhibitors of wild-type and mutated kinases to guide precision oncology.

Furthermore, ROCK1-mediated phosphorylation of S100A8 at Thr3/Ser90, which stabilized S100A8 by impairing its binding to Fbxo10 and inhibiting the subsequent ubiquitination-mediated degradation. Our study reveals the S100A8-ROS-mTORC1 axis as a cholesterol metabolic vulnerability in GSCs, providing new insights into cholesterol metabolism and highlighting novel metabolism therapeutic strategies in GBM.

Targeted modulation of this pathway represents a promising therapeutic strategy for restoring BBB function and improving CNS drug delivery. Further mechanistic and translational studies are warranted to advance clinical applications.

Our results indicate that ECE1c is a key regulator of GBM invasion through ROCK2 activation and interaction with ACTB. Targeting ECE1c may represent a viable therapeutic strategy for treating invasive GBM.

In orthotopic syngeneic GBM models, Mn-CDs remodel the immunosuppressive tumor microenvironment, suppress intracranial tumor progression, and prolong survival with favorable biosafety. Collectively, this work establishes a dual-targeted Mn-based carbon nanoplatform that converts GBM toward an immune-responsive state through convergent cGAS-STING activation and ICD-driven immune priming.

To enable clinical translation, we developed SRN-101, a clinical-grade AAV-hIFNβ construct with optimized potency and manufacturability, which achieved superior expression and in vivo efficacy vs. the research-grade vector. These findings establish AAV-vectorized cytokines as a durable, locally delivered immuno-gene therapy platform for high-grade gliomas.

Clinical data reflects this, with the mRNA vaccine mRNA-4157 (KEYNOTE-942) demonstrating a significant recurrence-free survival (RFS) benefit in the adjuvant setting...This reflects the logistical and biological complexities inherent in developing personalised vaccines, highlighting challenges in both manufacturing and subject recruitment. These remain key obstacles impeding the widespread clinical application of such vaccines.

Our results suggest that galactose and galacturonic acid may be partly responsible for the protein structural changes. The pectins induced significant cytotoxicity and reduced Gal-3 expression in vitro, suggesting that biomaterials with a similar Gal:Ara ratio may be employed as adjuvants in GBM therapy.

These findings collectively suggest that upregulation of IKBIP promotes the proliferation and invasive behaviors of glioma cells by activating the Wnt/β-catenin/EMT pathway. Overall, our findings suggest that SP1-IKBIP axis facilitates the proliferation and invasion of glioma through Wnt/β-catenin-associated EMT, and SP1-IKBIP axis may represent a promising target for the clinical diagnosis and treatment of glioma.

2-Deoxy-D-glucose (2DG), a glycolytic inhibitor, depleted ATP dose-dependently (30-300 μM) and prevented those increases both at the protein and transcriptional levels. This was also observed in 3D spheroids upon TGF-β transient siRNA-mediated silencing or when TGF-βR1 kinase activity was inhibited by galunisertib...3D spheroids require ATP and a TGF-β/TGF-βR1 autocrine signaling axis to recapitulate the apoptosis/autophagy phenotypes. Combining glycolysis inhibition with TGF-β signaling inhibition could offer a promising therapeutic strategy for this rare and lethal brain cancer.