Glioblastoma is the most aggressive brain tumor in adults. Multiple lines of evidence suggest that microglia create a microenvironment favoring glioma invasion and proliferation. Our previous studies and literature reports indicated the involvement of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) in glioma cell proliferation and invasion, stimulated by tumor-infiltrating microglia. However, the specific microglia-released factors that modulate Pyk2 and FAK signaling in glioma cells are unknown. In this study, 20 human glioblastoma specimens were evaluated with the use of RT-PCR and western blotting. A Pierson correlation test demonstrated a correlation (0.6–1.0) between the gene expression levels for platelet-derived growth factor β(PDGFβ), stromal-derived factor 1α (SDF-1α), IL-6, IL-8, and epidermal growth factor (EGF) in tumor-purified microglia and levels of p-Pyk2 (Y579/Y580) and p-FAK(Y925) in glioma cells. siRNA knockdown against Pyk2 or FAK in three primary glioblastoma cell lines, developed from the investigated specimens, in combination with the cytokine receptor inhibitors gefitinib (1 μM), DMPQ (200 nM), and burixafor (1 μM) identified EGF, PDGFβ, and SDF-1α as key extracellular factors in the Pyk2- and FAK-dependent activation of invadopodia formation and the migration of glioma cells. EGF and IL-6 were identified as regulators of the Pyk2- and FAK-dependent activation of cell viability and mitosis.

In this study, we identified the proton-coupled folate transporter (PCFT) as a route for targeted delivery of drugs to some gliomas. Using the techniques of confocal imaging, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and small interfering (siRNA) knockdown against the PCFT, we demonstrated that Gl261 and A172 glioma cells, but not U87 and primary cultured astrocytes, express the PCFT, which provides selective internalization of folic acid (FA)-conjugated cytochrome c-containing nanoparticles (FA-Cyt c NPs), followed by cell death. The FA-Cyt c NPs (100 µg/mL), had no cytotoxic effects in astrocytes but caused death in glioma cells, according to their level of expression of PCFT. Whole-cell patch clamp recording revealed FA-induced membrane currents in FA-Cyt c NPs-sensitive gliomas, that were reduced by siRNA PCFT knockdown in a similar manner as by application of FA-Cyt c NPs, indicating that the PCFT is a route for internalization of FA-conjugated NPs in these glioma cells. Analysis of human glioblastoma specimens revealed that at least 25% of glioblastomas express elevated level of either PCFT or folate receptor (FOLR1). We conclude that the PCFT provides a mechanism for targeted delivery of drugs to some gliomas as a starting point for the development of efficient methods for treating gliomas with high expression of PCFT and/or FOLR1.

Purpose Glioblastoma (GBM) is the most common malignant brain tumor in adults, and durable control or cure with current standard or investigational therapies is rare. Therefore, novel approaches are needed. This exploratory study evaluated whether defactinib and avutometinib, inhibitors of FAK/Pyk2 and RAF/MEK signaling respectively, penetrate GBM and produce measurable effects on their molecular targets. Methods Defactinib or avutometinib was administered to six subjects each, in two escalating dose levels: avutometinib at 3.2 mg and 4 mg, and defactinib at 200 mg and 400 mg (three patients per dose level). Administration occurred immediately prior to craniotomy for tumor resection. Tumor tissue, peritumoral brain tissue, and blood were collected during surgery. Drug concentrations were measured by liquid chromatography–mass spectrometry, and effects on the intended molecular targets were assessed by western blot analysis. Results Even after a single preoperative dose, both defactinib and, to a lesser extent, avutometinib were detectable in tumor tissue 3–4 h after administration. Peritumoral brain tissue contained lower concentrations of each agent. Exploratory pharmacodynamic analyses suggested target engagement: avutometinib (3.2 mg) reduced Erk1/2 phosphorylation approximately 28-fold, while defactinib (400 mg) reduced Pyk2 phosphorylation by 5.7-fold within tumor tissue. Effects in peritumoral tissue were minimal. Conclusion These exploratory findings demonstrate that defactinib and avutometinib can penetrate GBM tissue and produce measurable modulation of their intended molecular targets after a single dose, with limited impact on surrounding brain. While the small sample size and inherent tissue heterogeneity limit definitive conclusions, this study supports the feasibility of presurgical pharmacokinetic and pharmacodynamic evaluation in GBM and provides a rationale for further clinical studies to optimize dosing, target inhibition, and therapeutic efficacy. Trial Registration Number ClinicalTrials.gov NCT05798507. Date of Registration March 3, 2023.

Glioblastoma (GBM), an aggressive form of brain cancer, has a higher incidence in non-Hispanics when compared to the US Hispanic population. Using data from RT-PCR analysis of 21 GBM tissue from Hispanic patients in Puerto Rico, we identified significant correlations in the gene expression of focal adhesion kinase and proline-rich tyrosine kinase (PTK2 and PTK2B) with NGFR (nerve growth factor receptor), PDGFRB (platelet-derived growth factor receptor B), EGFR (epithelial growth factor receptor), and CXCR1 (C-X-C motif chemokine receptor 1). This study further explores these correlations found in gene expression while accounting for sex and ethnicity. Statistically significant (p < 0.05) correlations with an r value > ±0.7 were subsequently contrasted with mRNA expression data acquired from cBioPortal for 323 GBM specimens. Significant correlations in Puerto Rican male patients were found between PTK2 and PTK2B, NGFR, PDGFRB, EGFR, and CXCR1, which did not arise in non-Hispanic male patient data. The data for Puerto Rican female patients showed correlations in PTK2 with PTK2B, NGFR, PDGFRB, and EGFR, all of which did not appear in the data for non-Hispanic female patients. The data acquired from cBioPortal for non-Puerto Rican Hispanic patients supported the correlations found in the Puerto Rican population for both sexes. Our findings reveal distinct correlations in gene expression patterns, particularly involving PTK2, PTK2B, NGFR, PDGFRB, and EGFR among Puerto Rican Hispanic patients when compared to non-Hispanic counterparts.

Intramedullary spinal cord tumors (IMSCTs) harbor unique genetic mutations which may play a role in prognostication and management. To this end, we present the largest cohort of IMSCTs with genetic characterization in the literature from our multi-site institutional registry. A total of 93 IMSCT patient records were reviewed from the years 1999 to 2020. Out of these, 61 complied with all inclusion criteria, 14 of these patients had undergone genetic studies with 8 undergoing whole-genomic sequencing. Univariate analyses were used to assess any factors associated with progression-free survival (PFS) using the Cox proportional hazards model. Firth’s penalized likelihood approach was used to account for the low event rates. Fisher’s exact test was performed to compare whole-genome analyses and specific gene mutations with progression. PFS (months) was given as a hazard ratio. Only the absence of copy neutral loss of heterozygosity (LOH) was shown to be significant (0.05, p = 0.008). Additionally, higher risk of recurrence/progression was associated with LOH (p = 0.0179). Our results suggest LOH as a genetic predictor of shorter progression-free survival, particularly within ependymoma and glioblastoma tumor types. Further genomic research with larger multi-institutional datasets should focus on these mutations as possible prognostic factors.

Background: Glioblastoma (GBM) is a highly aggressive malignancy and the most common primary malignant brain tumor in adults, with significant variations in incidence and outcomes across different populations. Despite extensive research in the United States (U.S.), there is limited data on GBM epidemiology in Puerto Rico, a U.S. commonwealth with a unique demographic and healthcare system. This study aims to provide the first comprehensive population-based analysis of GBM in Puerto Rico, focusing on incidence, demographics, and geographic distribution. Methods: We performed a retrospective study of 1,423 GBM cases diagnosed in Puerto Rico from 2000 to 2020, including 1,334 cases with histopathologically confirmed diagnoses, utilizing data from the Puerto Rico Central Cancer Registry. Demographic, clinical, and geographic variables were analyzed to identify epidemiological patterns and treatment trends. Statistical analyses included age-adjusted incidence rates, temporal trends, and geolocation mapping. Results: The average age-adjusted incidence rate (AAAIR) of GBM in Puerto Rico was 1.78 per 100,000 people. The highest incidence was observed in the 65-74 age group (6.71 per 100,000). Municipalities such as Moca, Cayey, and San Sebastián exhibited the highest incidence rates, while Culebra reported no cases. A significant upward trend in GBM incidence was observed, with an annual percentage change (APC) of 4.85% (95% CI: 3.66%-6.04%). Conclusion: This study highlights unique epidemiological patterns of GBM in Puerto Rico, including lower incidence rates compared to the U.S. mainland and significant geographic variations. The findings underscore the need for further research into environmental, genetic, and socioeconomic factors influencing GBM in this population.