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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.

BackgroundEndometrial cancer is the most common gynecologic malignancy in Puerto Rico and the United States (US).MethodsWe compare the age-specific and age-adjusted incidence and mortality rates and the survival of endometrial cancer in Puerto Rico with that of non-Hispanic whites (NHW), non-Hispanic blacks (NHB) and Hispanics in the US. Data from the Puerto Rico Central Cancer Registry and the Surveillance, Epidemiology, and End Results program were analyzed from 1992-2003.ResultsAge-standardized incidence rates of endometrial cancer increased significantly (p < 0.05) in Puerto Rico (APC = 2.8%) and among NHB (APC = 1.9%) and remained constant (p > 0.05) for NHW (APC = -0.1%) and Hispanics in the US (APC = 0.4%). Mortality trends remained constant in all racial/ethnic groups (p > 0.05). For 1999-2003, women in Puerto Rico had similar incidence of endometrial cancer as Hispanics (Standardized rate ratio [SRR] = 0.94, 95% CI = 0.87-1.01), although their risk was lower than that of NHW (SRR = 0.56, 95% CI = 0.53-0.59) and NHB (SRR = 0.91, 95% CI = 0.84-0.98). Meanwhile, women in Puerto Rico had 15% higher risk of death than Hispanic women (SRR = 1.15, 95% CI = 1.03-1.30) similar risk than NHW (SRR = 0.93, 95% CI = 0.83-1.03), and lower risk than NHB (SRR = 0.51, 95% CI = 0.46-0.57). Puerto Rico (63.1%) and NHB (56.8%) had a lower 5-year survival than NHW (78.4%) and Hispanics (79.5%). An age-adjusted Cox proportional hazards model showed that compared with women in Puerto Rico, Hispanic women in the United States had 37% lower mortality risk (HR = 0.63, 95% CI = 0.56-0.71) and NHW had 53% lower mortality risk (HR = 0.47, 95% CI = 0.43-0.52) after 5 years of diagnosis; NHB women had 22% higher mortality risk than women in Puerto Rico (HR = 1.22, 95% CI = 1.09-1.36).ConclusionsThe lower burden of endometrial cancer in Puerto Rico suggests the presence of protective factors or lower exposure to risk factors in this population, although increases in incidence suggest changes in the occurrence of lifestyles and environmental risk factors. Meanwhile, the lower five-year survival from endometrial cancer among Puerto Ricans suggests a health disparity for this group in areas such as quality of care and/or differences in terms of stage at diagnosis and associated comorbidities. Assessment of disease risk factors and characteristics, and access and response to treatment is required to further understand these results.

Inhibition of the interaction between MDM2 and p53 has emerged as a promising strategy for combating cancer, including the treatment of glioblastoma (GBM). Numerous MDM2 inhibitors have been developed and are currently undergoing rigorous testing for their potential in GBM therapy. Encouraging results from studies conducted in cell culture and animal models suggest that MDM2 inhibitors could effectively treat a specific subset of GBM patients with wild-type TP53 or functional p53. Combination therapy with clinically established treatment modalities such as radiation and chemotherapy offers the potential to achieve a more profound therapeutic response. Furthermore, an increasing array of other molecularly targeted therapies are being explored in combination with MDM2 inhibitors to increase the effects of individual treatments. While some MDM2 inhibitors have progressed to early phase clinical trials in GBM, their efficacy, alone and in combination, is yet to be confirmed. In this article, we present an overview of MDM2 inhibitors currently under preclinical and clinical investigation, with a specific focus on the drugs being assessed in ongoing clinical trials for GBM patients.