Biophysical Control of the Glioblastoma Immunosuppressive Microenvironment: Opportunities for Immunotherapy.

GBM is the most aggressive and common form of primary brain cancer with a dismal prognosis. Current GBM treatments have not improved patient survival, due to the propensity for tumor cell adaptation and immune evasion, leading to a persistent progression of the disease. In recent years, the tumor microenvironment (TME) has been identified as a critical regulator of these pro-tumorigenic changes, providing a complex array of biomolecular and biophysical signals that facilitate evasion strategies by modulating tumor cells, stromal cells, and immune populations. Efforts to unravel these complex TME interactions are necessary to improve GBM therapy. Immunotherapy is a promising treatment strategy that utilizes a patient's own immune system for tumor eradication and has exhibited exciting results in many cancer types; however, the highly immunosuppressive interactions between the immune cell populations and the GBM TME continue to present challenges. In order to elucidate these interactions, novel bioengineering models are being employed to decipher the mechanisms of immunologically "cold" GBMs. Additionally, these data are being leveraged to develop cell engineering strategies to bolster immunotherapy efficacy. This review presents an in-depth analysis of the biophysical interactions of the GBM TME and immune cell populations as well as the systems used to elucidate the underlying immunosuppressive mechanisms for improving current therapies.

The CNS-penetrating taxane drug TPI 287 potentiates antiglioma activity of the AURKA inhibitor alisertib in vivo.

INTRODUCTION: Glioblastoma (GBM) has a very poor prognosis despite current treatment. We previously found cytotoxic synergy between the AURKA inhibitor alisertib and the CNS-penetrating taxane TPI 287 against GBM tumor cells in vitro. METHODS: We used an orthotopic human GBM xenograft mouse model to test if TPI 287 potentiates alisertib in vivo. Western blotting, immunohistochemistry, siRNA knockdown, annexin V binding, and 3-dimensional Matrigel invasion assays were used to investigate potential mechanisms of alisertib and TPI 287 treatment interactions. RESULTS: Alisertib + TPI 287 combination therapy significantly prolonged animal survival compared to vehicle (p = 0.011), but only marginally compared to alisertib alone. Alisertib, TPI 287, and combined alisertib + TPI 287 reduced animal tumor volume compared to vehicle-treated controls. This was statistically significant for the combination therapy at 4 weeks (p < 0.0001). Alisertib + TPI 287 treatment decreased anti-apoptotic Bcl-2 protein levels in vivo and in vitro. Expression of the pro-apoptotic protein Bak was significantly increased by combination treatment (p < 0.0001). Pro-apoptotic Bim and Bak knockdown by siRNA decreased apoptosis by alisertib + TPI 287 in GB9, GB30, and U87 cells (p = 0.0005 to 0.0381). Although alisertib and TPI 287 significantly reduced GBM cell invasion (p < 0.0001), their combination was no more effective than TPI 287 alone. CONCLUSIONS: Results suggest that apoptosis is the dominant mechanism of potentiation of GBM growth inhibition by alisertib + TPI 287, in part through effects on Bcl-2 family proteins, providing a rationale for further laboratory testing of an AURKA inhibitor plus TPI 287 as a potential therapy against GBM.

Ex vivo biomechanical comparison of four Center of Rotation Angulation Based Leveling Osteotomy fixation methods.

OBJECTIVE: To compare the strength of four constructs used to secure an osteotomy in a Center of Rotation Angulation (CORA)-Based Leveling Osteotomy (CBLO) in an ex vivo model. STUDY DESIGN: Ex vivo study. SAMPLE POPULATION: Thirty-two canine tibiae from 17 skeletally mature cadavers weighing between 18 and 33.2 kg. METHODS: Thirty-two paired tibiae with patella and patellar tendon were collected. Each tibia was randomly allocated to a construct group: plate and pin (Plate), plate with countersink compression screw (HCS), plate with tension band (TB), or plate with HCS and TB (HCSTB). Samples were loaded by distraction until failure. The stiffness, yield load, and ultimate load were compared between each fixation method. RESULTS: No difference in stiffness of the constructs was detected between groups (p = .6937). Yield load for the HCSTB group (1211.06 N) was greater than the TB group (1016.41 N), the HCS group (907.20 N), and the Plate group (787.73 N) (p = .0069). The ultimate load for the HCSTB group (1387.82 N) was greater than the TB group (1076.36 N), HCS group (926.62 N), and the Plate group (774.35 N) (p = .0004). CONCLUSIONS: CBLO fixation augmented with a TB and HCS provided a stronger construct that withstood a greater yield load and ultimate load than either augmentation strategy alone. CLINICAL SIGNIFICANCE: Augmenting a CBLO fixation with a TB and a HCS can provide increased construct strength.