B7–H3 (CD276), a member of the B7 superfamily, is an important factor in downregulating immune responses against tumors. It is also aberrantly expressed in many human malignancies. Beyond immune regulatory roles, its overexpression has been linked to invasive metastatic potential and poor prognosis in patients with cancer. Antibody-dependent cell-mediated cytotoxicity strategies targeting B7–H3 are currently in development, and early-phase clinical trials have shown encouraging preliminary results.To understand the role of B7–H3 in pediatric central nervous system (CNS) malignancies, a comprehensive panel of primary CNS tumors of childhood was examined by immunohistochemistry for levels and extent of B7–H3 expression. In addition, B7–H3 m-RNA expression status and association with overall survival in various pediatric CNS tumor types was accessed by curating publicly available patient gene expression data sets derived from bioinformatics analysis and visualization platforms (GlioVis).We demonstrate that B7–H3 is broadly expressed in pediatric glial and nonglial CNS tumors, and its aberrant expression, as determined by immunohistochemical staining intensity, correlates with tumor grade. Moreover, high B7–H3 m-RNA expression is significantly associated with worse survival and could potentially improve prognostication in various brain tumor types of childhood. B7–H3 can be used as a therapeutic target, given its tumor selectivity and the availability of targeted therapeutic agents to this antigen.
Thanks to the recent advances in the development of chemotherapeutics, the morbidity and mortality of many cancers has decreased significantly. However, compared to oncology in general, the field of neuro-oncology has lagged behind. While new molecularly targeted chemotherapeutics have emerged, the impermeability of the blood–brain barrier (BBB) renders systemic delivery of these clinical agents suboptimal. To circumvent the BBB, novel routes of administration are being applied in the clinic, ranging from intra-arterial infusion and direct infusion into the target tissue (convection enhanced delivery (CED)) to the use of focused ultrasound to temporarily disrupt the BBB. However, the current system depends on a “wait-and-see” approach, whereby drug delivery is deemed successful only when a specific clinical outcome is observed. The shortcomings of this approach are evident, as a failed delivery that needs immediate refinement cannot be observed and corrected. In response to this problem, new theranostic agents, compounds with both imaging and therapeutic potential, are being developed, paving the way for improved and monitored delivery to central nervous system (CNS) malignancies. In this review, we focus on the advances and the challenges to improve early cancer detection, selection of targeted therapy, and evaluation of therapeutic efficacy, brought forth by the development of these new agents.
The blood-brain barrier (BBB) represents a major obstacle in delivering therapeutics to brain lesions. Convection-enhanced delivery (CED), a method that bypasses the BBB through direct, cannula-mediated drug delivery, is one solution to maintaining increased, effective drug concentration at these lesions. CED was recently proven safe in a phase I clinical trial against diffuse intrinsic pontine glioma (DIPG), a childhood cancer. Unfortunately, the exact relationship between drug size, charge, and pharmacokinetic behavior in the brain parenchyma are difficult to observe in vivo. PET imaging of CEDdelivered agents allows us to determine these relationships. In this study, we label different modifications of the PDGFRA inhibitor dasatinib with fluorine-18 or via a nanofiber-zirconium-89 system so that the effect of drug structure on post-CED behavior can accurately be tracked in vivo, via PET. Relatively unchanged bioactivity is confirmed in patient-and animal-modelderived cell lines of DIPG. In nai ̈ve mice, significant individual variability in CED drug clearance is observed, highlighting a need to accurately understand drug behavior during clinical translation. Generally, the half-life for a drug to clear from a CED site is short for low molecular weight dasatinib analogs that bare different charge; 1−3 (1, 32.2 min (95% CI: 27.7−37.8), 2, 44.8 min (27.3−80.8), and 3, 71.7 min (48.6−127.6) minutes) and is much longer for a dasatinib-nanofiber conjugate, 5, (42.8−57.0 days). Positron emission tomography allows us to accurately measure the effect of drug size and charge in monitoring real-time drug behavior in the brain parenchyma of live specimens.
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