(b) Volume analysis demonstrates a … CED allows for direct assessment of newly selected drugs by maximizing the specific delivery

to the tumor, especially as the molecular understanding of human GBM continues to identify new potential targets. Based on the work of Verhaak et al., GBM has been subdivided based on 4 distinct molecular signatures: classical, neural, proneural, and mesenchymal [26]. Our group has developed a mouse model of glioma which is induced by injecting a retrovirus that expresses PDGF-B and cre recombinase into the subcortical white matter of transgenic mice that harbor floxed alleles of the tumor suppressor genes, PTEN and p53. We found that the expression profile Inhibitors,research,lifescience,medical of these tumors closely resembles the proneural subtype of GBM [27]. This model provides a powerful tool to assess therapies in treating this specific subtype of GBM. Also, by understanding the molecular profile of this subtype, rational

selection of antitumor Inhibitors,research,lifescience,medical agents can be pursued. Within human TCGA data, we found that topoisomerases are differentially expressed across the 4GBM subtypes, with proneural subtype showing the highest levels of both TOP2a and TOP2b expressions. The elevated expression of topoisomerase II seen in the proneural subgroup suggested that Inhibitors,research,lifescience,medical these tumors might be particularly sensitive to inhibitors of topoisomerase II. We also found elevated expression of topoisomerase Inhibitors,research,lifescience,medical II compared to topoisomerase I in our murine model of proneural GBM ( Carminucci et al. [28]). Based on these findings, we hypothesized that etoposide, a topoisomerase II inhibitor, would exhibit effective cytotoxicity against the proneural subtype of GBM. We are currently undergoing preclinical testing

with local, continuous delivery of etoposide in our mouse model of proneural GBM, which demonstrates significant antitumor Tacedinaline in vivo activity and prolonged survival (Carminucci et al. [28]). We hope Inhibitors,research,lifescience,medical to translate these findings into early Phase I and II trials and to assess clinical and radiographic response with an understanding of the specific molecular subtypes of tumors treated. Phosphatidylinositol diacylglycerol-lyase 5. Prolonged CED with Implantable Subcutaneous Pumps In our initial clinical trial, we demonstrated the ability of CED to deliver and effectively treat tumors with chemotherapy, all while bypassing the blood brain barrier and minimizing systemic toxicity. These clinical studies utilized externalized catheters, which, due to an increasing risk of infection with longer placement, shortened the treatment period to 4 days [6]. As mentioned above, in our rodent model, we demonstrated that prolonged delivery of topotecan is associated with increased survival. Therefore, we sought to develop a system for prolonged delivery that could be safely applied in the clinical setting.