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Core-sheath fibers containing a drug for brain tumor are reported. Mycophenolic acid (MPA), a FDA-approved immunosuppressant, has been demonstrated to inhibit several types of tumor cells growth. However, the effective serum MPA concentration for anti-tumor declines quickly in-vivodue to degradation in the liver, which hampers the development of MPA-based anti-tumor therapy. To overcome this issue, we have formed MPA-containing electrospun fiber membranes as local drug delivery vehicle and characterized MPA release profiles based on fiber composition and geometry. Coaxial fibers with poly(ε-caprolactone) (PCL)/MPA core and PCL sheath provided a more sustained release than homogenous fibers. In particular, thicker PCL sheath with 1:10 ratio of sheath thickness to fiber diameter provides gradual release in an initial period and higher MPA release after refreshing of media. The host polymer for MPA has a significant effect on the MPA release, with PCL/MPA single fiber providing more sustained release than coaxial fibers with polyvinylpyrrolidone (PVP)/MPA core and PCL sheath. In-vitroglioblastoma multiforme (GBM) tumor cell culture results show strong cell suppression effect by MPA-containing fiber membranes, with coaxial fiber membranes inhibiting GBM cell growth 3-5 × more than the single fiber membranes. This indicates that MPA-containing electrospun membranes have a promising potential for local treatment of GBM.

Genetic S6K1 inactivation can induce apoptosis in PTEN-deficient cells. We analyzed the therapeutic potential of S6K1 inhibitors in PTEN-deficient T cell leukemia and glioblastoma. Results revealed that the S6K1 inhibitor LY-2779964 was relatively ineffective as a single agent, while S6K1-targeting AD80 induced cytotoxicity selectively in PTEN-deficient cells. In vivo, AD80 rescued 50% of mice transplanted with PTEN-deficient leukemia cells. Cells surviving LY-2779964 treatment exhibited inhibitor-induced S6K1 phosphorylation due to increased mTOR-S6K1 co-association, which primed the rapid recovery of S6K1 signaling. In contrast, AD80 avoided S6K1 phosphorylation and mTOR co-association, resulting in durable suppression of S6K1-induced signaling and protein synthesis. Kinome analysis revealed that AD80 coordinately inhibits S6K1 together with the TAM family tyrosine kinase AXL. TAM suppression by BMS-777607 or genetic knockdown potentiated cytotoxic responses to LY-2779964 in PTEN-deficient glioblastoma cells. These results reveal that combination targeting of S6K1 and TAMs is a potential strategy for treatment of PTEN-deficient malignancy.

Goyama: Fuji Film: Research Funding. Iwamura:FUJIFILM Corporation: Employment. Saito:Fuji Film: Employment.

Cancers in which K-Ras activation drives tumor growth could be targeted by treatments blocking K-Ras ubiquitination.