The Koschmann lab is applying a novel precision medicine approach accounting for both unique tumor biology and optimization of blood brain barrier penetration. We are performing correlate biology work on ongoing precision medicine trials for children and young adults with brain tumors at the University of Michigan, including correlation of spinal fluid analysis with surveillance MRIs.
Dual therapy with mTOR inhibitors to improve precision medicine therapy delivery
Recent work has documented the mutation, amplification and up-regulation of PDGFRA in a significant subset of pediatric patients with high-grade glioma (HGG) (Koschmann et al, Oncotarget, 2016). There are multiple orally bioavailable tyrosine kinase inhibitors (TKIs) with published safety data in pediatric cancers. Many TKIs display favorable characteristics for BBB penetration (small size, high lipophilicity), but are substrates for the active efflux proteins P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which significantly limits their brain penetration.Recent pre-clinical strategies have included co-administration of TKIs with agents that inhibit these proteins, including mammalian target of rapamycin (mTOR) inhibitors. Everolimus displays active Bcrp1 and P-gp inhibition, which has been shown to improve brain parenchymal penetration of TKIs.
Dr. Carl Koschmann is the Principal Investigator of an ongoing clinical phase 2 trial that incorporates the use of dasatinib and everolimus for children with high-grade glioma and diffuse intrinsic pontine glioma (DIPG) (NCT03352427). As well, the Koschmann Lab is exploring the concept of improving targeted TKI delivery to brain tumors through in vitro and in vivo work in the Koschmann lab.