DIPG-41. EXPLORING BRAIN PENETRANT PEPTIDE-DRUG CONJUGATES IN DIFFUSE INTRINSIC PONTINE GLIOMA MODELS

Abstract

Abstract The blood brain barrier (BBB) tightly controls access of molecules to the brain, limiting the efficacy of therapeutics for diseases of the central nervous system. We recently developed a novel approach for drug delivery across the BBB using a perfluoroaryl macrocyclic peptide-drug conjugate, M13-Pt(IV). This approach showed accumulation of platinum (Pt) within the brain, and improved survival in murine xenograft models using adult patient-derived glioblastoma cells. We also found that uptake of M13-Pt(IV) into tumor tissue is further enhanced by 6-bromo-indirubin acetoxime (BIA), a small molecule with anti-invasive properties. Because diffuse intrinsic pontine glioma (DIPG) is an invasive brain tumor protected from systemic drugs by an intact BBB, we hypothesized that this approach may be of particular benefit in this tumor type. Therefore our goal here was to investigate peptide-mediated drug delivery across the BBB in DIPG, using M13-Pt(IV) as a tool compound. When tested across a panel of four distinct DIPG lines in vitro the M13-Pt(IV) conjugate showed tumor cell killing effects superior to Pt(IV). BIA significantly slowed DIPG cell migration and lowered endothelial cell permeability in vitro via reduced expression of tight junction proteins as shown by immunostaining and decrease in trans-endothelial resistance. Bi-weekly dose regimens of M13-Pt(IV) are well-tolerated in nude mice at a dose of 15mg/kg, 3-fold more than the reported tolerable cisplatin dose at 5 mg/kg. Moreover, in vivo BIA also enhanced drug M13-Pt(IV) uptake into adult glioblastoma tumors. In vivo uptake and efficacy studies in DIPG tumor-bearing mice are underway. Overall, our data using a prototype peptide-drug conjugate support the further development of BBB-crossing peptide-drug conjugates for DIPG. Identification of the optimal therapeutic combinations for clinical application is our focus for future studies.