This application addresses a major problem in therapy of solid tumors: poor penetration of anti-cancer drugs into tumor tissue and to infiltrating tumor cells. Recently, we have identified tumor penetrating peptides (TPP) that trigger specific penetration of co-administered un-conjugated drugs deep into tumor and increase their therapeutic index. Current TPP target angiogenic tumor vessels and may not be suitable for targeting slow-growing tumors and invasive tumor cells. TPP are composed of functional modules (tumor recruitment motif, cryptic tissue penetrating C-end Rule element, and a protease cleavage site), which can be rearranged to yield peptides of novel specificities.Our goal is to develop TPP platform for delivery of co-administered drugs to the deadliest brain tumor – glioblastoma (GBM). High-grade glioma is a target that is particularly evasive and well-suited for tissue penetrative drug delivery. We will develop glioma-specific TPP (gTPP) by combination of in vivo and ex vivo phage display of constrained peptide libraries on state-of-the-art glioma animal models. These gTPP will be able to penetrate gliomas (and potentially other tumors) independent of their angiogenic status, and to deliver drugs to infiltrating malignant cells far from the bulk glioma lesion. We will characterize, validate, and optimize the gTPP platform for enhanced glioma delivery of co-injected drugs. These studies will provide the preclinical data needed to advance the gTPP combination therapy of glioma to GLP toxicology and subsequent IND filing.