Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part I: Targeted Cytotoxic Therapy

Abstract

Glioblastoma (GBM), a primary brain tumor, remains an unmet medical need. One of the major obstacles to GBM treatment is the adequate properties of drugs. Complex pathobiology of GBM, including local invasion and intratumoral heterogeneity, represent major challenges to generating effective therapies. We discuss here the design of targeted cytotoxic drugs with an increased access to tumors and pathophysiologically important tumor compartments. Our research and others' have shown that interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, and EphA3 receptors are overexpressed in most patients with GBM, but not in normal brain, and also in spontaneous canine high-grade gliomas like GBM, an excellent translational model of GBM. These receptors and also the EphB2 receptor are overexpressed and are functional in several GBM compartments involved Delivering Cytotoxic Therapies to Glioblastoma 342 in tumor progression and/or resistance to therapies. We pursue the novel idea of targeting all four receptors with one targeted cytotoxic compound (QUAD-CTX). We are constructing a molecularly targeted anti-GBM drug that (i) may not require patient prescreening, (ii) will attack most tumor compartments known to be pathobiologically important, and (iii) performs these functions in one pharmaceutical entity, so it will be suitable for monotherapy. We thus wish to take advantage of a unique opportunity to produce an off-the-shelf, highly specific, molecularly targeted drug candidate suitable to treat perhaps even all patients with GBM. We envision that this "molecular resection" will translate into clear-cut durable responses in patients suffering from this dreadful disease.

Receptor-Targeted Glial Brain Tumor Therapies

“…Combined expression of EphA2, EphA3, EphB2, and IL-13RA2 is observed in almost 100% of patients with glioblastoma patients. Furthermore, expression of these receptors is also present in tumor-infiltrating cells, tumor-initiating cells or GSCs, and neovasculature [ 180 ]. Therefore, a cytotoxic agent that simultaneously targets these four receptors could be powerful in destroying the tumor ecosystem of GBM without allowing it to recover and cause recurrence.…”

Challenges to Successful Implementation of the Immune Checkpoint Inhibitors for Treatment of Glioblastoma

“…Treating GBM is much more challenging than other solid tumors because of the blood-brain barrier (BBB) which will be discussed in further detail below. Briefly, the BBB isolates the tumor from therapeutic accession by creating a selectively permeable barrier around most central nervous system (CNS) blood vessels [11,12]. GBM also has a so called blood-brain tumor barrier (BBTB) due to abnormal neovasculature with irregular blood flow further preventing drugs from exiting the circulation which has an effect on the treatment of the tumor when drugs are delivered systemically [11].…”

Identification of cephalomannine as a drug candidate for glioblastoma via high-throughput drug screening

“…Its prognosis remains poor, even with the current standard of care, i.e., a combination of surgery, radiotherapy, and chemotherapy 3,4) . The disease course of GBM is typically rapid, and it has a 5-year survival rate of only 10% and a median survival time of 15 months following intensive treatment [5][6][7][8] . Therefore, there remains a strong need for novel therapeutic strategies to treat GBM.…”