Glioblastoma (GBM) is the most aggressive primary malignant brain cancer that invariably results in a dismal prognosis. Chemotherapy and radiotherapy have not been completely effective as standard treatment options for patients due to recurrent disease. We and others have therefore developed molecular strategies to specifically target interleukin 13 receptor alpha 2 (IL13RA2), a GBM restricted receptor expressed abundantly on over 75% of GBM patients. In this work, we evaluated the potential of Pep-1L, a novel IL13RA2 targeted peptide, as a platform to deliver targeted lethal therapies to GBM. To demonstrate GBM-specificity, we radiolabeled Pep-1L with Copper-64 and performed in vitro cell binding studies, which demonstrated specific binding that was blocked by unlabeled Pep-1L. Furthermore, we demonstrated real-time GBM localization of [64Cu]Pep-1L to orthotopic GBMs using small animal PET imaging. Based on these targeting data, we performed an initial in vivo safety and therapeutic study using Pep-1L conjugated to Actinium-225, an alpha particle emitter that has been shown to potently and irreversibly kill targeted cells. We infused [225Ac]Pep-1L into orthotopic GBMs using convection-enhanced delivery and found no significant adverse events at injected doses. Furthermore, our initial data also demonstrated significantly greater overall, median and mean survival in treated mice when compared to those in control groups (p < 0.05). GBM tissue extracted from mice treated with [225Ac]Pep-1L showed double stranded DNA breaks, lower Ki67 expression and greater propidium iodide internalization, indicating anti-GBM therapeutic effects of [225Ac]Pep-1L. Based on our results, Pep-1L warrants further investigation as a potential targeted platform to deliver anti-cancer agents.
Glioblastoma (GBM) is the most common primary malignant astrocytoma associated with a poor patient survival. Apart from arising de novo, GBMs also occur due to progression of slower growing grade III astrocytomas. GBM is characterized by extensive hypoxia, angiogenesis, proliferation and invasion. Standard treatment options such as surgical resection, radiation therapy and chemotherapy have increased median patient survival to 14.6 months in adults but recurrent disease arising from treatment resistant cancer cells often results in patient mortality. These treatment resistant cancer cells have been found to exhibit stem cell like properties. Strategies to identify or target these Glioblastoma Stem Cells (GSC) have proven to be unsuccessful so far. Studies on cancer stem cells (CSC) within GBM and other cancers have highlighted the importance of paracrine signaling networks within their microenvironment on the growth and maintenance of CSCs. The study of GSCs and their communication with various cell populations within their microenvironment is therefore not only important to understand the biology of GBMs but also to predict response to therapies and to identify novel targets which could stymy support to treatment resistant cancer cells and prevent disease recurrence. The purpose of this chapter is to introduce the concept of GSCs and to detail the latest findings indicating the role of various cellular subtypes within their microenvironment on their survival, proliferation and differentiation.
Glioblastoma (GBM), an aggressive grade IV astrocytoma, is the most common primary malignant adult brain tumor characterized by extensive invasiveness, heterogeneity, and angiogenesis. Standard treatment options such as radiation and chemotherapy have proven to be only marginally effective in treating GBM because of its invasive nature. Therefore, extensive efforts have been put forth to develop tumor‐tropic stem cells as viable therapeutic vehicles with potential to treat even the most invasive tumor cells that are harbored within areas of normal brain. To this end, we discovered a newly described NG2‐expressing cell that we isolated from a distinct pericyte subtype found abundantly in cultures derived from peripheral muscle. In this work, we show the translational significance of these peripherally derived neural‐like stem cells (NLSC) and their potential to migrate toward tumors and act as therapeutic carriers. We demonstrate that these NLSCs exhibit in vitro and in vivo GBM tropism. Furthermore, NLSCs did not promote angiogenesis or transform into tumor‐associated stromal cells, which are concerns raised when using other common stem cells, such as mesenchymal stem cells and induced neural stem cells, as therapeutic carriers. We also demonstrate the potential of NLSCs to express a prototype therapeutic, tumor necrosis factor α‐related apoptosis‐inducing ligand and kill GBM cells in vitro. These data demonstrate the therapeutic potential of our newly characterized NLSC against GBM. Stem Cells Translational Medicine 2017;6:471–481
Peptides that target cancer cell surface receptors are promising platforms to deliver diagnostic and therapeutic payloads specifically to cancer but not normal tissue. IL13RA2 is a tumor-restricted receptor found to be present in several aggressive malignancies, including in the vast majority of high-grade gliomas and malignant melanoma. This receptor has been successfully targeted for diagnostic and therapeutic purposes using modified IL-13 ligand and more recently using a specific peptide, Pep-1L. In the current work, we establish the in vitro and in vivo tumor binding properties of radiolabeled Pep-1L, designed for tumor imaging. We radiolabeled Pep-1L with Copper-64 and demonstrated specific cell uptake in the IL13RA2-over expressing G48 glioblastoma cell line having abundant IL13RA2 expression. [64Cu]Pep-1L binding was blocked by unlabeled ligand, demonstrating specificity. To demonstrate in vivo tumor uptake, we intravenously injected into tumor-bearing mice and demonstrated that [64Cu]Pep-1L specifically bound tumors at 24 hours, which was significantly blocked (3-fold) by pre-injecting unlabeled peptide. To further demonstrate specificity of Pep-1L towards IL13RA2 in vivo, we exploited an IL13RA2-inducible melanoma tumor model that does not express receptor at baseline but expresses abundant receptor after treatment with doxycycline. We injected [64Cu]Pep-1L into mice bearing IL13RA2-inducible melanoma tumors and performed in vivo PET/CT and post-necropsy biodistribution studies and found that tumors that were induced to express IL13RA2 receptor by doxycycline pretreatment bound radiolabeled Pep-1L 3-4 fold greater than uninduced tumors, demonstrating receptor specificity. This work demonstrates that [64Cu]Pep-1L selectively binds hIL13RA2-expressing tumors and validates Pep-1L as an effective platform to deliver diagnostics and therapeutics to IL13RA2-expressing cancers.
The blood-brain barrier (BBB), comprised of brain endothelial cells with tight junctions (TJ) between them, regulates the extravasation of molecules and cells into and out of the central nervous system (CNS). Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of a broad range of brain disorders. Current strategies for BBB opening are invasive, not specific, and lack precise control over the site and timing of BBB opening, which may limit their clinical translation. In the present report, we describe a novel approach based on a combination of stem cell delivery, heat-inducible gene expression and mild heating with high-intensity focused ultrasound (HIFU) under MRI guidance to remotely permeabilize BBB. The permeabilization of the BBB will be controlled with, and limited to where selected pro-inflammatory factors will be secreted secondary to HIFU activation, which is in the vicinity of the engineered stem cells and consequently both the primary and secondary disease foci. This therapeutic platform thus represents a non-invasive way for BBB opening with unprecedented spatiotemporal precision, and if properly and specifically modified, can be clinically translated to facilitate delivery of different diagnostic and therapeutic agents which can have great impact in treatment of various disease processes in the central nervous system.
Retinoic acid receptor alpha (RAR-α) plays a significant role in a number of diseases, including neuroblastoma. Children diagnosed with high-risk neuroblastoma are treated 13-cis-retinoic acid, which reduces risk of cancer recurrence. Neuroblastoma cell death is mediated via RAR-α, and expression of RAR-α is upregulated after treatment. A molecular imaging probe that binds RAR-α will help clinicians to diagnose and stratify risk for patients with neuroblastoma, who could benefit from retinoid-based therapy. In this study, we report the radiolabeling, and initial in vivo evaluation of [18F]KBM-1, a novel RAR-α agonist. The radiochemical synthesis of [18F]KBM-1 was carried out through KHF2 assisted substitution of [−18F] from aryl-substituted pinacolatoesters-based retinoid precursor. In vitro cell uptake assay in human neuroblastoma cell line showed that the uptake of [18F]KBM-1 was significantly inhibited by all three blocking agents (KBM-1, ATRA, BD4) at all the selected incubation times. Standard biodistribution in mice bearing neuroblastoma tumors demonstrated increased tumor uptake from 5 min to 60 min post radiotracer injection and the uptake ratios for target to non-target (tumor: muscle) increased 2.2-fold to 3.7-fold from 30 min to 60 min post injection. Tumor uptake in subset of 30 min blocking group was 1.7-fold lower than unblocked. These results demonstrate the potential utility of [18F]KBM-1 as a RAR-α imaging agent.
Glioblastoma (GBM) is an aggressive and lethal disease that often results in a poor prognosis. Unlike most solid tumors, GBM is characterized by diffuse infiltrating margins, extensive angiogenesis, hypoxia, necrosis, and clonal heterogeneity. Recurrent disease is an unavoidable consequence for many patients as standard treatment options such as surgery, radiotherapy, and chemotherapy have proven to be insufficient in causing long-term survival benefits. Systemic delivery of promising drugs is hindered due to the blood-brain barrier and non-uniform perfusion within GBM tissue. In recent years, many investigations have highlighted the role of GBM stem cells (GSCs) and their microenvironment in the initiation and maintenance of tumor tissue. Preclinical and early clinical studies to target GSCs and microenvironmental components are currently underway. Of these strategies, immunotherapy using checkpoint inhibitors and redirected cytotoxic T cells have shown promising results in early investigations. But, GBM microenvironment is heterogenous and recent investigations have shown cell populations within this microenvironment to be plastic. These studies underline the importance of identifying the role of and targeting multiple cell populations within the GBM microenvironment which could have a synergistic effect when combined with novel therapies. Pericytes are multipotent perivascular cells that play a vital role within the GBM microenvironment by assisting in tumor initiation, survival, and progression. Due to their role in regulating the blood-brain barrier permeability, promoting angiogenesis, tumor growth, clearing extracellular matrix for infiltrating GBM cells and in helping GBM cells evade immune surveillance, pericytes could be ideal therapeutic targets for stymieing or exploiting their role within the GBM microenvironment. This chapter will introduce hallmarks of GBM and elaborate on the contributions of pericytes to these hallmarks by examining recent findings. In addition, the chapter also highlights the therapeutic value of targeting pericytes, while discussing conventional and novel GBM therapies and obstacles to their efficacy.
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