Innovative Brain Tumor Therapy

Gerardo Caruso, Lucia Merlo, Maria Caffo

• Publisher: Woodhead Publishing
• Year: 2014
• Print ISBN: 9781907568596
• eBook ISBN: 9781908818744
• Topic: Medicina
• Subtopic: Neurologia

Despite recent advances, therapeutic efforts have not been successful establishing a definitive strategy of treatment for brain gliomas, because of the presence of the blood-brain barrier. Innovative Brain Tumor Therapy presents a synopsis of the studies on nanoparticles as ideal devices for brain tumor treatment. Their nanometric size, electrostatic charge, and lipophilic characteristics allow them to penetrate into the brain tissue freely. Promising in-vitro results have been reported, but remain to be validated in humans. This title focuses on the blood-brain barrier pathophysiology in brain tumors, and the possibilities of overcoming this with nanoparticle-based systems. Relevant patents of nanoparticles used as drug delivery carriers are also reported, as well as future scenarios in nanoparticles and stem cells.

1

Brief introduction on brain tumor epidemiology and state of the art in therapeutics

Abstract

This chapter focuses on the epidemiology, epigenetics and therapy of brain tumors. Standard treatment includes maximal surgical resection with postoperative radiotherapy and concomitant and adjuvant chemotherapy. Even with the most advanced multimodal standard treatments malignant brain tumors, namely gliobastomas, still have a poor prognosis. Numerous studies have been performed, and many are still underway, to develop successful treatments, and a major challenge seems to be defining the real cellular origin of this tumor. Starting from the initial cellular mutations and epigenetic modifications it will be possible to find new epigenetic-based therapies. We also stress the importance of overcoming the blood–brain barrier in order to improve the therapeutic effects.

Key words

brain tumor

epidemiology

epigenetics

glioblastoma

treatment

The median worldwide incidence of primary central nervous system tumors has been estimated as 3.9 per 100 000 person-years,¹ gliomas accounting for 77% of the malignant subtypes.² The Central Brain Tumor Registry of the United States annual report on the 10-year period 1985–1994 revealed a slight (0.9%) but statistically significant annual increase in incidence,³ indicating how this disease is gradually increasing in the developed countries. In fact, there is around a fourfold difference between countries with a high incidence (e.g. Australia, Canada, Denmark, Finland, New Zealand, and the USA) and regions with low incidence (e.g. the Philippines and India).^4,5 Differences in diagnostic practices, medical care, and completeness of reporting make these geographic comparisons difficult.

The term “glioma” encompasses all the neoplasms originating from mutated neural stem cells, and classified by the World Health Organization into four grades of malignancy,⁶ starting from tumors with low proliferative potential and the possibility of being cured (e.g. pilocytic astrocytoma – grade I), to diffusely infiltrative astrocytic tumors with cytological atypia (e.g. diffuse astrocytoma – grade II, which are able to progress to higher grades of malignancy), to lesions with histological evidence of malignancy including nuclear atypia, anaplasia, and brisk mitotic activity (e.g. anaplastic astrocytoma – grade III), and finally to the cytologically malignant, mitotically active, necrosis-prone neoplasms, rich in microvascular proliferation, which are glioblastoma (GBM) – the highest grade tumor (grade IV).⁶

Patients with GBM have the highest median age at diagnosis and the worst prognosis. Survival time for people with malignant brain tumor is related not only to the histologic type of the tumor but also to age at diagnosis,⁷ Karnofsky Performance Score status,⁸ extent of surgical resection,⁹ ki-67 immunohistochemical markers,¹⁰ and sensitivity to chemotherapy as determined by genetic mutations such as IDH1,¹¹ PTEN,¹² EGFR amplification,¹³ and 1p19q codeletion.¹⁴ Estimates of median overall survival vary widely and range from 4.4 to 65.5 months¹⁵ for anaplastic astrocytomas whereas only 2% of patients aged 65 years or older, and only 30% of those under the age of 45 years at GBM diagnosis, survive for 2 years.³

To develop a successful treatment for GBM, a major challenge is defining the real cellular origin of this tumor. Although cells acquiring a mutation, like the tumor cells, may not be the same as the cell of origin,¹⁶ epigenetic modifications, enzymes, and noncoding RNAs are often cell-type specific and can aid in identification of the cell of origin so as to focus therapies directly on it. In a mouse glioma model proposed by Liu et al.¹⁷ the neural stem cells pass on mutations to downstream progeny such as oligodendrocyte precursor cells (OPCs), which become putative glioma cells of origin. By contrast, Koso et al.¹⁸ suggested that the cell of origin in some GBM is not an OPC but an astroglial-like cell, and that the originating mutations can occur in neural stem cells. Hence, it may be likely that multiple cells of origin give rise to gliomas. Further, studying the genetic and epigenetic landscape of human OPCs and other cells as they are differentiating could uncover epigenetic enzymes and pathways misregulated in gliomagenesis. As an example, recent studies suggest that epigenetic modification determination during neural differentiation will probably provide insight into dedifferentiation processes, which may give rise to GBM. Friedmann-Morvinski et al.¹⁹ demonstrated that mature neurons dedifferentiate and become tumor-initiating cells in mouse models of glioma. Parallel studies showed that targeting astrocytes promotes glioma formation.²⁰ Collectively, these findings suggest that gliomas may arise from either dedifferentiating neural stem cells or astrocytes. Importantly from a therapeutic point of view, dedifferentiating neurons or astrocytes that give rise to gliomas might be the very cells that are resistant to chemotherapy with temozolomide (TMZ) and that induce tumor recurrence.²¹

Moreover, recurrent genomic regions of alteration, net gains and losses, and DNA aberrations have been found as markers of gliomagenesis inside tumor samples. Whereas some of these regions contain known oncogenes and tumor suppressor genes, putative biologically relevant genes within other regions remain to be identified. The phenotypic and genotypic heterogeneities indicate that no isolated genetic event accounts for gliomagenesis, but rather that it is the cumulative effects of a number of alterations that operate in a concerted manner. In this pathological process are included activation of growth factor receptor signaling pathways, downregulation of many apoptotic mechanisms, and imbalance of pro- and antiangiogenic factors. Several growth factor receptors, such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), C-Kit, vascular endothelial growth factor receptor (VEGFR) are overexpressed, amplified, or mutated in gliomas. Hence, the modulation of gene expression at more levels, such as DNA, messenger RNA, proteins, and transduction signal pathways, may represent the most effective modality to downregulate or silence some specific gene functions in neoplastic cells.²²

Regardless of all these research advancements, efficacious treatments to cure GBM have yet to be developed. Standard GBM treatment includes maximal surgical resection with a postoperative combination of radiotherapy with concomitant and adjuvant TMZ chemotherapy.²³ Although this treatment improves the median overall survival from 6 to 14.6 months, GBM remains a lethal tumor. Maximal safe resection of a primary GBM still remains the mainstay and confers improved prognosis. Alarmingly, with this therapy, patient survival at 5 years is below 10%. This is in part due to the invasive behavior of the tumor and the resulting inability to resect more than 98% of the bulk. For this reason, recurrence even after the most advanced treatment may be inevitable, and even in cases where apparent gross total resection is achieved.¹⁵ Specifically, patients who receive a surgical resection greater than 98% of the tumor volume have a prognosis of 13.1 months compared with 8.8 months in patients from whom less of the tumor is resected.²⁴ The indefinable borders of GBM cell infiltration into the surrounding healthy tissue prevent complete surgical removal. For this reason, most GBM patients will follow a standard treatment regimen after the tumor is resected. This consists of 6 weeks of external beam radiation five times a week plus daily oral TMZ. However, TMZ is an alkylating agent that does not always have therapeutic efficacy on each tumor cell. Unfortunately, most patients will have a recurrence within 6.9 months of their primary diagnosis. Essentially, all GBMs recur, and, among these, at least 80% of GBM recurrences occur in the same area as the original tumor, but re-operation and re-radiation are options for only a minority of patients. In addition, genetic mutations, epigenetic modifications and microenvironmental heterogeneity cause resistance to radiotherapy and chemotherapy, resulting in a therapeutic scenario that is difficult to overcome. Therefore, the development of efficient therapeutic strategies to combat these tumors requires a better knowledge of genetic and proteomic alterations as well as of the infiltrative behavior of GBM cells and how this can be targeted.

Cerebral gliomas show a unique pattern of invasion and exceptionally metastasize outside the central nervous system. Their invasion comprises the translocation of active malignant cells through host cellular and extracellular matrix (ECM) barriers.^25,26 How they can evade immune detection and defer commitment to proliferation, remains mostly unknown. Basically, invading glioma cells migrate to distinct anatomical structures: the basement membrane of blood vessels, the subependymal space, the glial limitans externa, and parallel and intersecting nerve fiber tracts in the white matter. They adhere to proteins of the surrounding ECM, are able to degrade ECM components by secretion of proteases and migrate. The ECM is composed of proteoglycans, glycoproteins, and collagens and also contains fibronectin, laminin, tenascin, hyaluronic acid, and vitronectin. Key points in the process of invasion are the synthesis and deposition of ECM components by glioma and mesenchymal cells, the release of ECM-degrading factors for remodeling interstitial spaces, the presence of adhesion molecules, and the effects of cell–matrix interactions on the behavior of glioma cells. The importance of ECM modification lies in the loss of contact inhibition, allowing tumor cells to freely migrate. It is known that the proteolytic degradation of the...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright page
• List of figures
• List of abbreviations
• About the authors
• Introduction
• 1: Brief introduction on brain tumor epidemiology and state of the art in therapeutics
• 2: Blood–brain barrier pathophysiology in brain tumors
• 3: Brain drug-delivery attempts
• 4: Nanoparticles potential: types, mechanisms of action, actual in vitro and animal studies, recent patents
• 5: Future scenarios: nanoparticles and stem cells
• 6: Conclusions
• Index