Treatment Of Malignant Brain Tumors Research Articles

Role of Monocarboxylate Transporters in Drug Delivery to the Brain

Monocarboxylate transporters (MCTs) are known to mediate the transport of short chain monocarboxylates such as lactate, pyruvate and butyrate. Currently, fourteen members of this transporter family have been identified by sequence homology, of which only the first four members (MCT1- MCT4) have been shown to mediate the proton-linked transport of monocarboxylates. Another transporter family involved in the transport of endogenous monocarboxylates is the sodium coupled MCTs (SMCTs). These act as a symporter and are dependent on a sodium gradient for their functional activity. MCT1 is the predominant transporter among the MCT isoforms and is present in almost all tissues including kidney, intestine, liver, heart, skeletal muscle and brain. The various isoforms differ in terms of their substrate specificity and tissue localization. Due to the expression of these transporters in the kidney, intestine, and brain, they may play an important role in influencing drug disposition. Apart from endogenous short chain monocarboxylates, they also mediate the transport of exogenous drugs such as salicylic acid, valproic acid, and simvastatin acid. The influence of MCTs on drug pharmacokinetics has been extensively studied for γ-hydroxybutyrate (GHB) including distribution of this drug of abuse into the brain and the results will be summarized in this review. The physiological role of these transporters in the brain and their specific cellular localization within the brain will also be discussed. This review will also focus on utilization of MCTs as potential targets for drug delivery into the brain including their role in the treatment of malignant brain tumors.

Temozolomide Cocrystals Exhibit Drug Sensitivity in Glioblastoma Cells

Temozolomide is the only drug approved for the treatment of malignant brain tumors. The sensitivity of Temozolomide-Succinic acid and Temozolomide-Oxalic acid cocrystals (TMZ-SA and TMZ-OA) in inhibiting the proliferation and growth of human glioblastoma malignant cell lines U373, U87 and LN18 is comparable to the reference drug. Both TMZ-SA and TMZ-OA cocrystals are stable to long term storage (white color powder) whereas TMZ becomes tan brown within 2 months (indicative of degradation). These pharmaceutical cocrystals combine the desirable features of hyrolytic stability, good dissolution and cytotoxic activity for further preclinical studies. Inhibition of human glioblastom cell line U87 proliferation by Temozolomide-Succinic acid cocrystal. .

S6. Proffered paper: Anti-tumour immunomodulatory activity of heat shock protein Hsp70 in therapy of malignant brain tumours: preclinical and clinical data

Meeting abstracts Immunotherapy provides a specific anti-tumour activity with minimal side effects and thus could be used in treatment of malignant brain tumours. Molecular chaperone Hsp70 is well known for its ability to stimulate innate and adaptive anti-cancer immune response. In in vivo studies

The NFκB inhibitor, SN50, induces differentiation of glioma stem cells and suppresses their oncogenic phenotype

The malignant phenotype of glioblastoma multiforme (GBM) is believed to be largely driven by glioma stem-like cells (GSCs), and targeting GSCs is now considered a promising new approach to treatment of this devastating disease. Here, we show that SN50, a cell-permeable peptide inhibitor of NFκB, induced robust differentiation of human GSCs, causing loss of their oncogenic potential. We observed that following treatment of GSCs with SN50, their differentiated progeny cells showed significant decreases in their capability to form neuro-spheres and to invade in vitro and a reduction in their tumorigenicity in mouse xenograft models, but had increased sensitivity to the chemotherapeutic drug temozolomide and to radiation treatment. These results suggest that blocking the NFκB pathway may be explored as a useful mean to induce differentiation of GSCs, and provide another supportive evidence for the promise of differentiation therapy in treatment of malignant brain tumors.

Training stem cells for treatment of malignant brain tumors.

The treatment of malignant brain tumors remains a challenge. Stem cell technology has been applied in the treatment of brain tumors largely because of the ability of some stem cells to infiltrate into regions within the brain where tumor cells migrate as shown in preclinical studies. However, not all of these efforts can translate in the effective treatment that improves the quality of life for patients. Here, we perform a literature review to identify the problems in the field. Given the lack of efficacy of most stem cell-based agents used in the treatment of malignant brain tumors, we found that stem cell distribution (i.e., only a fraction of stem cells applied capable of targeting tumors) are among the limiting factors. We provide guidelines for potential improvements in stem cell distribution. Specifically, we use an engineered tissue graft platform that replicates the in vivo microenvironment, and provide our data to validate that this culture platform is viable for producing stem cells that have better stem cell distribution than with the Petri dish culture system.

STEM CELL THERAPY OF MALIGNANT BRAIN TUMORS: REALITY AND PROSPECTS

Modern methods for the treatment of malignant brain tumors are insufficiently effective. One reason for this is that the existing technologies and methods are focused on removing all neoplastic cellsfrom the body. Understanding the mechanisms of systemic migration of stem cells provides a new view on the role of this phenomenon in the development of malignant tumors. Migration and homing of normal stem cells, being originally the regulatory process, ensuring revascularization and remodeling of ischemic or traumatic injury of brain, play a role of the axial conductor of neoplastic process in carcinogenesis. The use of the phenomenon of migration and homing of stem cells in the tumor center for therapeutic purposes opens the possibility of overcoming the blood-brain barrier, reducing the toxicity of chemotherapy and increasing the radiation therapy efficiency, makes possible the directed influence on the hypoxic zone of the tumor, can directly affect to the key life processes of tumor stem cells. These arguments allow to consider the mechanisms of systemic migration and homing of stem cells to neoplastic foci as a fundamental theoretical platform for the creation of a fundamentally new class of anti-cancer, cell personalized medicines.

Neural Stem Cell-Mediated Delivery of Irinotecan-Activating Carboxylesterases to Glioma: Implications for Clinical Use

CPT-11 (irinotecan) has been investigated as a treatment for malignant brain tumors. However, limitations of CPT-11 therapy include low levels of the drug entering brain tumor sites and systemic toxicities associated with higher doses. Neural stem cells (NSCs) offer a novel way to overcome these obstacles because of their inherent tumor tropism and ability to cross the blood-brain barrier, which enables them to selectively target brain tumor sites. Carboxylesterases (CEs) are enzymes that can convert the prodrug CPT-11 (irinotecan) to its active metabolite SN-38, a potent topoisomerase I inhibitor. We have adenovirally transduced an established clonal human NSC line (HB1.F3.CD) to express a rabbit carboxylesterase (rCE) or a modified human CE (hCE1m6), which are more effective at converting CPT-11 to SN-38 than endogenous human CE. We hypothesized that NSC-mediated CE/CPT-11 therapy would allow tumor-localized production of SN-38 and significantly increase the therapeutic efficacy of irinotecan. Here, we report that transduced NSCs transiently expressed high levels of active CE enzymes, retained their tumor-tropic properties, and mediated an increase in the cytotoxicity of CPT-11 toward glioma cells. CE-expressing NSCs (NSC.CEs), whether administered intracranially or intravenously, delivered CE to orthotopic human glioma xenografts in mice. NSC-delivered CE catalyzed conversion of CPT-11 to SN-38 locally at tumor sites. These studies demonstrate the feasibility of NSC-mediated delivery of CE to glioma and lay the foundation for translational studies of this therapeutic paradigm to improve clinical outcome and quality of life in patients with malignant brain tumors.

Abstract 5606: Gallium maltolate inhibits brain tumor volume and blood volume in xenograft model.

Abstract Purpose: There are limited treatment options for glioblastomas (GBM). Tumor cells have a high requirement for iron; the latter is taken up by cells through transferrin receptor-mediated endocytosis of transferrin-iron. These receptors are highly expressed on GBM cells, which makes them an attractive target for transferrin receptor-directed therapies. Gallium is a group IIIa metal that can function as an iron mimetic by avidly binding to transferrin and incorporating into cells through the transferrin receptor. No studies have been performed to determine the efficacy of gallium-based therapies in brain tumors. Consequently, the goal of this study was to evaluate gallium maltolate in the treatment of a U87 xenograft brain tumor model. Methods: Athymc rats bearing U87 human grade IV astrocytoma cells were studied. Gallium maltolate (50 mg/kg/day, n=5) or saline (n=3) was given intravenously. via an alzet mini pump in the jugular vein. Magnetic resonance imaging (MRI) was performed on days 8 and 18 on a Bruker 9.4 T scanner. Enhancing tumor volumes were determined from the post-contrast T1w images, in all slices showing enhancing tumor. The spin and gradient echo relaxation rate changes were then determined giving estimates of microvascular and total blood volume. ((CBVmicro≈R2=R2MION-R*pre-MION CBVTotal≈ R2* = R2*MION-R2*pre-MION). Results: Gallium maltolate inhibited tumor growth (377132%), as measured by enhancing tumor volume, compared to saline controls (863481%). Treatment shows decrease of CBV micro and CBVTotal compared to the controls. The ratio of R2* /R2, which is a measure of mean vessel diameter, increased in saline treated controls but remained unchanged for the gallium maltolate treated rats. To our knowledge this is the first study performed that uses physiologic MRI measurements to investigate the effects of gallium maltolate on brain tumor xenografts. The differences shown are not statistically significant a result likely due to the small sample sizes, which is being remedied by ongoing additional studies. For the imaging studies included here tissue markers of proliferation (Ki67), hypoxia (HIF1) transferrin receptors, and vascular density (vWF) are being analyzed to provide additional information regarding mechanism of action. In general these results demonstrate, for the first time, that the novel gallium maltolate treatment holds promise for the treatment of malignant brain tumors. Citation Format: Kimberly R. Pechman, Andrew Lozen, Mona Al-Gizawiy, Kathleen Schmainda, Christopher R. Chitambar. Gallium maltolate inhibits brain tumor volume and blood volume in xenograft model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5606. doi:10.1158/1538-7445.AM2013-5606

Applications and Perspectives of Boron-Enriched Nanocomposites in Cancer Therapy

Recently, boron compounds have attracted increasing attention both in academic laboratories and in the pharmaceutical industry. Boron, in particular the (10)B isotope, has the unique capability of absorbing a slow neutron to initiate a nuclear reaction with release of energetic particles such as α- and Li-particles, which is not observed in its carbon analogues. The nuclear capture reaction concept has been adopted in radiation therapy and used in boron neutron capture therapy (BNCT). BNCT is a potentially promising treatment for malignant brain tumors as well as other cancers, despite the limitation of a scarcity of neutron sources. There is the need in advanced research centers to construct high boron-containing composites as BNCT agents and develop more efficient drug carriers. This review discusses recent works on the development of boron-based therapeutic nanomaterials as BNCT agents.

CCR2 Deficiency Prevents Neuronal Dysfunction and Cognitive Impairments Induced by Cranial Irradiation

Cranial irradiation can lead to long-lasting cognitive impairments in patients receiving radiotherapy for the treatment of malignant brain tumors. Recent studies have suggested inflammation as a major contributor to these deficits; we determined if the chemokine (C-C motif) receptor 2 (CCR2) was a mediator of cognitive impairments induced by irradiation. Two-month-old male Ccr2 knockout (-/-) and wild-type mice received 10 Gy cranial irradiation or sham-treatment. One month after irradiation, bromodeoxyuridine was injected intraperitoneally for seven consecutive days to label newly generated cells. At two months postirradiation, cognitive function was assessed by novel object recognition and Morris water maze. Our results show that CCR2 deficiency prevented hippocampus-dependent spatial learning and memory impairments induced by cranial irradiation. Hippocampal gene expression analysis showed that irradiation induced CCR2 ligands such as CCL8 and CCR2 deficiency reduced this induction. Irradiation reduced the number of adult-born neurons in both wild-type and Ccr2(-/-) mice, but the distribution pattern of the adult-born neurons through the granule cell layer was only altered in wild-type mice. Importantly, CCR2 deficiency normalized the fraction of pyramidal neurons expressing the plasticity-related immediate early gene Arc. These data offer new insight into the mechanism(s) of radiation-injury and suggest that CCR2 is a critical mediator of hippocampal neuronal dysfunction and hippocampal cognitive impairments after irradiation. Targeting CCR2 signaling could conceivably provide an effective approach to reduce or prevent the incidence and severity of this serious side effect of ionizing irradiation.

Viral and Non-Viral Gene Therapy for Glioblastoma: New Insights into the Treatment of Malignant Brain Tumors

Glioblastoma (GBM) is the most common and malignant type of primary brain tumor, due to its high heterogeneity and aggressive brain invasion patterns. Despite recent advances in imaging and surgical techniques, which allowed a more accurate diagnosis and enhanced tumoral resection while maintaining or even improving neurologic function, current therapeutic options for GBM lack effective long-term impact on disease control and patient survival remains around the year mark. Therefore, the development of new therapeutic strategies that provide highly specific tumor cell killing and effective/complete eradication of cancer is critical to improve the life expectancy of GBM patients. Driven by the tremendous advances in molecular biology, gene therapy has emerged as a promising strategy that uses nucleic acid delivery for the treatment of different forms of cancer, including GBM. In this regard, numerous/a wide range of therapeutic approaches involving versatile delivery vehicles, including non-replicating and oncolytic viruses, lipid- and polymer-based nanoparticles and stem cells, have been developed and tested for therapeutic potential. In this report, we review the principles behind such approaches and underscore their application to GBM treatment, by summarizing recent results obtained both in vitro and pre-clinical studies including the authors’, as well as those reported in patients. A brief discussion on the major achievements and the trends identified by these studies is intended to provide new prospects for future developments and further improvements of the existing approaches towards successful treatment of malignant brain tumors.

Multiphasic modelling of human brain tissue for intracranial drug‐infusion studies

AbstractA direct intracranial infusion of a therapeutic solution into the extra‐vascular space of human brain tissue is a promising medical application for the effective treatment of malignant brain tumours [1]. The advantage of this method, compared to an intra‐vascular medication, is the targeted delivery with the circumvention of the blood‐brain barrier (BBB), which prohibits the passing of therapeutic macro‐molecules across the vascular walls into the brain parenchyma.The prediction of the resulting therapeutical distribution by a numerical simulation is challenging, since the spreading is affected by the complex nature of living brain tissue. For this purpose, a macroscopic continuum‐mechanical model is established within the Theory of Porous Media (TPM), proceeding from a homogenisation of the underlying micro‐structure [5]. The ternary four‐component model consists of an elastically deformable solid skeleton (composed of tissue cells and vascular walls), which is perfused by two mobile but separated liquid phases, the blood and the overall interstitial fluid (treated as a real two‐component mixture of the liquid solvent and the dissolved therapeutic solute). The strongly coupled solid‐liquid‐transport problem is simultaneously approximated in all primary unknowns using mixed finite elements (uppc‐formulation) and consequently solved in a monolithic manner with an implicit time‐integration scheme.This numerical investigation allows the computational study of several circumstances influencing the irregular distribution of infused drugs, as observed in clinical studies. Therefore, the microstructural perfusion characteristics in the extra‐cellular space of the white‐matter tracts are considered by a spatial diversification of the anisotropic permeability tensors, provided by Diffusion Tensor Imaging (DTI). Furthermore, Magnetic Resonance Angiography (MRA) enables the in vivo location of blood vessels within the brain tissue. Finally, the selection of appropriate material parameters has a crucial influence on the drug distribution profile and further occurring effects beyond. (© 2012 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim)

Recombinant anti‐podoplanin (NZ‐1) immunotoxin for the treatment of malignant brain tumors

Our study demonstrates the glioma tumor antigen podoplanin to be present at very high levels (>90%) in both glioblastoma (D2159MG, D08-0308MG and D08-0493MG) and medulloblastoma (D283MED, D425MED and DAOY) xenografts and cell line. We constructed a novel recombinant single-chain antibody variable region fragment (scFv), NZ-1, specific for podoplanin from the NZ-1 hybridoma. NZ-1-scFv was then fused to Pseudomonas exotoxin A, carrying a C-terminal KDEL peptide (NZ-1-PE38KDEL). The immunotoxin (IT) was further stabilized by a disulfide (ds) bond between the heavy-chain and light-chain variable regions as the construct NZ-1-(scdsFv)-PE38KDEL. NZ-1-(scdsFv)-PE38KDEL exhibited significant reactivity to glioblastoma and medulloblastoma cells. The affinity of NZ-1-(scdsFv), NZ-1-(scdsFv)-PE38KDEL and NZ-1 antibody for podoplanin peptide was 2.1 × 10(-8) M, 8.0 × 10(-8) M and 3.9 × 10(-10) M, respectively. In a protein stability assay, NZ-1-(scdsFv)-PE38KDEL retained 33-98% of its activity, whereas that of NZ-1-PE38KDEL declined to 13% of its initial levels after incubation at 37°C for 3 days. In vitro cytotoxicity of the NZ-1-(scdsFv)-PE38KDEL was measured in cells isolated from glioblastoma xenografts, D2159MG, D08-0308MG and D08-0493MG, and in the medulloblastoma D283MED, D425MED and DOAY xenografts and cell line. The NZ-1-(scdsFv)-PE38KDEL IT was highly cytotoxic, with an 50% inhibitory concentration in the range of 1.6-29 ng/ml. Significantly, NZ-1-(scdsFv)-PE38KDEL demonstrated tumor growth delay, averaging 24 days (p < 0.001) and 21 days (p < 0.001) in D2159MG and D283MED in vivo tumor models, respectively. Crucially, in the D425MED intracranial tumor model, NZ-1-(scdsFv)-PE38KDEL caused a 41% increase in survival (p ≤ 0.001). In preclinical studies, NZ-1-(scdsFv)-PE38KDEL exhibited significant potential as a targeting agent for malignant brain tumors.

An Efficient and Practical Radiosynthesis of [11C]Temozolomide

Temozolomide (TMZ) is a prodrug for an alkylating agent used for the treatment of malignant brain tumors. A positron emitting version, [(11)C]TMZ, has been utilized to help elucidate the mechanism and biodistribution of TMZ. Challenges in [(11)C]TMZ synthesis and reformulation make it difficult for routine production. A highly reproducible one-pot radiosynthesis of [(11)C]TMZ with a radiochemical yield of 17 ± 5% and ≥97% radiochemical purity is reported.

Magnetic nanoparticles: an emerging technology for malignant brain tumor imaging and therapy

Magnetic nanoparticles (MNPs) represent a promising nanomaterial for the targeted therapy and imaging of malignant brain tumors. Conjugation of peptides or antibodies to the surface of MNPs allows direct targeting of the tumor cell surface and potential disruption of active signaling pathways present in tumor cells. Delivery of nanoparticles to malignant brain tumors represents a formidable challenge due to the presence of the blood–brain barrier and infiltrating cancer cells in the normal brain. Newer strategies permit better delivery of MNPs systemically and by direct convection-enhanced delivery to the brain. Completion of a human clinical trial involving direct injection of MNPs into recurrent malignant brain tumors for thermotherapy has established their feasibility, safety and efficacy in patients. Future translational studies are in progress to understand the promising impact of MNPs in the treatment of malignant brain tumors.

Computational modelling of drug infusion into the anisotropic white‐matter tracts of the human brain

AbstractUnfortunately, the human brain is compromised by an amount of brain diseases, such as strokes or cerebral tumours. In this contribution, special attention is paid to the constitutive modelling procedure and the numerical simulation of the so‐called convection‐enhanced delivery process, where an effective treatment of malignant brain tumours is achieved by bypassing the blood‐brain barrier via a direct infusion of therapeutic agents into the extra‐vascular space of the brain tissue using implanted catheters. The modelling approach of the complex brain‐tissue aggregate proceeds from the Theory of Porous Media including an elastically deformable solid skeleton, provided by the tissue cells and the vascular walls. The tissue is permeated by two liquid phases, the blood and the interstitial fluid. In order to describe a distribution process of the inserted drugs, the interstitial fluid phase is treated as a chemical solution of two components, the liquid solvent and the dissolved therapeutic solute. The inhomogeneous anisotropic nature of the white‐matter tracts is considered by spatially varying permeability tensors, obtained by diffusion‐weighted magnetic resonance imaging. The strongly coupled solid‐liquid transport problem is simultaneously approximated in all primary unknowns using mixed finite elements and solved in a monolithic manner with an implicit time‐integration scheme. The numerical investigation is applied to un‐bloody numerical studies. (© 2011 Wiley‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)

Physiopathology of radiation-induced neurotoxicity

Ionizing irradiation for the treatment of malignant brain tumors has associated with it a risk of inducing serious morphologic and functional deficits. While obvious tissue damage generally occurs after relatively high radiation doses, cognitive impairment can be seen after lower exposures. The mechanisms responsible for cognitive injury are not well understood, but may involve neurogenesis, a process that is affected by microenvironmental factors including oxidative stress and inflammation. In addition, damage to neurons, either directly or through environmental influences may have a profound impact on cognition. The relationships between cellular response, environmental factors and behavior are complex and difficult to study. However, understanding such issues should provide critical information relevant to the development of strategies and approaches to ameliorate or treat radiation-induced injuries that are associated with behavioral performance.

Augmentation of chemotherapy-triggered glioma cell apoptosis by blockade of arachidonic acid metabolism—the potential role of ceramide accumulation

There has been recent interest in using cyclooxygenase-2 inhibitors in an effort to increase the efficacy of chemotherapy and/or radiation for treatment of malignant brain tumors. Although the mechanism is unclear, one result may be the accumulation of arachidonic acid (AA). AA is the key substrate for several biochemical pathways involved in the inflammatory cascade, including the cyclooxygenase (COX) enzymes. Cyclooxygenase-1 and cyclooxygenase-2 metabolize AA to produce prostaglandins and thromboxanes. Levels of these enzymes and their products are upregulated in gliomas, especially in malignant tumors. Likewise, the enzyme 5-lipoxygenase, also elevated in malignant gliomas, metabolizes AA to produce leukotrienes. Alternatively, enzymes of the cytochrome p450 family can metabolize AA to various products, some of which may aid glioma growth and angiogenesis. Unmetabolized AA activates the enzyme neutral sphingomyelinase, which produces ceramide, a second messenger and potent activator of apoptosis. It is hypothesized that simultaneous blockade of the COX, lipoxygenase, and/or cytochrome p450-mediated pathways would lead to greater accumulation of intracellular AA, resulting in elevated ceramide levels, thereby priming glioma cells for treatment-induced apoptotic cell death. Manipulation of AA/bioactive lipid metabolism, using readily available, well-tolerated medications may have the potential to increase the efficacy of currently used glioma treatments.

A clinical trial protocol for second line treatment of malignant brain tumors with BNCT at University of Tsukuba

We have evaluated the efficacy and safety of boron neutron capture therapy (BNCT) for recurrent glioma and malignant brain tumor using a new protocol. One of the two patients enrolled in this trial is a man with recurrent glioblastoma and the other is a woman with anaplastic meningioma. Both are still alive and no severe adverse events have been observed. Our findings suggest that NCT will be safe as a palliative therapy for malignant brain tumors.

Targeted Toxins in Brain Tumor Therapy

Targeted toxins, also known as immunotoxins or cytotoxins, are recombinant molecules that specifically bind to cell surface receptors that are overexpressed in cancer and the toxin component kills the cell. These recombinant proteins consist of a specific antibody or ligand coupled to a protein toxin. The targeted toxins bind to a surface antigen or receptor overexpressed in tumors, such as the epidermal growth factor receptor or interleukin-13 receptor. The toxin part of the molecule in all clinically used toxins is modified from bacterial or plant toxins, fused to an antibody or carrier ligand. Targeted toxins are very effective against cancer cells resistant to radiation and chemotherapy. They are far more potent than any known chemotherapy drug. Targeted toxins have shown an acceptable profile of toxicity and safety in early clinical studies and have demonstrated evidence of a tumor response. Currently, clinical trials with some targeted toxins are complete and the final results are pending. This review summarizes the characteristics of targeted toxins and the key findings of the important clinical studies with targeted toxins in malignant brain tumor patients. Obstacles to successful treatment of malignant brain tumors include poor penetration into tumor masses, the immune response to the toxin component and cancer heterogeneity. Strategies to overcome these limitations are being pursued in the current generation of targeted toxins.