Therapy Of Malignant Brain Tumors Research Articles

Calcium Channels and Associated Receptors in Malignant Brain Tumor Therapy.

Malignant brain tumors are highly lethal and aggressive. Despite recent advances in the current therapies, which include the combination of surgery and radio/chemotherapy, the average survival rate remains poor. Altered regulation of ion channels is part of the neoplastic transformation, which suggests that ion channels are involved in cancer. Distinct classes of calcium-permeable channels are abnormally expressed in cancer and are likely involved in the alterations underlying malignant growth. Specifically, cytosolic Ca(2+) activity plays an important role in the regulation of cell proliferation, and Ca(2+) signaling is altered in proliferating tumor cells. A series of previous studies emphasized the importance of the T-type low-voltage-gated calcium channels (VGCC) in different cancer types, including gliomas, and remarkably, pharmacologic inhibition of T-type VGCC caused antiproliferative effects and triggered apoptosis of human glioma cells. Other calcium permeable channels, such as transient receptor potential (TRP) channels, contribute to changes in Ca(2+) by modulating the driving force for Ca(2+) entry, and some TRP channels are required for proliferation and migration in gliomas. Furthermore, recent evidence shows that TRP channels contribute to the progression and survival of the glioblastoma patients. Likewise, the purinergic P2X7 receptor acts as a direct conduit for Ca(2+)-influx and an indirect activator of voltage-gated Ca(2+)-channel. Evidence also shows that P2X7 receptor activation is linked to elevated expression of inflammation promoting factors, tumor cell migration, an increase in intracellular mobilization of Ca(2+), and membrane depolarization in gliomas. Therefore, this review summarizes the recent findings on calcium channels and associated receptors as potential targets to treat malignant gliomas.

Carboplatin loaded Surface modified PLGA nanoparticles: Optimization, characterization, and in vivo brain targeting studies

The carboplatin (CP) loaded poly-lactide-co-glycolide (PLGA) nanoparticles (NPs) were formulated by modified solvent evaporation method. Its surface modification is done by 1% polysorbate80 (P80) to improve their entry into the brain after intraperitoneal administration (i.p) via receptor-mediated pathways. A formulation with maximum entrapment efficiency and minimal particle size was optimized by central composite design (CCD) based on mean particle size, and entrapment efficiencies as responses. The optimized formulation was characterized by mean particle size, entrapment efficiency, zeta potential, Fourier transform infrared (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) analysis. The surface modified NPs were analysed for mean particle, zeta potential, FTIR, and in vitro release studies. The spherical particles with mean particle size 161.9nm, 162.4nm and zeta potential value of −26.5, −23.9 were obtained for unmodified and surface modified NPs respectively. The in vitro release experiments of the surface modified PLGA NPs exhibited sustained release for more than 48h, which was in accordance with Higuchi’s equation with Fickian diffusion-based release mechanism. The in vivo bio distribution of P80 coated CP loaded PLGA NPs was compared with CP solution, and CP loaded NPs, in adult wistar rats. In the brain, compared with CP solution, both types of NPs especially NPs coated with P80 increased the concentration of carboplatin by 3.27 fold. All these results suggest that the developed formulation may improve the targeted therapy for malignant brain tumors in future.

Dual targeting of solid lipid nanoparticles grafted with 83-14 MAb and anti-EGF receptor for malignant brain tumor therapy

AimsSolid lipid nanoparticles (SLNs) conjugated with surface 83-14 monoclonal antibody (8314MAb) and anti-epithelial growth factor receptor (AEGFR) were synthesized and applied to permeate the blood–brain barrier (BBB) and inhibit the growth of glioblastoma multiforme (GBM). Main methods8314MAb and AEGFR were crosslinked on SLNs to carry etoposide (ETP) across human brain-microvascular endothelial cells (HBMECs) and to treat U87MG cells. Key findingsAn increase in the 8314MAb concentration increased the permeability for propidium iodide (PI) and ETP across the BBB, however, decreased the 8314MAb grafting efficiency and transendothelial electrical resistance of the monolayer of HBMECs. In addition, an increase in the AEGFR concentration enhanced the viability of HBMECs and human astrocytes (HAs), however, reduced the AEGFR grafting efficiency and ETP release rate. An incorporation of both 8314MAb and AEGFR increased the particle size, however, decreased the zeta potential, ETP release rate, and viability of HBMECs and HAs. SignificanceThe conjugation of 8314MAb and AEGFR on ETP-loaded SLNs can be a promising strategy to deliver antitumor ETP to the brain and restrain the propagation of GBM.

Assessment of bystander killing-mediated therapy of malignant brain tumors using a multimodal imaging approach.

IntroductionIn this study, we planned to assess if adult stem cell-based suicide gene therapy can efficiently eliminate glioblastoma cells in vivo. We investigated the therapeutic potential of mouse Oct4− bone marrow multipotent adult progenitor cells (mOct4− BM-MAPCs) in a mouse glioblastoma model, guided by multimodal in vivo imaging methods to identify therapeutic windows.MethodsMagnetic resonance imaging (MRI) of animals, wherein 5 × 105 syngeneic enhanced green fluorescent protein-firefly luciferase-herpes simplex virus thymidine kinase (eGFP-fLuc-HSV-TK) expressing and superparamagnetic iron oxide nanoparticle labeled (1 % or 10 %) mOct4− BM-MAPCs were grafted in glioblastoma (GL261)-bearing animals, showed that labeled mOct4− BM-MAPCs were located in and in close proximity to the tumor. Subsequently, ganciclovir (GCV) treatment was commenced and the fate of both the MAPCs and the tumor were followed by multimodal imaging (MRI and bioluminescence imaging).ResultsIn the majority of GCV-treated, but not phosphate-buffered saline-treated animals, a significant difference was found in mOct4− BM-MAPC viability and tumor size at the end of treatment. Noteworthy, in some phosphate-buffered saline-treated animals (33 %), a significant decrease in tumor size was seen compared to sham-operated animals, which could potentially also be caused by a synergistic effect of the immune-modulatory stem cells.ConclusionsSuicide gene therapy using mOct4− BM-MAPCs as cellular carriers was effective in reducing the tumor size in the majority of the GCV-treated animals leading to a longer progression-free survival compared to sham-operated animals. This treatment could be followed and guided noninvasively in vivo by MRI and bioluminescence imaging. Noninvasive imaging is of particular interest for a rapid and efficient validation of stem cell-based therapeutic approaches for glioblastoma and hereby contributes to a better understanding and optimization of a promising therapeutic approach for glioblastoma patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0157-3) contains supplementary material, which is available to authorized users.

Blood-brain barrier permeable gold nanoparticles: an efficient delivery platform for enhanced malignant glioma therapy and imaging.

The blood-brain barrier (BBB) remains a formidable obstacle in medicine, preventing efficient penetration of chemotherapeutic and diagnostic agents to malignant gliomas. Here, a transactivator of transcription (TAT) peptide-modified gold nanoparticle platform (TAT-Au NP) with a 5 nm core size is demonstrated to be capable of crossing the BBB efficiently and delivering cargoes such as the anticancer drug doxorubicin (Dox) and Gd(3+) contrast agents to brain tumor tissues. Treatment of mice bearing intracranial glioma xenografts with pH-sensitive Dox-conjugated TAT-Au NPs via a single intravenous administration leads to significant survival benefit when compared to the free Dox. Furthermore, it is demonstrated that TAT-Au NPs are capable of delivering Gd(3+) chelates for enhanced brain tumor imaging with a prolonged retention time of Gd(3+) when compared to the free Gd(3+) chelates. Collectively, these results show promising applications of the TAT-Au NPs for enhanced malignant brain tumor therapy and non-invasive imaging.

Bevacizumab treatment leads to observable morphological and metabolic changes in brain radiation necrosis.

We investigated morphological and metabolic changes of radiation necrosis (RN) of the brain following bevacizumab (BEV) treatment by using neuroimaging. Nine patients with symptomatic RN, who had already been treated with radiation therapy for malignant brain tumors (6 glioblastomas, 1 anaplastic oligodendroglioma, and 2 metastatic brain tumors), were enrolled in this prospective clinical study. RN diagnosis was neuroradiologically determined with Gd-enhanced MRI and 11C-methionine positron emission tomography (MET-PET). RN clinical and radiological changes in MRI, magnetic resonance spectroscopy (MRS) and PET were assessed following BEV therapy. Karnofsky performance status scores improved in seven patients (77.8 %). Both volumes of the Gd-enhanced area and FLAIR-high area from MRI decreased in all patients after BEV therapy and the mean size reduction rates of the lesions were 80.0 and 65.0 %, respectively. MRS, which was performed in three patients, showed a significant reduction in Cho/Cr ratio after BEV therapy. Lesion/normal tissue (L/N) ratios in MET- and 11C-choline positron emission tomography (CHO-PET) decreased in 8 (89 %) and 9 patients (100 %), respectively, and the mean L/N ratio reduction rates were 24.4 and 60.7 %, respectively. BEV-related adverse effects of grade 1 or 2 (anemia, neutropenia and lymphocytopenia) occurred in three patients. These results demonstrated that BEV therapy improved RN both clinically and radiologically. BEV therapeutic mechanisms on RN have been suggested to be related not only to the effect on vascular permeability reduction by repairing the blood-brain barrier, but also to the effect on suppression of tissue biological activity, such as immunoreactions and inflammation.

OP0019 Immunomodulatory potency of recombinant heat shock protein HSP70 in therapy of malignant brain tumours

<h3>Background</h3> HSP70 is known to stimulate anti-tumour immunity, validating its possible application in immunotherapeutic approaches. In a series of in vitro experiments we demonstrated that HSP70, when added to cancer cells, can penetrate the latter inducing the translocation of endogenous HSP70 to plasma membrane. Interchange of exogenous and intracellular HSP70 induced lymphocyte-mediated anti-tumour activity. In an intracranial C6 glioma model, we administered HSP70 intratumourally. The infusion of the chaperone caused inhibition of tumour growth, as measured by high-field (7.1T) MRI, and significantly prolonged survival. These changes correlated with induction of the tumour-specific innate response mediated by NK cells (production of Granzyme B) and adaptive immune response generated by CD8+ T-lymphocytes (proved by IFN<i>γ</i> ELISPOT assay). Immunological changes were accompanied by glioma infiltration by NK-cells (Ly-6c+) and T-cells (i.e., CD3+, CD4+, CD8+). Following the in vivo experiments, the effects of intratumoural injection of HSP70 were explored in a pilot study for feasibility, safety, and possible systemic anti-tumour immune responses in patients with brain tumours. <h3>Methods</h3> Patients with untreated newly diagnosed tumours (<i>n</i>=12) were enrolled in the study. After tumour resection, five injections of HSP70 were performed into the residual tumour cavity through a catheter. Specific immune responses were evaluated with a delayed hypersensitivity test. <h3>Findings</h3> Intratumoural injections of HSP70 were well tolerated by patients. One patient had a complete clinical response documented by radiological findings and one patient had a partial response. In three patients we observed positive delayed hypersensitivity tests. In peripheral blood there was a shift toward cytokines of the Th1-cell mediated response that corresponded to changes in lymphocyte subpopulations. <h3>Interpretation</h3> The present pilot study shows the feasibility and safety of intratumoural delivery of recombinant HSP70 in patients. On the basis of our studies we propose a novel mechanism of immunomodulatory activity of HSP70.

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

Endovascular superselective treatment of brain tumors: a new endovascular era? A quick review

BackgroundIntra-arterial therapy for malignant brain tumors, especially high-grade gliomas, has been administered since the 1950s and 1960s when the structure of the blood–brain barrier was first described. However, only with...

Lentiviral Vector Mediated Delivery of RHBDD1 shRNA down Regulated the Proliferation of Human Glioblastoma Cells

Rhomboid domain containing 1 (RHBDD1) gene, a new member of rhomboid family of proteins is highly responsible for the regulation of apoptosis by cleaving pro-apoptotic Bcl-2 family protein BIK. Therefore, the higher expression levels of RHBDD1 in cancer tissues may have a direct influence on cancer progression by arresting apoptosis. With this background this study was focused to find out the effect of RHBDD1 silencing on the progression of human brain glioblastoma cells, U251 and U87MG. The results indicated that both cell lines show a higher expression level of RHBDD1 and RNA interference (RNA) mediated gene silencing successfully down regulated the RHBDD1 gene expression. As a result of RHBDD1 silencing the proliferation of both cell types was reduced by over 50%, 5 days after silencing. Moreover the colony formation was completely inhibited and there were no cells present following two week RHBDD1 gene silencing. The cell proliferation was inhibited as a result of cell cycle arrest due to RHBDD1 absence. Therefore, these results clearly indicate that, RHBDD1 is essential for the progression of glioblastoma cells and silencing of it is resulting in significant inhibition of cell cycle progression and cell proliferation. Collectively, this study shows that RHBDD1 gene engineering could be used as an effective tool in malignant brain tumor therapy.

Editorial (Hot Topic: Targeted Therapy of Malignant Brain Tumors)

Editorial (Hot Topic: Targeted Therapy of Malignant Brain Tumors)

Editorial (Hot Topic: Targeted Therapy of Malignant Brain Tumors)

Editorial (Hot Topic: Targeted Therapy of Malignant Brain Tumors)

Gliadel for brain metastasis

With therapies for systemic malignancy improving, life expectancy for cancer patients is becoming increasingly dependent on control of brain metastatic disease. Despite improvements in surgical and radiotherapy modalities for control of brain metastasis, the prognosis for patients with brain metastases is poor. The development of controlled release polymers has lead to novel new therapies for malignant brain tumors consisting of direct surgical delivery of chemotherapy agents to the tumor bed and sustained chemotherapy release over a prolonged period of time. Although there is a large body of literature in support of BCNU polymer wafer for primary brain malignancy and experimental brain metastases, clinical studies evaluating the BCNU polymer wafer for brain metastatic disease are relatively sparse. In this review, we discuss the role of the BCNU polymer wafer for brain metastasis focusing specifically on rationale for use of locally delivered sustained release polymers, history of the BCNU polymer wafer, and emerging studies examining the role of the BCNU polymer wafer for metastatic brain tumors.

Rat Multipotent Mesenchymal Stromal Cells Lack Long-Distance Tropism to 3 Different Rat Glioma Models

Viral gene therapy of malignant brain tumors has been restricted by the limited vector distribution within the tumors. Multipotent mesenchymal stromal cells (MSCs) and other precursor cells have shown tropism for gliomas, and these cells are currently being explored as potential vehicles for gene delivery in glioma gene therapy. To investigate MSC migration in detail after intratumoral and extratumoral implantation through syngeneic and orthotopic glioma models. Adult rat bone marrow-derived MSCs were transduced to express enhanced green fluorescent protein and implanted either directly into or at a distance from rat gliomas. We found no evidence of long-distance MSC migration through the intact striatum toward syngeneic D74(RG2), N32, and N29 gliomas in the ipsilateral hemisphere or across the corpus callosum to gliomas located in the contralateral hemisphere. After intratumoral injection, MSCs migrated extensively, specifically within N32 gliomas. The MSCs did not proliferate within tumors, suggesting a low risk of malignant transformation of in vivo grafted cell vectors. Using a model for surgical glioma resection, we found that intratumorally grafted MSCs migrate efficiently within glioma remnants after partial surgical resection. The findings point to limitations for the use of MSCs as vectors in glioma gene therapy, although intratumoral MSC implantation provides a dense and tumor-specific vector distribution.

Toxin-Based Targeted Therapy for Malignant Brain Tumors

Despite advances in conventional treatment modalities for malignant brain tumors—surgery, radiotherapy, and chemotherapy—the prognosis for patients with high-grade astrocytic tumor remains dismal. The highly heterogeneous and diffuse nature of astrocytic tumors calls for the development of novel therapies. Advances in genomic and proteomic research indicate that treatment of brain tumor patients can be increasingly personalized according to the characteristics of the targeted tumor and its environment. Consequently, during the last two decades, a novel class of investigative drug candidates for the treatment of central nervous system neoplasia has emerged: recombinant fusion protein conjugates armed with cytotoxic agents targeting tumor-specific antigens. The clinical applicability of the tumor-antigen-directed cytotoxic proteins as a safe and viable therapy for brain tumors is being investigated. Thus far, results from ongoing clinical trials are encouraging, as disease stabilization and patient survival prolongation have been observed in at least 109 cases. This paper summarizes the major findings pertaining to treatment with the different antiglioma cytotoxins at the preclinical and clinical stages.

Ethynyldeoxyuridine (EdU) suppresses in vitro population expansion and in vivo tumor progression of human glioblastoma cells

Thymidine analogs (TAs) are synthetic nucleosides that incorporate into newly synthesized DNA. Halogenated pyrimidines (HPs), such as bromodeoxyuridine (BrdU), are a class of TAs that can be detected with antibodies and are commonly used for birthdating individual cells and for assessing the proliferative index of cell populations. It is well established that HPs can act as radiosensitizers when incorporated into DNA chains, but they are generally believed not to impair normal cell function in the absence of secondary stressors. However, we and others have shown that HP incorporation leads to a sustained suppression of cell cycle progression in mammalian cells, resulting in cellular senescence in somatic cells. In addition, we have shown that HP incorporation results in delayed tumor progression in a syngeneic rat model of glioma. Here we examine ethynyldeoxyuridine (EdU), a newly developed and alkylated TA, for its anti-cancer activity, both in vitro and in vivo. We show that EdU, like HPs, leads to a severe reduction in the proliferation rate of normal and transformed cells in vitro. Unlike HPs, however, EdU incorporation also causes DNA damage resulting in the death of a substantial subset of treated cells. When administered over an extended time as a monotherapy to mice bearing subcutaneous xenografts of human glioblastoma multiforme tumors, EdU significantly reduces tumor volume and increases survival without apparent significant toxicity. These results, combined with the fact that EdU readily crosses the blood-brain barrier, support the continued investigation of EdU as a potential therapy for malignant brain tumors.

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.

Design and potential application of PEGylated gold nanoparticles with size-dependent permeation through brain microvasculature

Gold nanoparticles (AuNPs) have gained prominence in several targeting applications involving systemic cancers. Their enhanced permeation and retention within permissive tumor microvasculature provides a selective advantage for targeting. Malignant brain tumors also exhibit transport-permissive microvasculature secondary to blood-brain barrier disruption. Hence AuNPs may have potential relevance for brain tumor targeting. However, there are currently no studies that systematically examine brain microvasculature permeation of polyethylene glycol (PEG)-functionalized AuNPs. Such studies could pave the way for rationale AuNP design for passive targeting of malignant tumors. In this report we designed and characterized AuNPs with varying core particle sizes (4–24 nm) and PEG chain lengths [molecular weight 1000–10,000]. Using an in-vitro model designed to mimic the transport-permissive brain microvasculature, we demonstrate size-dependent permeation properties with respect to core particle size and PEG chain length. In general short PEG chain length (molecular weight 1000–2000) in combination with smallest core size led to optimum permeation in our model system. From the Clinical EditorIn this report the authors designed and characterized PEGylated gold NPs with varying core particle sizes and PEG chain lengths and demonstrate that short PEG chain length in combination with smallest core size led to optimum permeation of a blood-brain barrier model system. These findings may pave the way to optimized therapy of malignant brain tumors.

Simultaneous intraoperative diagnosis and photodynamic therapy for malignant brain tumors: The concept “to see and to treat”

Simultaneous intraoperative diagnosis and photodynamic therapy for malignant brain tumors: The concept “to see and to treat”

Identification and functional characterization of glioma-specific promoters and their application in suicide gene therapy

Suicide gene therapy has been shown to be effective in inducing tumor regression. In this study, a human brain tumor-specific promoter was identified and used to develop transcriptionally targeted gene therapy. We searched for genes with brain tumor-specific expression. By insilico and reverse-transcription polymerase chain reaction screening, MAGE-A3 and SSX4 were found to be expressed in a tumor-specific manner. SSX4 gene promoter activity was high in human brain tumor cells but not in normal human astrocyte cells, whereas the MAGE-A3 promoter showed activity in both tumor and normal cells. A retrovirus vector carrying a suicide gene, the herpes simplex virus thymidine kinase gene controlled by the SSX4 promoter, was constructed to evaluate the efficacy of the promoter in tumor-specific gene therapy. Glioma and human telomerase catalytic subunit-immortalized fibroblast BJ-5ta cell lines transduced with retrovirus vectors were assayed for killing activity by ganciclovir. Glioma cell lines were effectively killed by ganciclovir in a concentration-dependent manner, whereas BJ-5ta cells were not. By contrast, MAGE-A3 promoter failed to induce cytotoxicity in a brain tumor-specific manner. In addition, mouse glioma RSV-M cells transduced with retrovirus vector also showed suppressed tumor formation activity in syngeneic mice in response to ganciclovir administration. Therefore, the SSX4 promoter is a candidate for brain tumor-specific gene therapy and supports the efficacy and safety of suicide gene therapy for malignant brain tumors.