Malignant Glioma Tumor Research Articles

An eXplainable deep learning model for multi-modal MRI grading of IDH-mutant astrocytomas

IDH-Mutant-astrocytomas are malignant brain glioma tumors. They are graded as lower grade (grades 2 and 3) or higher grade (grade 4) according to their rate of growth and molecular features. Conventional IDH grading requires pathology examination, which is invasive, costly, and time-consuming. Advanced MRI modalities are widely used to overcome some of these limitations but require a high level of interpretation for tumor grading. Recent advances in deep learning have shown potential to aid and improve the accuracy and efficiency of tumor classification. This study proposes a novel non-invasive approach for grading IDH-Mutant-astrocytomas using a Light-weight Attention Network (LAN) that integrates multi-modal MRI data, including both conventional and advanced MRI modalities. The study addresses inter-modality heterogeneity using Principal Component Analysis (PCA) while minimizing computational complexity. LAN uses a 3D Convolutional Neural Network (CNN) and a volumetric attention mechanism to extract tumor patterns and classify grades 2 to 4. This is followed by an eXplainable AI approach that uses SHapley Additive exPlanations (SHAP) to interpret model decisions and identify key contributing features. The proposed LAN model outperforms other pre-trained state-of-the-art models, achieving an overall accuracy of 0.84. The SHAP attribution scores demonstrate that advanced MRI modalities such as Arterial Spin Labeling (ASL) and Diffusion-weighted Imaging (DWI), along with conventional MRI sequences such as FLAIR, T1-c and T2, contribute significantly to improving tumor heterogeneity visualization for aggressive grade 2 gliomas. This work demonstrates the feasibility of integrating explainable deep learning with multi-modal MRI data for precise and comprehensible early glioma grading, potentially leading to better clinical decision-making.

Emerging Recombinant Oncolytic Poliovirus Therapies Against Malignant Glioma: A Review.

Glioblastoma multiforme (GBM) is a fourth-grade malignant glioma that continues to be the main contributor to primary malignant brain tumour-related death in humans. The most prevalent primary brain tumours are gliomas. The most dangerous of these neoplasms, GBM, has been shown to be one of the most lethal and refractory tumours. For those who have been diagnosed with GBM, the median time to progression, as determined by magnetic resonance imaging, is roughly six months, and the median survival is approximately one year. GBM is challenging to manage with old treatments like chemotherapy, tumour debulking, and radiation therapy. Treatment outcomes are poor, and due to this effect, the treatment is not up to the mark. GBMalso shows diagnostic complexity due to limitations in the use of specific targeted therapies. The treatment protocol followed currently has an entire focus on safe resection and radiotherapy. Protein synthesis is not tightly regulated physiologically in malignant cells, which promotes unchecked growth and proliferation. An innovative, experimental technique for treating cancer uses polioviruses that have been genetically altered to target a fascinating aberration of translation regulation in cancer. This approach enables precise and effective cancer cell targeting based on the convergence of numerous variables. Oncolytic viruses have revolutionised cancer treatment. However, their effectiveness in glioblastoma remains restricted, necessitating more improvement. Oncolytic poliovirus has shown great potential in the treatment of GBM. Factors like the blood-brain barrier, immunosuppressive tumour microenvironment (TME), and tumour heterogeneity make treatment for malignant gliomas ineffective. In this review, we have focused on oncolytic viruses, specifically oncolytic poliovirus, and we explore malignant glioma treatments. We have also discussed currently available conventional treatment options for malignant glioma and other brain tumours.

Kynurenine produced by tryptophan 2,3-dioxygenase metabolism promotes glioma progression through an aryl hydrocarbon receptor-dependent signaling pathway.

The current studies associated with tumor biology continue to describe a high correlation between tryptophan (Trp) metabolism and tumor progression. These findings reflect the complex underlying mechanism of tumor development and highlight the need to explore additional drug targets for carcinoma-associated diseases. In our study, we reported that elevated Trp metabolism was observed in highly malignant glioma tumor tissues from patients. The elevated Trpmetabolism in glioma cells wereinduced by the overexpression of Trp2,3-dioxygenase 2 (TDO2), which further contributed to the production of the metabolite kynurenine (Kyn). Subsequently, the Kyn derived from Trp metabolism was able to mediate the activation of the aryl hydrocarbon receptor (AhR) and downstream PI3K/AKT signals, resulting in the strengthening of tumor stemness and growth. Meanwhile, the activation of the AhR could promote the process of epithelial-mesenchymal transitionin gliomas through a TGF-β-dependent mechanism, leading to enhanced tumor invasion in vitro and in vivo. Inhibition of the AhR using StemRegenin 1was demonstrated to suppress glioma growth and improve the outcome of traditional chemotherapy in subcutaneous tumor-bearing mice, representing a promising therapeutic target for clinical glioma treatment.

Effect of Anti-Podoplanin on Malignant Glioma Cell Viability, Invasion and Tumor Cell-Induced Platelet Aggregation

The transmembrane receptor podoplanin (PDPN) is a platelet aggregation-inducing factor, which is widely expressed in various malignant tumors such as squamous cell carcinomas, mesotheliomas, glioblastomas. Podoplanin regulates a pathway leading to cell invasion and migration. Glioblastoma multiforme (GBM) is the most aggressive and invasive tumor of the central nervous system. A high level of PDPN expression has been reported to be associated with reduced survival, cancer aggression and migration. Aim of study to determine the effect of anti-podoplanin antibody on cell-platelet aggregation, cell invasion and viability in Uppsala 87 malignant glioma (U87MG) cell lines. The expression of podoplanin on U87MG cells was measured using flowcytometry. The dimethyl-thiazol diphenyl-tetrazolium bromide (MTT) assay was used to measure U87MG cell proliferation after treatment by anti-podoplanin monoclonal antibody (NZ-1.3). The invasion of cancer cells was assessed by using a novel microfluidic based assay. The results show reduction of cell viability and cell migration after treatment with anti-podoplanin antibody. After co- treatment of U87MG cells and platelets with and without anti-podoplanin antibody, the cell-platelet aggregation was significantly reduced in anti-podoplanin treated cell. Podoplanin is involved in aggregation of gliobastoma cells, and their viability and invasion and its neutralizing antibody can inhibit this process. So, blocking of podoplanin may be representing a promising therapeutic approach to glioblastoma multiform cancer therapy.

COT-07 Cerebrovascular complications in adult patients with malignant brain tumor

Background: According to the development of new treatment modalities, patients with malignant brain tumor have longer survival and they have more chances to have stroke.Study Population: We retrospectively reviewed 509 patients with ischemic stroke and 445 patients with hemorrhagic stroke who visited Kyoto University Hospital between January 2010 and December 2019 and the association with malignant brain tumor was analyzed. The frequency of stroke in 287 patients with primary glioblastoma and 217 patients with metastatic brain tumor was also analyzed.Results: Twenty one (4.1%) patients with ischemic stroke and 26 (5.1%) patients with hemorrhagic stroke patients had malignant brain tumor, and most tumors were either malignant glioma or metastatic brain tumor. A medical history of cranial irradiation was seen in 66.7% of patients with ischemic stroke, and 80% of hemorrhagic stroke occurred within the tumor before starting the treatments. Either ischemic or hemorrhagic stroke occurred in 9.1% of patients with glioblastoma and 4.1% of patients with metastatic brain tumor, and the number of ischemic and hemorrhagic were almost the same. In patients with glioblastoma, nearly half of the stroke cases were associated with bevacizumab. Half of the cases of bevacizumab-related stroke were asymptomatic, while asymptomatic cases were seen in 21.4% for non-bevacizumab cases.Discussion: Stroke is not an uncommon complication in patients with malignant brain tumor but only a restricted number of cases were preventable. Including the cases of bevacizumab-related stroke, which is often asymptomatic, accurate diagnosis and the second prevention would be important.

Study of 2-hydroxyoleic Acid in Pediatric Patients With Malignant Glioma and Other Advanced Solid Tumors

Study of 2-hydroxyoleic Acid in Pediatric Patients With Malignant Glioma and Other Advanced Solid Tumors

CBMT-46. MICRORNA-206 ATTENUATES GLIOMA CELL PROLIFERATION, MIGRATION, AND INVASION BY BLOCKING THE WNT/β-CATENIN PATHWAY VIA DIRECT TARGETING OF FRIZZLED 7

Abstract Glioma is one of the most frequent primary malignant brain tumours in adults and accumulating evidence has shown that microRNAs (miRNAs) are associated with various types of tumours, including glioma. It is essential to acquire a better understanding of the roles and mechanisms of miRNAs in WNT-driven glioblastoma (GBM). Here, we report that miR-206 inhibited the WNT/β-catenin pathway by directly targeting Frizzled 7 (FZD7) and functioned as a tumour-suppressor in glioma. The expression of miR-206 in human samples and glioma cells was assessed by real-time quantitative PCR (RT-qPCR), fluorescence in situ hybridization (FISH), and histological analysis. Cell Counting Kit-8 (CCK-8), colony formation, EdU, flow cytometry, wound healing, transwell invasion, and three-dimensional migration were performed to observe cellular proliferation, migration, and invasion in vitro. The effects of miR-206 in vivo were investigated using a xenograft nude mouse model. miR-206 expression was significantly downregulated in glioma specimens. FZD7 was confirmed as a direct target of miR-206. GBM cell proliferation, migration, and invasion were blocked by restoring the expression of miR-206. Moreover, intracranial glioma models demonstrated an inhibitory effect of miR-206 on intracranial glioma tumour growth. Our results suggested that miR-206 plays a key role in blocking the WNT/β-catenin signalling pathway by suppressing FZD7 and provides a prospective therapeutic strategy for the treatment of malignant glioma and other WNT-driven tumours.

MSI2-TGF-β/TGF-β R1/SMAD3 positive feedback regulation in glioblastoma.

Glioblastoma is the most malignant glioma tumors with inevitable relapse and resistance to chemotherapy; however, the mechanisms driving chemoresistance remain to be fully elucidated. This study is to explore the molecular and cellular mechanisms involving in the chemoresistance of glioblastoma. The expression of musashi (MSI) RNA-binding protein in the tumor tissues and cells of glioblastoma was measured. The effects of MSI2 in epithelial-to-mesenchymal transition (EMT), resistance to temozolomide (TMZ), tumor cell invasion, migration, and proliferation and associated signaling were evaluated. High MSI2 expression was observed in the glioblastoma tissues. Silencing or overexpression of MSI2 significantly affected tumor cells invasion, migration, and proliferation. Silencing of MSI2 expression significantly inhibited O6-methylguanine-DNA methyltransferase (MGMT) expression and tumor growth, and reversed resistance to TMZ in xenograft tumor models. MSI2 expression regulated EMT through activating the transcription factors Snail and the TGFβ R1/SMAD3 signaling. Our study demonstrated a positive feedback loop of MSI2-TGFβ/SMAD3 signaling which activates the EMT and MGMT which may contribute to chemoresistance in glioblastoma. This study also highlights that MSI2 could be a new target for the therapy of glioblastoma.

LIM and SH3 protein 1 induces glioma growth and invasion through PI3K/AKT signaling and epithelial-mesenchymal transition

PurposeThis study investigated the underlying mechanism of LIM and SH3 protein 1 (LASP1)-induced malignant glioma growth and invasion. Materials and methodsWe compared the expression of LASP1 in malignant glioma tumor tissues and low-grade glioma tissues by immunohistochemistry. We also compared LASP1 overexpression and LASP1 knockout glioma cell proliferation and invasion in vitro and in vivo. We detected activation of the PI3K/AKT signaling pathway and epithelial-mesenchymal transition (EMT) process in tumor cells by western blotting or immunofluorescence. Glioma-bearing mice were used to investigate the anticancer effects of PI3K/AKT inhibitors in combination with temozolomide. ResultsWe observed the enhanced expression of LASP1 in malignant glioma tumor tissues compared to low-grade glioma tissues, and LASP1 overexpression in glioma cells revealed an elevated capability of proliferation and invasion in vitro and in vivo. LASP1 overexpression also facilitated PI3K/AKT signaling and the EMT process through the downstream transcription factor Snail, which resulted in the intensive invasion of cancer cells. We combined PI3K/AKT inhibitors and temozolomide to block the LASP1/PI3K/AKT/Snail signaling pathway, which dramatically enhanced tumor suppression and provides an innovative approach for clinical glioma treatment. ConclusionLASP1 is upregulated in malignant glioma and facilitates glioma cell proliferation and invasion by activation the PI3K/AKT/Snail signaling pathway. Blockade of the PI3K/AKT signal efficiently enhanced the anticancer effects of chemotherapeutic agents, which provides an innovative target in glioma treatment.

Targeting CAIX with [64Cu]XYIMSR-06 Small Molecular Radiotracer Enables Noninvasive PET Imaging of Malignant Glioma in U87 MG Tumor Cell Xenograft Mice.

Carbonic anhydrase IX (CAIX) plays an important role in glioma cell proliferation, invasion, metastasis, and resistance to radiotherapy and chemotherapy. An effective and noninvasive PET molecular imaging agent targeting CAIX would help its diagnosis and treatment but is not currently available. Recently, a low-molecular-weight (LMW) CAIX targeting agent, [64Cu]XYIMSR-06, was reported to have significantly improved properties for targeting clear cell renal cell carcinoma (ccRCC). We are encouraged to investigate the feasibility of adapting this agent for the diagnosis and treatment of CAIX-overexpressing malignant glioma. In vitro cell uptake and binding affinity assays were used to verify the binding capacity of [64Cu]XYIMSR-06 to U87 MG tumor cells in which CAIX overexpression was confirmed. The U87 MG tumor-bearing mouse (in situ and subcutaneous) model was built, and mice were injected with the radiotracer and/or coinjected with acetazolamide (0.2 g/kg) as a blocking agent for noninvasive micro-PET imaging. Micro-PET imaging was performed at 2, 4, and 8 h postinjection. ROI (region of interest)-based semiquantification was performed in an orthotopic glioma tumor model. Biodistribution throughout each organ was performed at 2, 4, 4 h block, 8, and 24 h postinjection. Hematoxylin and eosin (HE) staining and immunofluorescence or immunohistochemistry (IF/IHC) staining were implemented postimaging to assess the expression of CAIX in tumor organs. In vitro, [64Cu]XYIMSR-06 exhibits greater uptake in glioma cells (high CAIX expression) than in HCT116 cells (low CAIX expression). The binding affinity of [64Cu]XYIMSR-06 to U87 MG cell lines reaches up to 4.22 nM. Both orthotopic and subcutaneous tumors were clearly visualized at 2-8 h postinjection. Biodistribution studies demonstrated a maximum tumor uptake of 3.13% ID/g at 4 h postinjection, and the tumor to brain ratio (T/brain) was 6.51 at 8 h postinjection. The ROI-based T/brain values were 7.03 and 5.46 at 2 and 8 h postinjection, respectively. Histopathological analysis confirmed the overexpression of CAIX in gliomas, and the area of CAIX-positive IF staining is extremely consistent with the morphology on micro-PET imaging. In this study, [64Cu]XYIMSR-06 demonstrated specific accumulation in CAIX-expressing U87 MG glioma tumors, indicating that the radiotracer has the potential for noninvasively monitoring and guiding personalized treatment of malignant glioma and other tumors overexpressing CAIX.

ID2011 Potential strategies to improve Temozolomide/ radiation therapy of malignant gliomas by targeting glycolytic energy metabolism

The current standard treatment of Malignant Gliomas includes surgery, followed by Temozolomide (TMZ) - Radiotherapy. It leads to increased survival as compared to radiotherapy alone. However, haematological toxicities are also increased by the combination treatments. Therefore, it is important to carry out further preclinical studies, to develop more effective treatment for these tumors. 2-Deoxy-D-Glucose (2-DG), an inhibitor of glycolytic energy metabolism, has been shown earlier to differentially inhibit repair processes, growth and survival of cancer cells. It has been tolerated very well in combination with radiotherapy in clinical trials on Malignant Gliomas. In this study, we investigated the effects of combination of clinically relevant concentrations of 2-DG (0.5mM and 1mM) and TMZ (2µM and 5µM) ± Radiation (1Gy) on cell proliferation, total cellular damage (TCD) and colony formation in an established Glioblastoma cell line (U251MG), and primary cultures derived from malignant glioma tumor pieces. The monolayer cultures were grown on cover slips and stained with Acridine Orange (0.002%) after drug treatments and irradiation, for the study of cellular damage and death. Exponentially growing cells were exposed to drugs and Gamma irradiation. Drugs were removed 4 hrs after irradiation and cultures were processed for different assays of cell death and damage. Our results showed that combination of 2-DG with TMZ±Radiation significantly inhibited the cell proliferation up to 6 days. The TCD was significantly increased by the combination of drugs in primary as well as in established cell line. Cell proliferation as measured by MTT assay showed that drugs ± radiation significantly reduced proliferation response. Cell survival inhibition after combination of TMZ+2-DG+Gamma (2µM+0.5mM+1Gy) showed more than additive effects. These results suggest that targeting glycolytic energy metabolism by agents such as 2-DG can enhance the efficacy of TMZ+Radiation Therapy for Malignant Gliomas, without increasing toxic side effects

Abstract 3309: Tumor-treating fields decrease proliferation and clonogenicity of patient-derived WHO grade IV glioma cell lines

Abstract Despite decades of research, efficacious treatments for malignant glioma tumors are limited. Tumor-treating fields (TTFields) are FDA-approved for the treatment of newly-diagnosed and recurrent glioblastoma. In this study, in vitro experiments comparing TTFields to untreated controls were performed on patient-derived grade IV glioma cell lines to determine the effects of TTFields on cell proliferation and clonogenicity. Methods: Studies utilizing patient tumor specimens were approved by the Wayne State University Institutional Review Board and written informed consent was obtained from participants. Patient tumor specimens (glioblastoma and gliosarcoma) were collected immediately following microsurgical resection. Single-cell suspensions from the tumor tissues were prepared by enzymatic and mechanical disruption. Equal numbers of cells were plated on plastic coverslips in DMEM/F12 media supplemented with 10% fetal bovine serum. TTFields were applied at 200 kHz to half of the coverslips. Culture media was replaced every day. At the conclusion of the 2 week treatment, cell proliferation was assessed with the XTT assay and cells were harvested and replated for clonogenic assays (10,000 cells/well). The resulting colonies were fixed and stained with crystal violet and counted with an automated colony counter. Control vs. TTFields treated groups were compared by two-tailed t-tests. Results: The two-week TTFields treatment significantly reduced cell proliferation in both the glioblastoma (41.6 ± 11.1 % control; n=4; p<0.001) and in the gliosarcoma (41.6 ± 16.6 % control; n=4; p<0.002) as measured by XTT assay. The clonogenic assay revealed that the number of colonies generated from both cell lines was reduced by TTFields treatment. For the glioblastoma cell line, control cells yielded 847 colonies with an average diameter of 462.8 ± 5.6 µM while TTFields-treated cells yielded 561 colonies with an average diameter of 435.1 ± 7.3 µM, which was a statistically significant decrease (p=0.0022). For the gliosarcoma cell line, control cells yielded 809 colonies vs. 144 colonies from the TTFields treated cells, although the average diameter of the colonies was unchanged between groups (control 375.1 ± 176.1 µM; TTFields 362.9 ± 196.0 µM). Conclusions: In vitro application of TTFields markedly reduced cell proliferation and clonogenicity in both patient-derived WHO grade IV glioblastoma and gliosarcoma cell lines. This is the first report on the in vitro effects of TTFields on gliosarcoma. Citation Format: Sharon K. Michelhaugh, Sam Kiousis, Adrianne Wallace-Povirk, Sandeep Mittal. Tumor-treating fields decrease proliferation and clonogenicity of patient-derived WHO grade IV glioma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3309. doi:10.1158/1538-7445.AM2017-3309

Functional analysis of the DEPDC1 oncoantigen in malignant glioma and brain tumor initiating cells.

DEP domain containing 1 (DEPDC1) is a novel oncoantigen expressed in cancer cells, which presents oncogenic activity and high immunogenicity. Although DEPDC1 has been predicted to be a useful antigen for the development of a cancer vaccine, its pathophysiological roles in glioma have not been investigated. Here, we analyzed the expression and function of DEPDC1 in malignant glioma. DEPDC1 expression in glioma cell lines, glioma tissues, and brain tumor initiating cells (BTICs) was assessed by western blot and quantitative polymerase chain reaction (PCR). The effect of DEPDC1 downregulation on cell growth and nuclear factor kappa B (NFκB) signaling in glioma cells was investigated. Overall survival was assessed in mouse glioma models using human glioma cells and induced mouse brain tumor stem cells (imBTSCs) to determine the effect of DEPDC1 suppression in vivo. DEPDC1 expression was increased in glioma cell lines, tissues, and BTICs. Suppression of endogenous DEPDC1 expression by small interfering RNA (siRNA) inhibited glioma cell viability and induced apoptosis through NFκB signaling. In mouse glioma models using human glioma cells and imBTSCs, downregulation of DEPDC1 expression prolonged overall survival. These results suggest that DEPDC1 represents a target molecule for the treatment of glioma.

Pediatric optic ner-glioma: A case study

An optic nerve glioma is a type of brain tumor. There are multiple kinds with brain tumors and glioma’s account for approximately one-third of brain tumors. They are typically named after the kind of cells they affect. It is a rare kind of cancer, they are considered low-grade and do not grow as quickly as other types of brain tumors. They are found in the optic chiasm, where the optic nerves cross or surround the optic nerves. They are also referred to as optic glioma or juvenile pilocytic astrocytoma. It is rarely found in individuals over the age of 20. It has also been associated with the genetic disorder neurofibromatosis Type 1, or NF1. Evidence suggests that adult malignant gliomas (glioblastoma) are rare & almost always occur in adult males with a very poor prognosis & almost certain death within one year. Optic-nerve gliomas comprise about 1% of all intracranial tumors and Optic nerve glioma is a slow-growing tumours, which typically affects children. 30% of patients have associated neurofibromatosis type 1 & those have better prognosis. However, optic nerve glioma of children is discussed in this article. Keywords: Optic nerve glioma, Juvenile pilocytic astrocytoma, Brain tumors, Malignant glioma (glioblastoma) and intracranial tumors

What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas?

The current neurosurgical goal for patients with malignant gliomas is maximal safe resection of the contrast-enhancing tumor. However, a complete resection of the contrast-enhancing tumor is achieved only in a minority of patients. One reason for this limitation is the difficulty in distinguishing viable tumor from normal adjacent brain during surgery at the tumor margin using conventional white-light microscopy. To overcome this limitation, fluorescence-guided surgery (FGS) using 5-aminolevulinic acid (5-ALA) has been introduced in the treatment of malignant gliomas. FGS permits the intraoperative visualization of malignant glioma tissue and supports the neurosurgeon with real-time guidance for differentiating tumor from normal brain that is independent of neuronavigation and brain shift. Tissue fluorescence after oral administration of 5-ALA is associated with unprecedented high sensitivity, specificity, and positive predictive values for identifying malignant glioma tumor tissue. 5-ALA-induced tumor fluorescence in diffusely infiltrating gliomas with non-significant magnetic resonance imaging contrast-enhancement permits intraoperative identification of anaplastic foci and establishment of an accurate histopathological diagnosis for proper adjuvant treatment. 5-ALA FGS has enabled surgeons to achieve a significantly higher rate of complete resections of malignant gliomas in comparison with conventional white-light resections. Consequently, 5-ALA FGS has become an indispensable surgical technique and standard of care at many neurosurgical departments around the world. We conducted an extensive literature review concerning the surgical benefit of using 5-ALA for FGS of malignant gliomas. According to the literature, there are a number of reasons for the neurosurgeon to perform 5-ALA FGS, which will be discussed in detail in the current review.

GATA2 promotes glioma progression through EGFR/ERK/Elk-1 pathway.

Among the gliomas, glioblastoma (GBM) is the highest grade and the most malignant glioma tumor. GATA2 is a hematopoietic factor that has been intensely studied in hematopoietic malignancies. Recently, the functions of GATA2 as an oncogene in other types of human cancer have been reported. However, no role for GATA2 in the development and progression of glioma has been reported to date. In the present study, we found that the expression level of GATA2 is upregulated in GBM and is correlated with GBM outcome. Ectopic expression of GATA2 or RNAi-mediated knockdown of GATA2 significantly enhanced or inhibited proliferation, migration and invasion of glioma cells. Moreover, we found that epidermal growth factor receptor and extracellular signal-regulated kinase, as upstream components of the signaling pathway, upregulate GATA2 expression; moreover, GATA2 promotes Elk-1 expression. Therefore, a genetic approach or pharmacological intervention targeting GATA2 could potentially serve as an effective strategy for treating glioma patients.

Efficient delivery of docetaxel for the treatment of brain tumors by cyclic RGD-tagged polymeric micelles.

The treatment of glioblastoma, and other types of brain cancer, is limited due to the poor transport of drugs across the blood brain barrier and poor penetration of the blood‑brain‑tumor barrier. In the present study, cyclic Arginine‑Glycine‑Aspartic acid‑D‑Tyrosine‑Lysine [c(RGDyK)], that has a high binding affinity to integrin αvβ3 receptors, that are overexpressed in glioblastoma cancers, was employed as a novel approach to target cancer by delivering therapeutic molecules intracellularly. The c(RGDyK)/docetaxel polylactic acid‑polyethylene glycol (DTX‑PLA‑PEG) micelle was prepared and characterized for various in vitro and in vivo parameters. The specific binding affinity of the Arginine‑Glycine‑Aspartic acid (RGD) micelles, to the integrin receptor, enhanced the intracellular accumulation of DTX, and markedly increased its cytotoxic efficacy. The effect of microtubule stabilization was evident in the inhibition of glioma spheroid volume. Upon intravenous administration, c(RGDyK)/DTX‑PLA‑PEG showed enhanced accumulation in brain tumor tissues through active internalization, whereas non‑targeted micelles showed limited transport ability. Furthermore, RGD‑linked micelles showed marked anti‑glioma activity in U87MG malignant glioma tumor xenografts, and significantly suppressed the growth of tumors without signs of systemic toxicity. In conclusion, the results of the present study suggest that ligand‑mediated drug delivery may improve the efficacy of brain cancer chemotherapy.

A phase I trial of MK‐2206 in children with refractory malignancies: A Children's Oncology Group study

We report results of a phase I trial designed to estimate the maximum tolerated dose (MTD), describe dose-limiting toxicities (DLT), and characterize the pharmacokinetic profile of MK-2206, an AKT inhibitor, in children with refractory or recurrent malignancies. MK-2206 was administered either every other day (Schedule 1), or once a week (Schedule 2) in a 28-day cycle. Dose escalations in increments of ∼30% were independently made in each part using the rolling-six design. Serial pharmacokinetic (PK) studies were obtained. Biological studies include analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and post-therapy in PBMC and in tumors at diagnosis or recurrence. Fifty patients (26 males, median age 12.6 years [range, 3.1-21.9]) with malignant glioma (16), ependymoma (4), hepatocellular carcinoma (3), gliomatosis cereberi (2), or other tumors (22) were enrolled; 40 were fully evaluable for toxicity (Schedule 1, n = 23; Schedule 2, n = 17). Schedule 1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m(2) ; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45 mg/m(2) ; and grade 3 rash in 3/6 patients at dose level 4 (58 mg/m(2) ). Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90 mg/m(2) ; grade 3 rash in 1/6 patients at 120 mg/m(2) ; and grade 3 rash in 2/6 patients at 155 mg/m(2) . The recommended pediatric phase 2 dose of MK-2206 is 45 mg/m(2) /dose every other day or 120 mg/m(2) /dose weekly. PK appeared linear over the dose range studied.

Treatment of malignant glioma using hyperthermia.

Thirty pathologically diagnosed patients with grade III–IV primary or recurrent malignant glioma (tumor diameter 3–7 cm) were randomly divided into two groups. The control group underwent conventional radiotherapy and chemotherapy. In the hyperthermia group, primary cases received hyperthermia treatment, and patients with recurrent tumors were treated with hyperthermia in com-bination with radiotherapy and chemotherapy. Hyperthermia treatment was administered using a 13.56-MHz radio frequency hyperthermia device. Electrodes were inserted into the tumor with the aid of a CT-guided stereotactic apparatus and heat was applied for 1 hour. During 3 months after hyperthermia, patients were evaluated with head CT or MRI every month. Gliomas in the hyper-thermia group exhibited growth retardation or growth termination. Necrosis was evident in 80% of the heated tumor tissue and there was a decrease in tumor diameter. Our findings indicate that ra-dio frequency hyperthermia has a beneficial effect in the treatment of malignant glioma.

Phase I/II study of dianhydrogalactitol in patients with recurrent malignant glioma or progressive secondary brain tumor.

2093 Background: Recurrent glial tumors of the brain continue to be one of the most challenging malignancies to treat, and median survival for patients with recurrent disease is approximately 6 months for glioblastoma multiforme (GBM). The front-line therapy for GBM - temozolomide (TMZ) - is subject to resistance by DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), leading to poor prognoses for patients with recurrent GBM. Dianhydrogalactitol (VAL-083)is a first-in-class bi-functional N7 DNA alkylating agent shown to cross the blood-brain barrier, accumulate in brain tissue, and have activity against GBM. Studies suggest that VAL-083 overcomes MGMT-driven drug resistance in vitro and targets cancer stem cells. The purpose of this study is to determine the maximal tolerated dose (MTD) of VAL-083 in patients with recurrent GBM or progressive secondary brain tumor, and explore the safety, pharmacokinetics and tumor responses to treatment. Methods: Open-label phase I/II dose-escalation study of VAL-083 in patients with histologically confirmed primary WHO grade 4 malignant GBM, now recurrent, previously treated for GBM with surgery and/or radiation, if appropriate, and have failed both bevacizumab and temozolomide; or progressive secondary brain tumor, has failed standard brain radiotherapy, and has brain tumor progression after at least one line of systemic therapy. The study uses a 3 + 3 dose escalation design, until reaching the MTD or maximum specified dose. Patients receive IV VAL-083 on days 1, 2, and 3 of each 21-day treatment cycle. In phase II, additional patients are treated at the MTD (or selected optimum dose) to measure tumor responses. Results: Cohort 1 (3 patients) and cohort 2 (4 patients) were completed without any DLT’s. Adverse events (AEs) have all been grade 1/2, with only 1 grade 3 AE, unrelated to treatment. Cohort 3 currently has 4 patient enrolled, without reaching the MTD. 1/7 (14.3%) patients in cohorts 1and 2 has prolonged stable disease (15+ cycles) on VAL-083 treatment. Conclusions: VAL-083 up to the 2nd dose level was well tolerated without any safety signals. Dose escalation is continuing. Clinical trial information: NCT01478178.