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Item Comment on 'Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma'(British Journal of Cancer, 2015-12-01) Ellsworth, Susannah; Grossman, Stuart A.; Department of Radiation Oncology, IU School of MedicineItem Ex vivo Dynamics of Human Glioblastoma Cells in a Microvasculature-on-a-Chip System Correlates with Tumor Heterogeneity and Subtypes(Wiley, 2019-02-10) Xiao, Yang; Kim, Dongjoo; Dura, Burak; Zhang, Kerou; Yan, Runchen; Li, Huamin; Han, Edward; Ip, Joshua; Zou, Pan; Liu, Jun; Chen, Ann Tai; Vortmeyer, Alexander O.; Zhou, Jiangbing; Fan, Rong; Pathology and Laboratory Medicine, School of MedicineThe perivascular niche (PVN) plays an essential role in brain tumor stem-like cell (BTSC) fate control, tumor invasion, and therapeutic resistance. Here, a microvasculature-on-a-chip system as a PVN model is used to evaluate the ex vivo dynamics of BTSCs from ten glioblastoma patients. BTSCs are found to preferentially localize in the perivascular zone, where they exhibit either the lowest motility, as in quiescent cells, or the highest motility, as in the invasive phenotype, with migration over long distance. These results indicate that PVN is a niche for BTSCs, while the microvascular tracks may serve as a path for tumor cell migration. The degree of colocalization between tumor cells and microvessels varies significantly across patients. To validate these results, single-cell transcriptome sequencing (10 patients and 21 750 single cells in total) is performed to identify tumor cell subtypes. The colocalization coefficient is found to positively correlate with proneural (stem-like) or mesenchymal (invasive) but not classical (proliferative) tumor cells. Furthermore, a gene signature profile including PDGFRA correlates strongly with the “homing” of tumor cells to the PVN. These findings demonstrate that the model can recapitulate in vivo tumor cell dynamics and heterogeneity, representing a new route to study patient-specific tumor cell functions.Item GammaTile for Gliomas: A Single-Center Case Series(Springer Nature, 2021-11) Budnick, Hailey C.; Richardson, Angela M.; Shiue, Kevin; Watson, Gordon; Ng, Sook K.; Le, Yi; Shah, Mitesh V.; Radiation Oncology, School of MedicineGammaTile® (GT Medical Technologies, Tempe, Arizona) is a surgically targeted radiation source, approved by FDA for brachytherapy in primary and secondary brain neoplasms. Each GammaTile is composed of a collagen sponge with four seeds of cesium 131 and is particularly useful in recurrent tumors. We report our early experience in seven patients with recurrent gliomas to assess this type of brachytherapy with particular attention to ease of use, complication, and surgical planning. This study represents a retrospective chart review of surgical use and early clinical outcomes of GammaTile in recurrent gliomas. The number of tiles was planned using pre-operative imaging and dosimetry was planned based on post-operative imaging. Patients were followed during their hospital stay and were followed up after discharge. Parameters such as case length, resection extent, complication, ICU length of stay (LOS), hospital LOS, pre-operative Glasgow Coma Scale (GCS), immediate post-operative GCS, post-operative imaging findings, recurrence at follow-up, length of follow-up, and dosimetry were collected in a retrospective manner. Seven patients were identified that met the inclusion criteria. Two patients were diagnosed with recurrent glioblastoma multiforme (GBM), one lower-grade glioma that recurred as a GBM, one GBM that recurred as a gliosarcoma, and two recurrent oligodendrogliomas. We found that operation time, ICU LOS, hospital LOS, pre- and post-operative GCS, and post-operative complications were within the expected ranges for tumor resection patients. Further, dosimetry data suggests that six out of seven patients received adequate radiation coverage, with the seventh having implantation limitations due to nearby organs at risk. We report no postoperative complications that can be attributed to the GammaTiles themselves. In our cohort, we report seven cases where GammaTiles were implanted in recurrent gliomas. No implant-related post-operative complications were identified. This early data suggests that GammaTile can be a safe form of brachytherapy in recurrent gliomas.Item MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma(Elsevier, 2017-12-11) Huang, Tianzhi; Kim, Chung Kwon; Alvarez, Angel A.; Pangeni, Rajendra P.; Wan, Xuechao; Song, Xiao; Shi, Taiping; Yang, Yongyong; Sastry, Namratha; Horbinski, Craig M.; Lu, Songjian; Stupp, Roger; Kessler, John A.; Nishikawa, Ryo; Nakano, Ichiro; Sulman, Erik P.; Lu, Xinghua; James, Charles David; Yin, Xiao-Ming; Hu, Bo; Cheng, Shi-Yuan; Pathology and Laboratory Medicine, School of MedicineATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B activities using genetic approaches or an inhibitor of ATG4B suppresses autophagy and the tumorigenicity of glioblastoma (GBM) cells. Furthermore, radiation induces MST4 expression, ATG4B phosphorylation, and autophagy. Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM xenograft markedly slows tumor growth and provides a significant survival benefit. Our work describes an MST4-ATG4B signaling axis that influences GBM autophagy and malignancy, and whose therapeutic targeting enhances the anti-tumor effects of radiotherapy., • MST4 kinase regulates the growth, sphere formation, and tumorigenicity of GBM cells • MST4 stimulates autophagy by activating ATG4B through phosphorylation of ATG4B S383 • Radiation increases MST4 expression and ATG4B phosphorylation, inducing autophagy • Inhibiting ATG4B enhances the anti-tumor effects of radiotherapy in GBM PDX models , Huang et al. show that radiation induces MST4 expression and that MST4 phosphorylates ATG4B at serine 383, which increases ATG4B activity and autophagic flux. Inhibition of ATG4B reduces autophagy and tumorigenicity of glioblastoma (GBM) cells and improves the impact of radiotherapy on GBM growth in mice.Item Novel therapeutics and drug-delivery approaches in the modulation of glioblastoma stem cell resistance(T&F, 2022-04) Smiley, Shelby B.; Zarrinmayeh, Hamideh; Das, Sudip K.; Pollok , Karen E.; Vannier, Michael W.; Veronesi, Michael C.; Radiology and Imaging Sciences, School of MedicineGlioblastoma (GBM) is a deadly malignancy with a poor prognosis. An important factor contributing to GBM recurrence is high resistance of GBM cancer stem cells (GSCs). While temozolomide (TMZ), has been shown to consistently extend survival, GSCs grow resistant to TMZ through upregulation of DNA damage repair mechanisms and avoidance of apoptosis. Since a single-drug approach has failed to significantly alter prognosis in the past 15 years, unique approaches such as multidrug combination therapy together with distinctive targeted drug-delivery approaches against cancer stem cells are needed. In this review, a rationale for multidrug therapy using a targeted nanotechnology approach that preferentially target GSCs is proposed with discussion and examples of drugs, nanomedicine delivery systems, and targeting moieties.Item PPARγ agonists inhibit growth and expansion of CD133+ brain tumour stem cells(Cancer Research UK, 2008-11-18) Chearwae, W.; Bright, J.J.; Medicine, School of MedicineBrain tumour stem cells (BTSCs) are a small population of cells that has self-renewal, transplantation, multidrug resistance and recurrence properties, thus remain novel therapeutic target for brain tumour. Recent studies have shown that peroxisome proliferator-activated receptor gamma (PPARγ) agonists induce growth arrest and apoptosis in glioblastoma cells, but their effects on BTSCs are largely unknown. In this study, we generated gliospheres with more than 50% CD133+ BTSC by culturing U87MG and T98G human glioblastoma cells with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). In vitro treatment with PPARγ agonist, 15-Deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2) or all-trans retinoic acid resulted in a reversible inhibition of gliosphere formation in culture. Peroxisome proliferator-activated receptor gamma agonists inhibited the proliferation and expansion of glioma and gliosphere cells in a dose-dependent manner. Peroxisome proliferator-activated receptor gamma agonists also induced cell cycle arrest and apoptosis in association with the inhibition of EGF/bFGF signalling through Tyk2-Stat3 pathway and expression of PPARγ in gliosphere cells. These findings demonstrate that PPARγ agonists regulate growth and expansion of BTSCs and extend their use to target BTSCs in the treatment of brain tumour.Item Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell–like spheroids, and tumor xenografts through multiple cell signaling pathways(AANS, 2017-12) Bijangi-Vishehsaraei, Khadijeh; Saadatzadeh, M. Reza; Wang, Haiyan; Nguyen, Angie; Kamocka, Malgorzata M.; Cai, Wenjing; Cohen-Gadol, Aaron A.; Halum, Stacey L.; Sarkaria, Jann N.; Pollok, Karen E.; Safa, Ahmad R.; Pharmacology and Toxicology, School of MedicineOBJECTIVE Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)—a constituent of cruciferous vegetables with a multitargeted effect—as a therapeutic agent for GBM. METHODS The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models. RESULTS SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of γ-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell–induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN administration at 100 mg/kg for 5-day cycles repeated for 3 weeks significantly decreased the growth of ectopic xenografts that were established from the early passage of primary cultures of GBM10. CONCLUSIONS These results suggest that SFN is a potent anti-GBM agent that targets several apoptosis and cell survival pathways and further preclinical and clinical studies may prove that SFN alone or in combination with other therapies may be potentially useful for GBM therapy.Item Tumor Treating Fields Utilization in a Glioblastoma Patient with a Preexisting Cardiac Pacemaker: The First Reported Case(Elsevier, 2018-11) McClelland, Shearwood, III; Henrikson, Charles A.; Ciporen, Jeremy N.; Jaboin, Jerry J.; Mitin, Timur; Radiation Oncology, School of MedicineBackground Tumor-treating fields (TTFs) have become an important, evidence-based modality in the treatment of glioblastoma (GBM). In patients requiring cardiac pacemakers, TTF therapy is complicated by theoretical concerns regarding possible electrical interaction between the devices. Case Description A 57-year-old man with past medical history of sick sinus syndrome requiring cardiac pacemaker implantation suffered an acute neurologic change associated with a left parieto-occipital lesion, which was found to be GBM. After completion of guideline-concordant chemoradiation, he chose to undergo TTF therapy. Because of the absence of cardiac symptoms and the theoretical risk of far-field sensing by the pacemaker of the TTF device (potentially resulting in pacemaker inhibition), the pacemaker was turned off before receiving TTF. Following TTF implementation, the patient responded well; he remains alive more than 25 months following his GBM diagnosis, exceeding the median 20.9-month survival of the recently completed phase III TTF randomized clinical trial for newly diagnosed GBM. Furthermore, he has exhibited neither cardiac morbidity nor adverse scalp reactions to TTF therapy. Conclusions The first reported case of successful TTF administration in a GBM patient with a previously implanted cardiac pacemaker may allay the concerns of neuro-oncologists, cardiologists, radiation oncologists, and all certified TTF prescribers regarding the applicability of TTF in suitable candidates with preexisting cardiac pacemakers. This case indicates that TTF therapy may be efficacious in patients with indwelling magnetic resonance image−conditional cardiac pacemakers turned to the off position and that physical removal of the pacemaker is not necessary before starting TTF.Item Tumor-responsive, multifunctional CAR-NK cells cooperate with impaired autophagy to infiltrate and target glioblastoma(bioRxiv, 2020) Wang, Jiao; Toregrosa-Allen, Sandra; Elzey, Bennett D.; Utturkar, Sagar; Lanman, Nadia Atallah; Bernal-Crespo, Victor; Behymer, Matthew M.; Knipp, Gregory T.; Yun, Yeonhee; Veronesi, Michael C.; Sinn, Anthony L.; Pollok, Karen E.; Brutkiewicz, Randy R.; Nevel, Kathryn S.; Matosevic, Sandro; Radiology and Imaging Sciences, School of MedicineTumor antigen heterogeneity, a severely immunosuppressive tumor microenvironment (TME) and lymphopenia resulting in inadequate immune intratumoral trafficking have rendered glioblastoma (GBM) highly resistant to therapy. As a result, GBM immunotherapies have failed to demonstrate sustained clinical improvements in patient overall survival (OS). To overcome these obstacles, here we describe a novel, sophisticated combinatorial platform for GBM: the first multifunctional immunotherapy based on genetically-engineered, human NK cells bearing multiple anti-tumor functions, including local tumor responsiveness, that addresses key drivers of GBM resistance to therapy: antigen escape, poor immune cell homing, and immunometabolic reprogramming of immune responses. We engineered dual-specific CAR-NK cells to bear a third functional moiety that is activated in the GBM TME and addresses immunometabolic suppression of NK cell function: a tumor-specific, locally-released antibody fragment which can inhibit the activity of CD73 independently of CAR signaling and decrease the local concentration of adenosine. The multifunctional human NK cells targeted patient-derived GBM xenografts, demonstrated local tumor site specific activity in the tissue and potently suppressed adenosine production. We also unveil a complex reorganization of the immunological profile of GBM induced by inhibiting autophagy. Pharmacologic impairment of the autophagic process not only sensitized GBM to antigenic targeting by NK cells, but promoted a chemotactic profile favorable to NK infiltration. Taken together, our study demonstrates a promising new NK cell-based combinatorial strategy that can target multiple clinically-recognized mechanisms of GBM progression simultaneously.Item Use of multimodality imaging, histology, and treatment feasibility to characterize a transgenic Rag2-null rat model of glioblastoma(Frontiers, 2022-11-22) Jackson, Luke R.; Masi, Megan R.; Selman, Bryce M.; Sandusky, George E.; Zarrinmayeh, Hamideh; Das, Sudip K.; Maharjan, Surendra; Wang, Nian; Zheng, Qi-Huang; Pollok, Karen E.; Snyder, Scott E.; Sun, Phillip Zhe; Hutchins, Gary D.; Butch, Elizabeth R.; Veronesi, Michael C.; Pediatrics, School of MedicineMany drugs that show potential in animal models of glioblastoma (GBM) fail to translate to the clinic, contributing to a paucity of new therapeutic options. In addition, animal model development often includes histologic assessment, but multiparametric/multimodality imaging is rarely included despite increasing utilization in patient cancer management. This study developed an intracranial recurrent, drug-resistant, human-derived glioblastoma tumor in Sprague–Dawley Rag2-Rag2 tm1Hera knockout rat and was characterized both histologically and using multiparametric/multimodality neuroimaging. Hybrid 18F-fluoroethyltyrosine positron emission tomography and magnetic resonance imaging, including chemical exchange saturation transfer (18F-FET PET/CEST MRI), was performed for full tumor viability determination and characterization. Histological analysis demonstrated human-like GBM features of the intracranially implanted tumor, with rapid tumor cell proliferation (Ki67 positivity: 30.5 ± 7.8%) and neovascular heterogeneity (von Willebrand factor VIII:1.8 to 5.0% positivity). Early serial MRI followed by simultaneous 18F-FET PET/CEST MRI demonstrated consistent, predictable tumor growth, with exponential tumor growth most evident between days 35 and 49 post-implantation. In a second, larger cohort of rats, 18F-FET PET/CEST MRI was performed in mature tumors (day 49 post-implantation) for biomarker determination, followed by evaluation of single and combination therapy as part of the model development and validation. The mean percentage of the injected dose per mL of 18F-FET PET correlated with the mean %CEST (r = 0.67, P < 0.05), but there was also a qualitative difference in hot spot location within the tumor, indicating complementary information regarding the tumor cell demand for amino acids and tumor intracellular mobile phase protein levels. Finally, the use of this glioblastoma animal model for therapy assessment was validated by its increased overall survival after treatment with combination therapy (temozolomide and idasanutlin) (P < 0.001). Our findings hold promise for a more accurate tumor viability determination and novel therapy assessment in vivo in a recently developed, reproducible, intracranial, PDX GBM.