scholarly journals Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1357
Author(s):  
Cyntanna C. Hawkins ◽  
Tomader Ali ◽  
Sasanka Ramanadham ◽  
Anita B. Hjelmeland
Keyword(s):  
Brain Tumors ◽  
Biological Effects ◽  
Standard Of Care ◽  
Sphingolipid Metabolism ◽  
Metastatic Brain Tumors ◽  
Current Standard ◽  
Adaptive Immune Cells ◽  
Dismal Prognosis ◽  
Wide Range ◽  
Sphingosine 1 Phosphate

Glioblastoma (GBM) is a primary malignant brain tumor with a dismal prognosis, partially due to our inability to completely remove and kill all GBM cells. Rapid tumor recurrence contributes to a median survival of only 15 months with the current standard of care which includes maximal surgical resection, radiation, and temozolomide (TMZ), a blood–brain barrier (BBB) penetrant chemotherapy. Radiation and TMZ cause sphingomyelinases (SMase) to hydrolyze sphingomyelins to generate ceramides, which induce apoptosis. However, cells can evade apoptosis by converting ceramides to sphingosine-1-phosphate (S1P). S1P has been implicated in a wide range of cancers including GBM. Upregulation of S1P has been linked to the proliferation and invasion of GBM and other cancers that display a propensity for brain metastasis. To mediate their biological effects, SMases and S1P modulate signaling via phospholipase C (PLC) and phospholipase D (PLD). In addition, both SMase and S1P may alter the integrity of the BBB leading to infiltration of tumor-promoting immune populations. SMase activity has been associated with tumor evasion of the immune system, while S1P creates a gradient for trafficking of innate and adaptive immune cells. This review will explore the role of sphingolipid metabolism and pharmacological interventions in GBM and metastatic brain tumors with a focus on SMase and S1P.

scholarly journals Response to Immunotherapy in Combination With Mitotane in Patients With Metastatic Adrenocortical Cancer

2019 ◽  
Vol 3 (12) ◽  
pp. 2295-2304 ◽  
Author(s):  
Lia Head ◽  
Katja Kiseljak-Vassiliades ◽  
Toshimasa J Clark ◽  
Hilary Somerset ◽  
Jonathan King ◽  
...  
Keyword(s):  
Evaluation Criteria ◽  
Standard Of Care ◽  
Response Evaluation ◽  
Adrenocortical Cancer ◽  
First Line ◽  
Current Standard ◽  
Dismal Prognosis ◽  
Grade 3 ◽  
Combined Immunotherapy ◽  
First Line Treatment

Abstract Adrenocortical carcinoma (ACC) is a rare orphan disease with a dismal prognosis. Surgery remains the first-line treatment, but most patients eventually develop metastatic disease. Mitotane is often used with chemotherapy with modest success. Little information is available concerning the efficacy of immunotherapy in combination with mitotane. We conducted a retrospective review of our initial six patients with metastatic ACC, for whom mitotane alone or with chemotherapy failed, and who were subsequently treated with a combination of pembrolizumab and mitotane, between July 2016 and March 2019. Imaging was analyzed per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Two patients had a partial response and four patients had stable disease (8 to 19 months). One patient had grade 3 hepatitis and pembrolizumab was discontinued after 8 months. She died with disease progression 16 months after initiating pembrolizumab. One patient developed brain metastasis after 19 months of treatment and was transitioned to hospice. One patient had focal pneumonitis after 18 months of treatment, and pembrolizumab was discontinued. Three remaining patients continue pembrolizumab plus mitotane at the time of this writing. The current standard of care for ACC is a combination of etoposide, doxorubicin, cisplatin, and mitotane with an overall survival of 14.8 months. All six patients lived for at least 16 months after starting pembrolizumab added to mitotane therapy. The therapy appeared to be effective in both microsatellite instability-high and microsatellite stable tumors, suggesting some synergistic effect with mitotane. Combined immunotherapy and mitotane should be considered in future clinical trials in patients with ACC.

scholarly journals A Review of Newly Diagnosed Glioblastoma

2021 ◽  
Vol 10 ◽  
Author(s):  
Bryan Oronsky ◽  
Tony R. Reid ◽  
Arnold Oronsky ◽  
Navjot Sandhu ◽  
Susan J. Knox
Keyword(s):  
Brain Tumor ◽  
Surgical Resection ◽  
Standard Of Care ◽  
Newly Diagnosed ◽  
Current Standard ◽  
Genetic Characteristics ◽  
Dismal Prognosis ◽  
Newly Diagnosed Glioblastoma ◽  
Temozolomide Chemotherapy

Glioblastoma is an aggressive and inevitably recurrent primary intra-axial brain tumor with a dismal prognosis. The current mainstay of treatment involves maximally safe surgical resection followed by radiotherapy over a 6-week period with concomitant temozolomide chemotherapy followed by temozolomide maintenance. This review provides a summary of the epidemiological, clinical, histologic and genetic characteristics of newly diagnosed disease as well as the current standard of care and potential future therapeutic prospects.

scholarly journals Glioblastoma’s Next Top Model: Novel Culture Systems for Brain Cancer Radiotherapy Research

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 44 ◽  
Author(s):  
Seamus Caragher ◽  
Anthony J. Chalmers ◽  
Natividad Gomez-Roman
Keyword(s):  
Mouse Models ◽  
Standard Of Care ◽  
Primary Brain Tumor ◽  
Current Standard ◽  
Meaningful Improvement ◽  
Nutrient Sources ◽  
Culture Systems ◽  
Novel Treatments ◽  
Wide Range

Glioblastoma (GBM), the most common and aggressive primary brain tumor in adults, remains one of the least treatable cancers. Current standard of care—combining surgical resection, radiation, and alkylating chemotherapy—results in a median survival of only 15 months. Despite decades of investment and research into the development of new therapies, most candidate anti-glioma compounds fail to translate into effective treatments in clinical trials. One key issue underlying this failure of therapies that work in pre-clinical models to generate meaningful improvement in human patients is the profound mismatch between drug discovery systems—cell cultures and mouse models—and the actual tumors they are supposed to imitate. Indeed, current strategies that evaluate the effects of novel treatments on GBM cells in vitro fail to account for a wide range of factors known to influence tumor growth. These include secreted factors, the brain’s unique extracellular matrix, circulatory structures, the presence of non-tumor brain cells, and nutrient sources available for tumor metabolism. While mouse models provide a more realistic testing ground for potential therapies, they still fail to account for the full complexity of tumor-microenvironment interactions, as well as the role of the immune system. Based on the limitations of current models, researchers have begun to develop and implement novel culture systems that better recapitulate the complex reality of brain tumors growing in situ. A rise in the use of patient derived cells, creative combinations of added growth factors and supplements, may provide a more effective proving ground for the development of novel therapies. This review will summarize and analyze these exciting developments in 3D culturing systems. Special attention will be paid to how they enhance the design and identification of compounds that increase the efficacy of radiotherapy, a bedrock of GBM treatment.

scholarly journals Knockdown of USP18 Increases Alpha 2a Interferon Signaling and Induction of Interferon-Stimulating Genes but Does Not Increase Antiviral Activity in Huh7 Cells

2011 ◽  
Vol 55 (9) ◽  
pp. 4311-4319 ◽  
Author(s):  
E. J. Murray ◽  
Frances Burden ◽  
Nigel Horscroft ◽  
Caroline Smith-Burchnell ◽  
Mike Westby
Keyword(s):  
Standard Of Care ◽  
Huh7 Cell ◽  
Encephalomyocarditis Virus ◽  
Interferon Signaling ◽  
Oligoadenylate Synthetase ◽  
Current Standard ◽  
Subgenomic Replicon ◽  
Virus Assay ◽  
Huh7 Cells ◽  
Wide Range

ABSTRACTThe current standard of care for hepatitis C virus (HCV) patients is cotreatment with human alpha interferon (IFN-α) and ribavirin. The host factor USP18 functions to regulate the interferon signaling pathway by acting as an off-switch. In order to understand whether the inhibition of USP18 represents a valid target for the enhancement of interferon treatment for chronic viral diseases, we have used a wide range of RNA interference (RNAi) reagents to suppress USP18 gene expression in Huh7 cell lines. We demonstrate that a USP18 knockdown results in IFN-α2a signaling (measured by increased IFN-stimulated response element [ISRE] reporter gene activity, 2′,5′-oligoadenylate synthetase [2-5 OAS] expression, and ISG15 induction) that is increased by ∼100-fold, whereas the antiviral (AV) potency in both the Huh7 HCV subgenomic replicon assay and the Huh7.5 HCV infectious virus assay increased by ∼3-fold. While the degree of the USP18 knockdown of USP18 elicited by the different RNAi reagents correlated with the enhancement of IFN-α2a signaling, it did not correlate with the enhancement of AV activity. The failure of increased IFN-α2a signaling to fully translate into increased AV potency was also observed for encephalomyocarditis virus (EMCV) assays using Huh7.5 cells. These data suggest that the IFN-mediated AV response in Huh7.5 cells has only a limited dependence on USP18 activity.

scholarly journals Ewing Sarcoma—Diagnosis, Treatment, Clinical Challenges and Future Perspectives

2021 ◽  
Vol 10 (8) ◽  
pp. 1685
Author(s):  
Stefan K. Zöllner ◽  
James F. Amatruda ◽  
Sebastian Bauer ◽  
Stéphane Collaud ◽  
Enrique de Álava ◽  
...  
Keyword(s):  
Ewing Sarcoma ◽  
Local Treatment ◽  
Standard Of Care ◽  
Current Standard ◽  
Potential Therapeutic Target ◽  
Dismal Prognosis ◽  
Physical Burden ◽  
International Collaborations ◽  
Multiple Cycles ◽  
Tissue Cancer

Ewing sarcoma, a highly aggressive bone and soft-tissue cancer, is considered a prime example of the paradigms of a translocation-positive sarcoma: a genetically rather simple disease with a specific and neomorphic-potential therapeutic target, whose oncogenic role was irrefutably defined decades ago. This is a disease that by definition has micrometastatic disease at diagnosis and a dismal prognosis for patients with macrometastatic or recurrent disease. International collaborations have defined the current standard of care in prospective studies, delivering multiple cycles of systemic therapy combined with local treatment; both are associated with significant morbidity that may result in strong psychological and physical burden for survivors. Nevertheless, the combination of non-directed chemotherapeutics and ever-evolving local modalities nowadays achieve a realistic chance of cure for the majority of patients with Ewing sarcoma. In this review, we focus on the current standard of diagnosis and treatment while attempting to answer some of the most pressing questions in clinical practice. In addition, this review provides scientific answers to clinical phenomena and occasionally defines the resulting translational studies needed to overcome the hurdle of treatment-associated morbidities and, most importantly, non-survival.

scholarly journals Sphingolipid metabolism governs Purkinje cell patterned degeneration in Atxn1[82Q]/+ mice

2021 ◽  
Vol 118 (36) ◽  
pp. e2016969118
Author(s):  
François G. C. Blot ◽  
Wilhelmina H. J. J. Krijnen ◽  
Sandra Den Hoedt ◽  
Catarina Osório ◽  
Joshua J. White ◽  
...  
Keyword(s):  
Regional Differences ◽  
Neuroprotective Effect ◽  
Causal Link ◽  
Sphingolipid Metabolism ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 1 ◽  
Transgenic Expression ◽  
Wide Range ◽  
Sphingosine 1 Phosphate

Patterned degeneration of Purkinje cells (PCs) can be observed in a wide range of neuropathologies, but mechanisms behind nonrandom cerebellar neurodegeneration remain unclear. Sphingolipid metabolism dyshomeostasis typically leads to PC neurodegeneration; hence, we questioned whether local sphingolipid balance underlies regional sensitivity to pathological insults. Here, we investigated the regional compartmentalization of sphingolipids and their related enzymes in the cerebellar cortex in healthy and pathological conditions. Analysis in wild-type animals revealed higher sphingosine kinase 1 (Sphk1) levels in the flocculonodular cerebellum, while sphingosine-1-phosphate (S1P) levels were higher in the anterior cerebellum. Next, we investigated a model for spinocerebellar ataxia type 1 (SCA1) driven by the transgenic expression of the expanded Ataxin 1 protein with 82 glutamine (82Q), exhibiting severe PC degeneration in the anterior cerebellum while the flocculonodular region is preserved. In Atxn1[82Q]/+ mice, we found that levels of Sphk1 and Sphk2 were region-specific decreased and S1P levels increased, particularly in the anterior cerebellum. To determine if there is a causal link between sphingolipid levels and neurodegeneration, we deleted the Sphk1 gene in Atxn1[82Q]/+ mice. Analysis of Atxn1[82Q]/+; Sphk1−/− mice confirmed a neuroprotective effect, rescuing a subset of PCs in the anterior cerebellum, in domains reminiscent of the modules defined by AldolaseC expression. Finally, we showed that Sphk1 deletion acts on the ATXN1[82Q] protein expression and prevents PC degeneration. Taken together, our results demonstrate that there are regional differences in sphingolipid metabolism and that this metabolism is directly involved in PC degeneration in Atxn1[82Q]/+ mice.

scholarly journals Harnessing the Activation of RIG-I Like Receptors to Inhibit Glioblastoma Tumorigenesis

2021 ◽  
Vol 14 ◽  
Author(s):  
Francesca Bufalieri ◽  
Irene Basili ◽  
Lucia Di Marcotullio ◽  
Paola Infante
Keyword(s):  
Tumor Antigens ◽  
Standard Of Care ◽  
Innate Immune ◽  
Molecular Heterogeneity ◽  
Type I ◽  
Current Standard ◽  
Adaptive Immune ◽  
Wide Range ◽  
Anti Cancer ◽  
Immunosuppressive Microenvironment

Glioblastoma (GB) is an incurable form of brain malignancy in an adult with a median survival of less than 15 months. The current standard of care, which consists of surgical resection, radiotherapy, and chemotherapy with temozolomide, has been unsuccessful due to an extensive inter- and intra-tumoral genetic and molecular heterogeneity. This aspect represents a serious obstacle for developing alternative therapeutic options for GB. In the last years, immunotherapy has emerged as an effective treatment for a wide range of cancers and several trials have evaluated its effects in GB patients. Unfortunately, clinical outcomes were disappointing particularly because of the presence of tumor immunosuppressive microenvironment. Recently, anti-cancer approaches aimed to improve the expression and the activity of RIG-I-like receptors (RLRs) have emerged. These innovative therapeutic strategies attempt to stimulate both innate and adaptive immune responses against tumor antigens and to promote the apoptosis of cancer cells. Indeed, RLRs are important mediators of the innate immune system by triggering the type I interferon (IFN) response upon recognition of immunostimulatory RNAs. In this mini-review, we discuss the functions of RLRs family members in the control of immune response and we focus on the potential clinical application of RLRs agonists as a promising strategy for GB therapy.

scholarly journals UCP2 as a Potential Biomarker for Adjunctive Metabolic Therapies in Tumor Management

2021 ◽  
Vol 11 ◽  
Author(s):  
Frederic A. Vallejo ◽  
Steven Vanni ◽  
Regina M. Graham
Keyword(s):  
Brain Tumors ◽  
Standard Of Care ◽  
Tumor Grade ◽  
Metabolic Reprogramming ◽  
Proliferative Potential ◽  
Current Standard ◽  
Protein Levels ◽  
Ucp2 Expression ◽  
Potential Biomarker ◽  
Tumor Management

Glioblastoma (GBM) remains one of the most lethal primary brain tumors in both adult and pediatric patients. Targeting tumor metabolism has emerged as a promising-targeted therapeutic strategy for GBM and characteristically resistant GBM stem-like cells (GSCs). Neoplastic cells, especially those with high proliferative potential such as GSCs, have been shown to upregulate UCP2 as a cytoprotective mechanism in response to chronic increased reactive oxygen species (ROS) exposure. This upregulation plays a central role in the induction of the highly glycolytic phenotype associated with many tumors. In addition to shifting metabolism away from oxidative phosphorylation, UCP2 has also been implicated in increased mitochondrial Ca2+ sequestration, apoptotic evasion, dampened immune response, and chemotherapeutic resistance. A query of the CGGA RNA-seq and the TCGA GBMLGG database demonstrated that UCP2 expression increases with increased WHO tumor-grade and is associated with much poorer prognosis across a cohort of brain tumors. UCP2 expression could potentially serve as a biomarker to stratify patients for adjunctive anti-tumor metabolic therapies, such as glycolytic inhibition alongside current standard of care, particularly in adult and pediatric gliomas. Additionally, because UCP2 correlates with tumor grade, monitoring serum protein levels in the future may allow clinicians a relatively minimally invasive marker to correlate with disease progression. Further investigation of UCP2’s role in metabolic reprogramming is warranted to fully appreciate its clinical translatability and utility.

scholarly journals Endoscopic Ultrasound-Guided Intratumoural Therapy for Pancreatic Cancer

2008 ◽  
Vol 22 (4) ◽  
pp. 405-410 ◽  
Author(s):  
Brian M Yan ◽  
Jacques Van Dam
Keyword(s):  
Pancreatic Cancer ◽  
Endoscopic Ultrasound ◽  
Standard Of Care ◽  
Current Standard ◽  
Interventional Eus ◽  
Therapeutic Modalities ◽  
Dismal Prognosis ◽  
Ablative Techniques ◽  
Fine Needle Injection ◽  
Pancreatic Cancer Therapy

Pancreatic cancer is the second most frequent gastrointestinal malignancy and carries a dismal prognosis. The current standard of care includes resection, if possible, as well as systemic chemoradiation therapy. Endoscopic ultrasound (EUS) is an established technique for the diagnosis and staging of pancreatic adenocarcinoma. Interventional EUS via fine needle injection (FNI) for the treatment of pancreatic cancer is a rapidly expanding field. The present article reviews the up-to-date developments in EUS FNI for intratumoural pancreatic cancer therapy, including antitumoural agents, immunotherapy, ablative techniques and new delivery systems. The therapeutic modalities discussed are currently under development and will hopefully reach clinical practice if benefit is demonstrated through clinical trials. EUS FNI may be an exciting new technique for the delivery of desperately needed novel therapies for pancreatic cancer.

scholarly journals Glioblastoma’s Next Top Model: Novel Culture Systems for Brain Cancer Radiotherapy Research

2018 ◽  
Author(s):  
Seamus P. Caragher ◽  
Anthony J. Chalmers ◽  
Natividad Gomez-Roman
Keyword(s):  
Mouse Models ◽  
Standard Of Care ◽  
Primary Brain Tumor ◽  
Current Standard ◽  
Meaningful Improvement ◽  
Nutrient Sources ◽  
Culture Systems ◽  
Novel Treatments ◽  
Wide Range

Glioblastoma (GBM), the most common and aggressive primary brain tumor in adults, remains one of the least treatable cancers. Current standard of care—combining surgical resection, radiation, and alkylating chemotherapy—results in a median survival of only 15 months. Despite decades of investment and research into the development of new therapies, most candidate anti-glioma compounds fail to translate into effective treatments in clinical trials. One key issue underlying this failure of therapies that work in pre-clinical models to generate meaningful improvement in human patients is the profound mismatch between drug discovery systems—cell cultures and mouse models—and the actual tumors they are supposed to imitate. Indeed, current strategies that evaluate the effects of novel treatments on GBM cells in vitro fail to account for a wide range of factors known to influence tumor growth. These include secreted factors, the brain’s unique extracellular matrix, circulatory structures, the presence of non-tumor brain cells, and nutrient sources available for tumor metabolism. While mouse models provide a more realistic testing ground for potential therapies, they still fail to account for the full complexity of tumor-microenvironment interactions, as well as the role of the immune system. Based on the limitations of current models, researchers have begun to develop and implement novel culture systems that better recapitulate the complex reality of brain tumors growing in situ. A rise in the use of patient derived cells, creative combinations of added growth factors and supplements, may provide a more effective proving ground for the development of novel therapies. This review will summarize and analyze these exciting developments in 3D culturing systems. Special attention will be paid to how they enhance the design and identification of compounds that increase the efficacy of radiotherapy, a bedrock of GBM treatment.

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