Oncolytic myxoma virus synergizes with standard of care for treatment of glioblastoma multiforme

Gliomas are the most common type of brain tumor that occur in adults and children. Glioblastoma multiforme (GBM) is the most common, aggressive form of brain cancer in adults and is universally fatal. The current standard-of-care options for GBM include surgical resection, radiotherapy, and concomitant and/or adjuvant chemotherapy. One of the major challenges that impedes success of chemotherapy is the presence of the blood–brain barrier (BBB). Because of the tightly regulated BBB, immune surveillance in the central nervous system (CNS) is poor, contributing to unregulated glioma cell growth. This review gives a comprehensive overview of the latest advances in treatment of GBM with emphasis on the significant advances in immunotherapy and novel therapeutic delivery strategies to enhance treatment for GBM.

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Direct Evidence of Plasticity within Human Primary Motor and Somatosensory Cortices of Patients with Glioblastoma

Neural Plasticity ◽

10.1155/2020/8893708 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

William R. Gibb ◽

Nathan W. Kong ◽

Matthew C. Tate

Keyword(s):

Glioblastoma Multiforme ◽

Direct Evidence ◽

Standard Of Care ◽

Extent Of Resection ◽

Brain Regions ◽

Primary Brain Tumor ◽

Indirect Measures ◽

Somatosensory Cortices ◽

New Finding ◽

Subcortical Regions

Glioblastoma multiforme (GBM) is a devastating disease without cure. It is also the most common primary brain tumor in adults. Although aggressive surgical resection is standard of care, these operations are limited by tumor infiltration of critical cortical and subcortical regions. A better understanding of how the brain can recover and reorganize function in response to GBM would provide valuable clinical data. This ability, termed neuroplasticity, is not well understood in the adult human brain. A better understanding of neuroplasticity in GBM could allow for improved extent of resection, even in areas classically thought to have critical, static function. The best evidence to date has demonstrated neuroplasticity only in slower growing tumors or through indirect measures such as functional MRI or transcranial magnetic stimulation. In this novel study, we utilize a unique experimental paradigm to show direct evidence of plasticity via serial direct electrocortical stimulation (DES) within primary motor (M1) and somatosensory (S1) cortices in GBM patients. Six patients with glioblastoma multiforme in or near the primary motor or somatosensory cortex were included in this retrospective observational study. These patients had two awake craniotomies with DES to map cortical motor and sensory sites in M1 and S1. Five of six patients exhibited at least one site of neuroplasticity within M1 or S1. Out of the 51 total sites stimulated, 32 (62.7%) demonstrated plasticity. Of these sites, 14 (43.7%) were in M1 and 18 (56.3%) were in S1. These data suggest that even in patients with GBM in or near primary brain regions, significant functional reorganization is possible. This is a new finding which may lead to a better understanding of the fundamental factors promoting or inhibiting plasticity. Further exploration may aid in treatment of patients with brain tumors and other neurologic disorders.

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Radiotherapy with concurrent and adjuvant temozolomide: a new standard of care for glioblastoma multiforme

Progress in Neurotherapeutics and Neuropsychopharmacology ◽

10.1017/cbo9780511663529.005 ◽

2010 ◽

pp. 37-52 ◽

Cited By ~ 1

Author(s):

Warren P. Mason ◽

René O. Mirimanoff ◽

Roger Stupp

Keyword(s):

Glioblastoma Multiforme ◽

Standard Of Care ◽

Adjuvant Temozolomide

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ReoGlio: REOLYSIN® plus GM-CSF in combination with standard of care chemotherapy and radiotherapy for patients with glioblastoma multiforme (GBM)

http://isrctn.com/ ◽

10.1186/isrctn70044565 ◽

2017 ◽

Author(s):

Amber Reid

Keyword(s):

Glioblastoma Multiforme ◽

Standard Of Care ◽

Gm Csf

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BRCAness as a Biomarker of Susceptibility to PARP Inhibitors in Glioblastoma Multiforme

Biomolecules ◽

10.3390/biom11081188 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1188

Author(s):

Mary-Ann Xavier ◽

Fernando Rezende ◽

Ricardo Titze-de-Almeida ◽

Bart Cornelissen

Keyword(s):

Glioblastoma Multiforme ◽

Growth Factor Receptor ◽

Standard Of Care ◽

Parp Inhibitors ◽

Genetic Alterations ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Damage Repair ◽

Cancer Types ◽

Epidermal Growth

Glioblastoma multiforme (GBM) is the most common primary brain cancer. GBMs commonly acquire resistance to standard-of-care therapies. Among the novel means to sensitize GBM to DNA-damaging therapies, a promising strategy is to combine them with inhibitors of the DNA damage repair (DDR) machinery, such as inhibitors for poly(ADP-ribose) polymerase (PARP). PARP inhibitors (PARPis) have already shown efficacy and have received regulatory approval for breast, ovarian, prostate, and pancreatic cancer treatment. In these cancer types, after PARPi administration, patients carrying specific mutations in the breast cancer 1 (BRCA1) and 2 (BRCA2) suppressor genes have shown better response when compared to wild-type carriers. Mutated BRCA genes are infrequent in GBM tumors, but their cells can carry other genetic alterations that lead to the same phenotype collectively referred to as ‘BRCAness’. The most promising biomarkers of BRCAness in GBM are related to isocitrate dehydrogenases 1 and 2 (IDH1/2), epidermal growth factor receptor (EGFR), phosphatase and tensin homolog (PTEN), MYC proto-oncogene, and estrogen receptors beta (ERβ). BRCAness status identified by accurate biomarkers can ultimately predict responsiveness to PARPi therapy, thereby allowing patient selection for personalized treatment. This review discusses potential biomarkers of BRCAness for a ‘precision medicine’ of GBM patients.

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Multiprong control of glioblastoma multiforme invasiveness: blockade of pro-inflammatory signaling, anti-angiogenesis, and homeostasis restoration

Cancer and Metastasis Reviews ◽

10.1007/s10555-021-09987-x ◽

2021 ◽

Author(s):

Nicolas G. Bazan ◽

Madigan M. Reid ◽

Valerie A. Cruz Flores ◽

Juan E. Gallo ◽

William Lewis ◽

...

Keyword(s):

Overall Survival ◽

Glioblastoma Multiforme ◽

Platelet Activating Factor ◽

Angiogenesis Inhibitor ◽

Standard Of Care ◽

Lipid Mediator ◽

Glial Tumor ◽

Poor Overall Survival ◽

Adaptive Mutations ◽

Novel Host

AbstractGlioblastoma multiforme (GBM) is the most invasive type of glial tumor with poor overall survival, despite advances in surgical resection, chemotherapy, and radiation. One of the main challenges in treating GBM is related to the tumor’s location, complex and heterogeneous biology, and high invasiveness. To meet the demand for oxygen and nutrients, growing tumors induce new blood vessels growth. Antibodies directed against vascular endothelial growth factor (VEGF), which promotes angiogenesis, have been developed to limit tumor growth. Bevacizumab (Avastin), an anti-VEGF monoclonal antibody, is the first approved angiogenesis inhibitor with therapeutic promise. However, it has limited efficacy, likely due to adaptive mutations in GBM, leading to overall survival compared to the standard of care in GBM patients. Molecular connections between angiogenesis, inflammation, oxidative stress pathways, and the development of gliomas have been recognized. Improvement in treatment outcomes for patients with GBM requires a multifaceted approach due to the converging dysregulation of signaling pathways. While most GBM clinical trials focus on “anti-angiogenic” modalities, stimulating inflammation resolution is a novel host-centric therapeutic avenue. The selective therapeutic possibilities for targeting the tumor microenvironment, specifically angiogenic and inflammatory pathways expand. So, a combination of agents aiming to interfere with several mechanisms might be beneficial to improve outcomes. Our approach might also be combined with other therapies to enhance sustained effectiveness. Here, we discuss Suramab (anti-angiogenic), LAU-0901 (a platelet-activating factor receptor antagonist), Elovanoid (ELV; a novel lipid mediator), and their combination as potential alternatives to contain GBM growth and invasiveness.

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P.038 Investigating the role of long non-coding RNAs in glioblastoma multiforme

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2018.140 ◽

2018 ◽

Vol 45 (s2) ◽

pp. S26-S26

Author(s):

A Lebel ◽

V Charest ◽

P Whitlock ◽

D Charest ◽

P Morin

Keyword(s):

Survival Rate ◽

Glioblastoma Multiforme ◽

Brain Tumors ◽

Malignant Gliomas ◽

Standard Of Care ◽

Qrt Pcr ◽

Resistance Modulation ◽

Non Coding Rnas ◽

One Year

Background: Malignant gliomas are the most common and deadly brain tumors. Mean survival rate for a patient diagnosed with a glioblastoma multiforme (GBM) remains slightly over one year. Standard of care consists of treatment with temozolomide (TMZ) and radiotherapy. Recent work has highlighted functions of long non-coding RNAs (lncRNAs) in GBM progression and TMZ response even though the information regarding these newly discovered molecules is sparse. The overarching objective of this project was thus to assess the expression of select lncRNAs in GBM tumor samples and in models of TMZ resistance. Methods: A qRT-PCR-based approach was undertaken to measure six lncRNAs in 19 primary GBM samples, four GBM cell lines and in-house developed TMZ-resistant GBM cells. Results: Elevated levels of Hotair and H19 were observed in primary GBM tumors while decreased expression of MEG3 was recorded in the same samples. Interestingly, levels of PANDA increased 3.4-fold in GBM cells resistant to TMZ when compared with their sensitive counterparts. Conclusions: Overall, this work provides evidence of lncRNA deregulation in GBM tumors and reveals a previously unexplored lncRNA potentially involved in TMZ resistance. Modulation of lncRNA targets via RNAi-mediated approaches is envisioned to clarify their function and to strengthen their position as therapeutic options in GBMs.

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Using Light for Therapy of Glioblastoma Multiforme (GBM)

Brain Sciences ◽

10.3390/brainsci10020075 ◽

2020 ◽

Vol 10 (2) ◽

pp. 75 ◽

Cited By ~ 5

Author(s):

Alex Vasilev ◽

Roba Sofi ◽

Ruman Rahman ◽

Stuart J. Smith ◽

Anja G. Teschemacher ◽

...

Keyword(s):

Glioblastoma Multiforme ◽

Protoporphyrin Ix ◽

Standard Of Care ◽

Toxic Effects ◽

Current Standard ◽

Molecular Fingerprint ◽

Light Delivery ◽

Primary Brain Tumour ◽

The Brain ◽

Selective Accumulation

Glioblastoma multiforme (GBM) is the most malignant form of primary brain tumour with extremely poor prognosis. The current standard of care for newly diagnosed GBM includes maximal surgical resection followed by radiotherapy and adjuvant chemotherapy. The introduction of this protocol has improved overall survival, however recurrence is essentially inevitable. The key reason for that is that the surgical treatment fails to eradicate GBM cells completely, and adjacent parenchyma remains infiltrated by scattered GBM cells which become the source of recurrence. This stimulates interest to any supplementary methods which could help to destroy residual GBM cells and fight the infiltration. Photodynamic therapy (PDT) relies on photo-toxic effects induced by specific molecules (photosensitisers) upon absorption of photons from a light source. Such toxic effects are not specific to a particular molecular fingerprint of GBM, but rather depend on selective accumulation of the photosensitiser inside tumour cells or, perhaps their greater sensitivity to the effects, triggered by light. This gives hope that it might be possible to preferentially damage infiltrating GBM cells within the areas which cannot be surgically removed and further improve the chances of survival if an efficient photosensitiser and hardware for light delivery into the brain tissue are developed. So far, clinical trials with PDT were performed with one specific type of photosensitiser, protoporphyrin IX, which tends to accumulate in the cytoplasm of the GBM cells. In this review we discuss the idea that other types of molecules which build up in mitochondria could be explored as photosensitisers and used for PDT of these aggressive brain tumours.

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20 Disparities in survival for patients with glioblastoma multiforme

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2018.262 ◽

2018 ◽

Vol 45 (S3) ◽

pp. S4-S4

Author(s):

Mostafa Fatehi ◽

Camille Hunt ◽

Roy Ma ◽

Brian Toyota

Keyword(s):

British Columbia ◽

Overall Survival ◽

Glioblastoma Multiforme ◽

Median Overall Survival ◽

Performance Status ◽

Treatment Strategies ◽

Standard Of Care ◽

Extent Of Resection ◽

Pathologic Classification ◽

Genetic Features

Background: Glioblastoma multiforme (GBM) is the most common malignant primary brain cancer in adults. Recent efforts have elucidated genetic features of tumor cells and thus enhanced our knowledge of GBM pathophysiology. The most recent clinical trials report median overall survival between 14 and 20 months. However, real-world outcomes are quite variable and there is a paucity of data within the literature. Methods: Three hundred seventy two GBM patients were diagnosed in the province of British Columbia between January 2013 and January 2015. We have performed a retrospective review on the survival outcomes of the 278 patients who underwent surgical resection as part of the initial treatment. Results: Our results indicate a median age of 61.8y at time of diagnosis with a slight preponderance of males. The median overall survival was 10 months for patients who underwent surgery. As expected, patients over the age of 65 and those with worse initial Karnofsy Performance Status (KPS) scores had a poorer prognosis. Moreover, we have found extent of resection (EOR), treatment strategies and treatment location affect overall survival. Conclusion: The present study highlights factors which affect patient survival after surgery in British Columbia. Our outcomes are slightly worse than survival reported in the US. Variability in pathologic classification and in treatment strategy likely contribute to this difference. Further efforts should ensure access to the gold-standard of care.

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NCOG-27. INCREASED OVERALL SURVIVAL AMONG RACIAL MINORITIES AND SUBOPTIMAL USE OF STANDARD OF CARE TREATMENT IN GLIOBLASTOMA MULTIFORME

Neuro-Oncology ◽

10.1093/neuonc/noaa215.565 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii134-ii135

Author(s):

Stephanie Boisclair ◽

Shenae Samuels ◽

Arjun Khunger ◽

Delia A Wietecha ◽

Alejandro Lopez Cohen ◽

...

Keyword(s):

Palliative Care ◽

Overall Survival ◽

Glioblastoma Multiforme ◽

Academic Research ◽

Surgical Techniques ◽

Standard Of Care ◽

Poor Overall Survival ◽

Asian Ethnicity ◽

Weibull Regression ◽

Significant Difference

Abstract Glioblastoma Multiforme (GBM) is the most common primary central nervous system (CNS) tumor and is always considered grade IV given its aggressive nature and poor overall survival (OS). Despite advancements in surgical techniques and cancer therapies, GBM treatment has remained the same since 2005: total resection followed by temozolomide and radiation. We hypothesized that OS has increased over the years and is similar among all races/ethnic groups without reduction of mortality based upon treatment facility. METHODS: The National Cancer Database from 2004-2016 was utilized to obtain demographic, tumor and treatment factors of GBM (excluding gliosarcomas). Multivariate Weibull regression model was used to evaluate prognostic factors for OS in months(m). RESULTS: A total of 119,496 patients were identified. There was a significant difference(P=0.000) in OS for patients diagnosed in 2012-2016 (10.2m) compared to 2008-2011 (9.2m) and 2004-2007 (8.1m). Among racial groups, the highest incidence was among whites (91.8%) whom also had the lowest OS (9.0m), followed by Blacks (10.5m), Hispanics (11.7m) and Asians (12.9m)(P=0.000). Patients with unilateral tumors (72.1%) and tumor size < 3cm (18.3%) had an increased OS (9.8m-10.2m and 11.2m, respectively) compared with patients having bilateral tumors or larger size ≥ 3cm (OS of 4.8m and 8.9m, respectively)(P=0.000). Increasing age (HR=1.03) and comorbidity score ≥ 3 (HR=1.40) were independent predictors of death (P=0.000), while female sex (HR=0.88), Asian ethnicity (HR=0.75) and treatment at an academic/research facility (HR=0.86) were independent predictors of survival(P< 0.01). Only 60.1% of patients (n=59,112) received ideal treatment (surgery, chemotherapy and radiation), while only 3.2% of all GBM patients received palliative care. DISCUSSION: Decreased OS was found among white race, large and bilateral tumors. Despite a statistically significant, although minimal, increase in OS since 2004-2007, there is notable underutilization of ideal treatment and palliative care. Further studies should focus on access inequalities and limitations to treatment.

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