Treatment of Pediatric Glioblastoma with Combination Olaparib and Temozolomide Demonstrates 2-Year Durable Response.

In this report, we present the case of a 3-year-old girl with glioblastoma who continues to experience an exceptional and durable response (>2 years) to the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib. Our patient presented with persistent and progressive seizure activity that upon workup was the result of a large heterogeneously enhancing, mixed cystic and solid mass in the left frontal-parietal-temporal region. Histopathologic analysis of resected tumor tissue confirmed the diagnosis of glioblastoma, and comprehensive genomic profiling demonstrated absence of any BRAF or H3F3A mutations. Genomic profiling, however, did reveal a probable germline heterozygous BRCA2 Lys3326Ter (K3226*) nonsense variant. After debulking surgery, the patient received standard-of-care treatment with radiation and temozolomide. Nine months later the PARP inhibitor olaparib was administered in combination with temozolomide for 16 cycles. This regimen was well tolerated by the patient and serial imaging showed reduction in tumor size. Since completion of the regimen, the patient remains neurologically intact with no evidence of tumor recurrence. To our knowledge, this represents the first case of a pediatric glioblastoma that maintains a durable response to a therapeutic strategy that included the PARP inhibitor olaparib and more generally highlights the potential clinical utility of incorporating these agents into the treatment of pediatric high-grade gliomas. KEY POINTS: Germ...
Source: The Oncologist - Category: Cancer & Oncology Authors: Tags: Oncologist Source Type: research

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SummaryThe PI3K/AKT/mTOR pathway activation plays a central role in glioblastoma multiforme (GBM) development and progression, and in resistance to anti-cancer therapies. Inhibition of the PI3K pathway has been shown to sensitize cultured glioma cells and tumor xenografts to the effects of temozolomide (TMZ) and radiation. Vistusertib is an oral inhibitor of mTORC1/2 complexes. The primary objective of this Canadian Cancer Trials Group phase I study was to determine the recommended phase II dose (RP2D) of vistusertib in patients with GBM receiving TMZ at first progression following primary treatment. Vistusertib was admini...
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research
Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): David H. Gutmann, Helmut KettenmannOne of the most common brain tumors in children and adults is glioma or astrocytoma. There are few effective therapies for these cancers, and patients with malignant glioma fare poorly, even after aggressive surgery, chemotherapy, and radiation. Over the past decade, it is now appreciated that these tumors are composed of numerous distinct neoplastic and non-neoplastic cell populations, which could each influence overall tumor biology and response to therapy. Among these noncancerous cell types, monocytes (micr...
Source: Neuron - Category: Neuroscience Source Type: research
Authors: Roshandel AK, Busch CM, Mullekom JV, Cuoco JA, Rogers CM, Apfel LS, Marvin EA, Sontheimer HW, Umans RA Abstract Tumor protein 53 (p53) regulates fundamental pathways of cellular growth and differentiation. Aberrant p53 expression in glioblastoma multiforme, a terminal brain cancer, has been associated with worse patient outcomes and decreased chemosensitivity. Therefore, correctly identifying p53 status in glioblastoma is of great clinical significance. p53 immunohistochemistry is used to detect pathological presence of the TP53 gene product. Here, we examined the relationship between p53 immunoreactivity ...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
In the dog, primary intracranial neoplasia represents ~2–5% of all cancers and is especially common in certain breeds including English and French bulldogs and Boxers. The most common types of primary intracranial cancer in the dog are meningioma, glioma, and choroid plexus tumors, generally occurring in middle aged to older dogs. Much work has recently been done to understand the characteristic imaging and clinicopathologic features of these tumors. The gross and histologic landscape of these tumors in the dog compare favorably to their human counterparts with many similarities noted in histologic patterns, subtype,...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
ConclusionsAt present, we conclude that current evidence does not support the widespread use of TMZ over PCV for all patients with high ‐risk LGG, and we instead recommend tailoring chemotherapy recommendation based onIDH status, favoring adjuvant PCV for patients with anyIDH mutant tumors, both those that harbor 1p/19q codeletion and those non ‐1p/19q codeleted. Given the critical role radiation plays in the treatment of LGG, radiation oncologists should be actively involved in discussions regarding chemotherapy choice in order to optimize treatment for their patients.
Source: Cancer Medicine - Category: Cancer & Oncology Authors: Tags: REVIEW Source Type: research
Abstract Xanthatin is a natural sesquiterpene lactone purified from Xanthium strumarium L., which has shown prominent antitumor activity against a variety of cancer cells. In the current study, we investigated the effect of xanthatin on the growth of glioma cells in vitro and in vivo, and elucidated the underlying mechanisms. In both rat glioma C6 and human glioma U251 cell lines, xanthatin (1-15 μM) dose-dependently inhibited cell viability without apparent effect on the cell cycle. Furthermore, xanthatin treatment dose-dependently induced glioma cell apoptosis. In nude mice bearing C6 glioma tumor xeno...
Source: Acta Pharmacologica Sinica - Category: Drugs & Pharmacology Authors: Tags: Acta Pharmacol Sin Source Type: research
Gliomas are the most common malignant primary brain tumors with poor prognosis. The migration-inducing gene-7 (Mig-7) protein is a cysteine-rich protein. Vasculogenic mimicry can replace endothelium-dependent blood vessels and supply blood to tumors, thus promoting tumor invasion and metastasis. They have also been shown to play critical roles in the development and progression of various cancers. We attempted to explore the role of Mig-7 and vasculogenic mimicry in glioma progression. We demonstrated that Mig-7 and vasculogenic mimicry were not expressed in normal tissues. In glioma, Mig-7 expression was positively associ...
Source: NeuroReport - Category: Neurology Tags: Cellular, Molecular and Developmental Neuroscience Source Type: research
Glioma is the most common central nervous system (CNS) tumour. p62, an important autophagy adaptor, plays a crucial role in cancer. However, the role of p62 in the progression of glioma is poorly characterized.
Source: Cancer Cell International - Category: Cancer & Oncology Authors: Tags: Primary research Source Type: research
Abstract Glioblastoma (GBM), a primary malignant tumor of the central nervous system, has a very poor prognosis. Analysis of global GBM samples has revealed a variety of long non-coding RNAs (lncRNAs) associated with prognosis; nevertheless, there remains a lack of accurate prognostic markers. Using RNA-Seq, methylation, copy number variation (CNV), mutation and clinical follow-up data for GBM patients from The Cancer Genome Atlas, we performed univariate analysis, multi-cluster analysis, differential analysis of different subtypes of lncRNA and coding genes, weighted gene co-expression network analyses, gene set ...
Source: Aging - Category: Biomedical Science Authors: Tags: Aging (Albany NY) Source Type: research
Purpose of review Checkpoint inhibitors (CPIs) represent the forefront of novel immunotherapeutic approaches for the treatment of solid cancers. However, the clinical development of CPIs in glioblastoma (GBM) has been challenging owing to an immunosuppressive tumor microenvironment and, possibly, low tumor mutation burden. Here, we review possible mechanisms responsible for the success of programmed cell death-1 (PD-1) blockade in patients with hypermutated GBM, recent clinical trials of anti-PD-1 monotherapy, trials incorporating neoadjuvant strategies, and trials of immunotherapy combination approaches in GBM. Mechanis...
Source: Current Opinion in Neurology - Category: Neurology Tags: NEOPLASMS: Edited by Antonio Omuro Source Type: research
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