Novel Therapies for Glioblastoma

Liu, Elisa K.; Sulman, Erik P.; Wen, Patrick Y.; Kurz, Sylvia C.

doi:10.1007/s11910-020-01042-6

Cited by 58 publications

(40 citation statements)

References 97 publications

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“…However, anti-tumor immune responses have been observed in brain tumors [ 59 ], which are proposed to be facilitated by the presence of a lymphatic system [ 60 ]. In general, immunotherapy has been more successful in treating tumors with a high mutational burden [ 61 ], but GBM has a low tumor mutational burden, while also displaying an immunosuppressive environment [ 62 ], and the added complication that chemotherapeutics can also promote an immunosuppressive effect [ 63 ]. Nevertheless, as immunotherapy involves harnessing the immune system to eradicate tumor cells, several different strategies have been explored with the goal to boost host immunity against GBM.…”

Section: Therapeutic Strategies For Glioblastomamentioning

confidence: 99%

Novel Treatment Strategies for Glioblastoma

Stylli

2020

Cancers

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Glioblastoma (GBM) is the most common primary central nervous system tumor in adults. It is a highly invasive disease, making it difficult to achieve a complete surgical resection, resulting in poor prognosis with a median survival of 12–15 months after diagnosis, and less than 5% of patients survive more than 5 years. Surgical, instrument technology, diagnostic and radio/chemotherapeutic strategies have slowly evolved over time, but this has not translated into significant increases in patient survival. The current standard of care for GBM patients involving surgery, radiotherapy, and concomitant chemotherapy temozolomide (known as the Stupp protocol), has only provided a modest increase of 2.5 months in median survival, since the landmark publication in 2005. There has been considerable effort in recent years to increase our knowledge of the molecular landscape of GBM through advances in technology such as next-generation sequencing, which has led to the stratification of the disease into several genetic subtypes. Current treatments are far from satisfactory, and studies investigating acquired/inherent resistance to current therapies, restricted drug delivery, inter/intra-tumoral heterogeneity, drug repurposing and a tumor immune-evasive environment have been the focus of intense research over recent years. While the clinical advancement of GBM therapeutics has seen limited progression compared to other cancers, developments in novel treatment strategies that are being investigated are displaying encouraging signs for combating this disease. This aim of this editorial is to provide a brief overview of a select number of these novel therapeutic approaches.

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Section: Therapeutic Strategies For Glioblastomamentioning

confidence: 99%

Novel Treatment Strategies for Glioblastoma

Stylli

2020

Cancers

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“…Thus far, three major signaling pathways have been identified as the most deregulated ones in glioblastoma, namely, the activation of the receptor tyrosine kinase (RTK)/Ras/phosphoinositide 3-kinase (PI3K) pathway and inhibition of the p53 and retinoblastoma protein (Rb) signaling pathways (The Cancer Genome Atlas Research Network, 2008 [1]). Identification of new agents potentially capable of exploiting the metabolic sensitivity of cancer cells and their effect on molecular markers of GBM is necessary and obligatory [5][6][7][8]. The efficacy of small compounds with a potential inhibitory effect on the key signaling pathways in cancer cells has been evaluated [5,9].…”

Section: Introductionmentioning

confidence: 99%

Implications of Oxidative Stress in Glioblastoma Multiforme Following Treatment with Purine Derivatives

et al. 2021

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Recently, small compound-based therapies have provided new insights into the treatment of glioblastoma multiforme (GBM) by inducing oxidative impairment. Kinetin riboside (KR) and newly designed derivatives (8-azaKR, 7-deazaKR) selectively affect the molecular pathways crucial for cell growth by interfering with the redox status of cancer cells. Thus, these compounds might serve as potential alternatives in the oxidative therapy of GBM. The increased basal levels of reactive oxygen species (ROS) in GBM support the survival of cancer cells and cause drug resistance. The simplest approach to induce cell death is to achieve the redox threshold and circumvent the antioxidant defense mechanisms. Consequently, cells become more sensitive to oxidative stress (OS) caused by exogenous agents. Here, we investigated the effect of KR and its derivatives on the redox status of T98G cells in 2D and 3D cell culture. The use of spheroids of T98G cells enabled the selection of one derivative—7-deazaKR—with comparable antitumor activity to KR. Both compounds induced ROS generation and genotoxic OS, resulting in lipid peroxidation and leading to apoptosis. Taken together, these results demonstrated that KR and 7-deazaKR modulate the cellular redox environment of T98G cells, and vulnerability of these cells is dependent on their antioxidant capacity.

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“…Increasing evidence has revealed that autophagy is associated with therapeutic resistance in a stressful environment. In addition, studies have shown that autophagy in CSCs mediates therapeutic resistance [ 17 , 18 , 19 ]. Our study revealed that autophagy increased with GSC markers, including CD133, CD44, Nestin, and SOX2 and correlated with IR in dose- and fraction-dependent manners, especially the fraction-dependent manner (clinical manner).…”

Section: Discussionmentioning

confidence: 99%

“…Reports by investigators have showed that autophagy activity increased after IR and chemotherapy. It is an escape mechanism for cell survival in response to cytotoxic agents, including IR and Temozolomide (TMZ) in GBM treatment [ 18 , 19 ]. Although recent studies have revealed that autophagy could modulate CSCs in cancers, it is unclear whether autophagy activation is involved in IR-induced/enhanced/selected GSCs to result in radioresistance.…”

Section: Introductionmentioning

confidence: 99%

Ionizing Radiation Induces Resistant Glioblastoma Stem-Like Cells by Promoting Autophagy via the Wnt/β-Catenin Pathway

Tsai

Huang³

et al. 2021

Life

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Therapeutic resistance in recurrent glioblastoma multiforme (GBM) after concurrent chemoradiotherapy (CCRT) is a challenging issue. Although standard fractionated radiation is essential to treat GBM, it has led to local recurrence along with therapy-resistant cells in the ionizing radiation (IR) field. Lines of evidence showed cancer stem cells (CSCs) play a vital role in therapy resistance in many cancer types, including GBM. However, the molecular mechanism is poorly understood. Here, we proposed that autophagy could be involved in GSC induction for radioresistance. In a clinical setting, patients who received radiation/chemotherapy had higher LC3II expression and showed poor overall survival compared with those with low LC3 II. In a cell model, U87MG and GBM8401 expressed high level of stemness markers CD133, CD44, Nestin, and autophagy marker P62/LC3II after receiving standard fractionated IR. Furthermore, Wnt/β-catenin proved to be a potential pathway and related to P62 by using proteasome inhibitor (MG132). Moreover, pharmacological inhibition of autophagy with BAF and CQ inhibit GSC cell growth by impairing autophagy flux as demonstrated by decrease Nestin, CD133, and SOX-2 levels. In conclusion, we demonstrated that fractionated IR could induce GSCs with the stemness phenotype by P62-mediated autophagy through the Wnt/β-catenin for radioresistance. This study offers a new therapeutic strategy for targeting GBM in the future.

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Novel Therapies for Glioblastoma

Cited by 58 publications

References 97 publications

Novel Treatment Strategies for Glioblastoma

Novel Treatment Strategies for Glioblastoma

Implications of Oxidative Stress in Glioblastoma Multiforme Following Treatment with Purine Derivatives

Ionizing Radiation Induces Resistant Glioblastoma Stem-Like Cells by Promoting Autophagy via the Wnt/β-Catenin Pathway

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