Frontiers in the treatment of glioblastoma: Past, present and emerging

Janjua, Taskeen Iqbal; Rewatkar, Prarthana; Ahmed-Cox, Aria; Saeed, Iqira; Mansfeld, Friederike M.; Kulshreshtha, Ritu; Kumeria, Tushar; Ziegler, David S.; Kavallaris, Maria; Mazzieri, Roberta; Popat, Amirali

doi:10.1016/j.addr.2021.01.012

Cited by 170 publications

(142 citation statements)

References 389 publications

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“…Development of glioma-specific nanoparticles (NPs) has been an area of intense research over the past years. These drug delivery systems (DDS) have the capacity to be loaded with therapeutic agents and functionalized with different ligands (e.g., transferrin, chlorotoxin (CTX), hyaluronic acid) that allow targeting and crossing the BBB [ 63 , 64 ]. Thus, in this strategy, the ability to cross the BBB does not depend on the structure of the drug, but on the physicochemical properties of the NP, which can be improved.…”

Section: Nanotechnology To Improve Anti-glioblastoma Drugsmentioning

confidence: 99%

“…Thus, in this strategy, the ability to cross the BBB does not depend on the structure of the drug, but on the physicochemical properties of the NP, which can be improved. NP play an important role in the release of drugs through the BBB by passive diffusion, which results in a high concentration gradient between the blood and the brain and have the ability to diffuse in the vasculature with leakage of tumor tissues due to the increase in permeability and retention effect [ 64 , 65 ]. The deficient lymphatic drainage allows the NP to reach concentrations much higher than their concentrations in plasma [ 66 ].…”

Section: Nanotechnology To Improve Anti-glioblastoma Drugsmentioning

confidence: 99%

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Small Molecules of Marine Origin as Potential Anti-Glioma Agents

et al. 2021

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Marine organisms are able to produce a plethora of small molecules with novel chemical structures and potent biological properties, being a fertile source for discovery of pharmacologically active compounds, already with several marine-derived agents approved as drugs. Glioma is classified by the WHO as the most common and aggressive form of tumor on CNS. Currently, Temozolomide is the only chemotherapeutic option approved by the FDA even though having some limitations. This review presents, for the first time, a comprehensive overview of marine compounds described as anti-glioma agents in the last decade. Nearly fifty compounds were compiled in this document and organized accordingly to their marine sources. Highlights on the mechanism of action and ADME properties were included. Some of these marine compounds could be promising leads for the discovery of new therapeutic alternatives for glioma treatment.

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Section: Nanotechnology To Improve Anti-glioblastoma Drugsmentioning

confidence: 99%

Section: Nanotechnology To Improve Anti-glioblastoma Drugsmentioning

confidence: 99%

Small Molecules of Marine Origin as Potential Anti-Glioma Agents

et al. 2021

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“…After the EORTC 26981-22981/NCIC CE3 trial, which demonstrated the efficacy of TMZ combined with RT in prolonging patients survival, all subsequent randomized studies assessing the efficacy of new treatments against high grade gliomas (HGG) invariably failed, despite being based on apparently good preclinical results [7]. The most recent case is that of the checkpoint inhibitor Nivolumab (anti programmed cell death protein 1 (PD1)): despite "successful" preclinical studies, three different randomized trials in patients were uncapable to demonstrate a survival benefit in the experimental arm compared to controls [8][9][10].…”

Section: Discussionmentioning

confidence: 99%

“…Such dismal prognosis did not substantially changed in the last 15 years [1]. Despite the fact that many treatments have been proven to be effective in preclinical testing, none of them was capable to significantly prolong patients survival [7]. Even the most recent randomized clinical trials for checkpoints inhibitors showed negative results despite being supported by seemingly good preclinical data, confirming the presence of a significant translational gap between the preclinical setting and the clinical reality [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Towards more accurate preclinical glioblastoma modelling: reverse translation of clinical standard of care in a glioblastoma mouse model

Riva

Bevers

Wouters

et al. 2021

Preprint

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Introduction: Contrarily to clinical trials, where glioblastoma (GBM) patients are usually heavily pre-treated (surgery, radio-therapy (RT) and temozolomide (TMZ)) before receiving the experimental therapies, in preclinical GBM studies experimental treatments have mostly been administered as monotherapy or combined with a very limited part of the clinical standard of care. This discrepancy can explain the failed clinical translation of preclinically successful treatments. This study is aimed at evaluat-ing the feasibility and survival impact of the clinical standard of care in glioma-bearing mice. Methods. Neurospheres CT-2A tumor-bearing mice were treated with fluorescence-guided tumor resection, focal RT and oral TMZ. Results: The implementation of postoperative intensive care treatment reduced surgical mortality by approximately 50% and increased experimental cost-effectiveness. Partial and total tumor resection significantly prolonged survival, the latter showing the strongest effect. Mice treated with surgery combined with RT or with RT and TMZ survived significantly longer than un-treated controls. Conclusions: Implementing the current GBM clinical standard of care in preclinical research is feasible and it leads to results in line with those obtained in patients. Systematic preclinical evaluation of the efficacy of experimental therapies in combination with standard of care treatments could improve the translational impact of next generation GBM animal studies.

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“…For example, the DNA alkylating drug Temozolomide (TMZ), with a molecular weight of 194.154 g/mol and poor solubility in water, readily crosses the BBB and is one of the few treatments available for glioblastoma multiforme (GBM) [ 15 , 16 ]. However, it should be noted that a high degree of lipid solubility alone does not guarantee successful accumulation of meaningful drug concentrations in the brain, since drugs may still be metabolized or removed by efflux pumps [ 17 , 18 ]. Drugs bound to plasma proteins are also unavailable for crossing the BBB, since those proteins may only cross the BBB via specific transporters.…”

Section: Introductionmentioning

confidence: 99%

Emerging Nano-Carrier Strategies for Brain Tumor Drug Delivery and Considerations for Clinical Translation

2021

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Treatment of brain tumors is challenging since the blood–brain tumor barrier prevents chemotherapy drugs from reaching the tumor site in sufficient concentrations. Nanomedicines have great potential for therapy of brain disorders but are still uncommon in clinical use despite decades of research and development. Here, we provide an update on nano-carrier strategies for improving brain drug delivery for treatment of brain tumors, focusing on liposomes, extracellular vesicles and biomimetic strategies as the most clinically feasible strategies. Finally, we describe the obstacles in translation of these technologies including pre-clinical models, analytical methods and regulatory issues.

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Frontiers in the treatment of glioblastoma: Past, present and emerging

Cited by 170 publications

References 389 publications

Small Molecules of Marine Origin as Potential Anti-Glioma Agents

Small Molecules of Marine Origin as Potential Anti-Glioma Agents

Towards more accurate preclinical glioblastoma modelling: reverse translation of clinical standard of care in a glioblastoma mouse model

Emerging Nano-Carrier Strategies for Brain Tumor Drug Delivery and Considerations for Clinical Translation

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