Convection-enhanced delivery of etoposide is effective against murine proneural glioblastoma

Sonabend, Adam M.; Carminucci, Arthur; Amendolara, Benjamin; Bansal, Mukesh; Leung, Richard; Liu, Liang; Realubit, Ronald; Li, Hai; Karan, Charles; Yun, Jonathan; Showers, Christopher; Rothcock, Robert; Jane, O; Califano, Andrea; Canoll, Peter; Bruce, Jeffrey N.

doi:10.1093/neuonc/nou026

Cited by 36 publications

(38 citation statements)

References 37 publications

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“…Another limitation is balancing efficacy while avoiding the dose limiting bone marrow suppression seen with systemic administration. This raises the possibility of administering KIF11 inhibitors intracerebrally with technologies that are being used clinically, such as convection-enhanced delivery (CED), which would provide for prolonged intracerebral CED using a subcutaneous implantable infusion pump (50). These considerations make clear that KIF11 inhibitors may be relevant therapies for GBM, particularly when combined with existing treatments.…”

Section: Discussionmentioning

confidence: 99%

The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma

et al. 2015

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The proliferative and invasive nature of malignant cancers drives lethality. In glioblastoma, these two processes are presumed mutually exclusive and hence termed “go or grow”. Here, we identified a molecular target that shuttles between these disparate cellular processes—the molecular motor KIF11. Inhibition of KIF11 with a highly specific small molecule inhibitor stopped the growth of both the more treatment resistant glioblastoma tumor initiating cells (TICs, or cancer stem cells) as well as non-TICs and impeded tumor initiation and self-renewal of the TIC population. Targeting KIF11 also hit the other arm of the “go or grow” cell fate decision by reducing glioma cell invasion. Administration of a KIF11 inhibitor to mice bearing orthotopic glioblastoma prolonged their survival. In its role as a shared molecular regulator of cell growth and motility across intratumoral heterogeneity, KIF11 is a compelling target for glioblastoma.

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Section: Discussionmentioning

confidence: 99%

The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma

et al. 2015

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“…18 Various antineoplastic agents, mostly immunotoxins, are under investigation for use through CED. 59,62,84,100,107 Another approach involves chemotherapeutic delivery via CED of nanoparticles. 14,128 Although these studies have demonstrated effectiveness in vivo, more work must be conducted to investigate the long-term effects of potential accumulations of the nanoparticles in the brain.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Therapeutic strategies to improve drug delivery across the blood-brain barrier

Azad¹,

Pan²,

Connolly³

et al. 2015

FOC

107

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Resection of brain tumors is followed by chemotherapy and radiation to ablate remaining malignant cell populations. Targeting these populations stands to reduce tumor recurrence and offer the promise of more complete therapy. Thus, improving access to the tumor, while leaving normal brain tissue unscathed, is a critical pursuit. A central challenge in this endeavor lies in the limited delivery of therapeutics to the tumor itself. The blood-brain barrier (BBB) is responsible for much of this difficulty but also provides an essential separation from systemic circulation. Due to the BBB's physical and chemical constraints, many current therapies, from cytotoxic drugs to antibody-based proteins, cannot gain access to the tumor. This review describes the characteristics of the BBB and associated changes wrought by the presence of a tumor. Current strategies for enhancing the delivery of therapies across the BBB to the tumor will be discussed, with a distinction made between strategies that seek to disrupt the BBB and those that aim to circumvent it.

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“…Consistent with our expectation, OncoTreat analysis of Patel et al cells revealed that individual drugs are predicted to have highly quadrant-specific sensitivity. For instance, sensitivity to etoposide was predicted to be highest in proliferative proneural cells (Figure 7A), confirming that etoposide is an effective treatment for proneural GBM mouse models (Sonabend et al, 2014); in contrast, sensitivity to RO4929097 was higher in mesenchymal vs. proneural cells (Figure 7B). Finally, panobinostat sensitivity was highest in proliferative cells, independent of their mesenchymal vs. proneural status (Figure 7C).…”

Section: Resultsmentioning

confidence: 54%

Single-cell based elucidation of molecularly-distinct glioblastoma states and drug sensitivity

Ding

Burgenske

Zhao

et al. 2019

Preprint

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Glioblastoma heterogeneity and plasticity remain controversial, with proposed subtypes representing the average of highly heterogeneous admixtures of independent transcriptional states. Single-cell, protein-activity-based analysis allowed full quantification of >6,000 regulatory and signaling proteins, thus providing a previously unattainable single-cell characterization level. This helped identify four novel, molecularly distinct subtypes that successfully harmonize across multiple GBM datasets, including previously published bulk and single-cell profiles and single cell profiles from seven orthotopic PDX models, representative of prior subtype diversity. GBM is thus characterized by the plastic coexistence of single cells in two mutually-exclusive developmental lineages, with additional stratification provided by their proliferative potential. Consistently, all previous subtypes could be recapitulated by single-cell mixtures drawn from newly identified states. Critically, drug sensitivity was predicted and validated as highly state-dependent, both in single-cell assays from patient-derived explants and in PDX models, suggesting that successful treatment requires combinations of multiple drugs targeting these distinct tumor states. Significance We propose a new, 4-subtype GBM classification, which harmonizes across bulk and single-cell datasets. Single-cell mixtures from these subtypes effectively recapitulate all prior classifications, suggesting that the latter are a byproduct of GBM heterogeneity. Finally, we predict single-cell level activity of three clinically-relevant drugs, and validate them in patient-derived explant.

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Convection-enhanced delivery of etoposide is effective against murine proneural glioblastoma

Cited by 36 publications

References 37 publications

The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma

The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma

Therapeutic strategies to improve drug delivery across the blood-brain barrier

Single-cell based elucidation of molecularly-distinct glioblastoma states and drug sensitivity

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