Multireceptor targeting of glioblastoma

Sharma, Puja; Sonawane, Poonam; Herpai, Denise; D’Agostino, Ralph B.; Rossmeisl, John H.; Tatter, Stephen B.; Debinski, Waldemar

doi:10.1093/noajnl/vdaa107

Cited by 10 publications

(15 citation statements)

References 49 publications

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“…There were 29 males (26 neutered, 3 intact) and 17 females (16 spayed, 1 intact). Tumor histopathologic diagnoses were obtained by stereotactic brain biopsy in all dogs, and additionally at necropsy in 28/46 (61%) of dogs 11‐14 . Histopathological diagnoses included 26 oligodendrogliomas (9 low‐grade, 17 high‐grade), 16 astrocytomas (7 low‐grade, 9 high‐grade), and 4 undefined gliomas (3 low‐grade, 1 high‐grade).…”

Section: Resultsmentioning

confidence: 99%

Comparison of linear and volumetric criteria for the determination of therapeutic response in dogs with intracranial gliomas

Mora

Robertson

Hsu

et al. 2022

Veterinary Internal Medicne

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Background: Brain tumor therapeutic responses can be quantified from magnetic resonance images (MRI) using 1-(1D) and 2-dimensional (2D) linear and volumetric methods, but few studies in dogs compare these techniques.Hypotheses: Linear methods will be obtained faster, but have less agreement than volumetric measurements. Therapeutic response agreement will be highest with the total T2W tumor volumetric (TTV) method. Therapeutic response at 6-weeks will correlate with overall survival (OS).Animals: Forty-six dogs with intracranial gliomas.Methods: Prospective study. Three raters measured tumors using 1D and 2D linear, TTV, and contrast-enhancing volumetric (CEV) techniques on 143 brain MRI to determine agreement between methods, define therapeutic responses, and assess relations with OS.Results: Raters performed 1D the fastest (2.9 ± 0.57 minutes) and CEV slowest (17.8 ± 6.2 minutes). Inter-and intraobserver agreements were excellent (intraclass correlations ≥.91) across methods. Correlations between linear (1D vs 2D; ρ > .91) and volumetric (TTV vs CEV; ρ > .73) methods were stronger than linear to volumetric comparisons (ρ range, .26-.59). Incorporating clinical and imaging data resulted in fewer discordant therapeutic responses across methods. Dogs having partial tumor responses at 6 weeks had a lower death hazard than dogs with stable or progressive disease when assessed using 2D, CEV, and TTV (hazard ration 2.1; 95% confidence interval, 1.22-3.63; P = .008).Conclusions and Clinical Importance: One-dimensional, 2D, CEV, and TTV are comparable for determining therapeutic response. Given the simplicity, universal applicability, and superior performance of the TTV, we recommend its use to standardize glioma therapeutic response criteria.

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Section: Resultsmentioning

confidence: 99%

Comparison of linear and volumetric criteria for the determination of therapeutic response in dogs with intracranial gliomas

Mora

Robertson

Hsu

et al. 2022

Veterinary Internal Medicne

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“…Bx, stereotactic biopsy. CED, convection-enhanced delivery of QUAD-doxorubicin ( 11 ). Chemo, CCNU and chlorambucil chemotherapy ( 12 ).…”

Section: Resultsmentioning

confidence: 99%

Cerebrospinal Fluid Drop Metastases of Canine Glioma: Magnetic Resonance Imaging Classification

et al. 2021

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Dissemination of glioma in humans can occur as leptomeningeal nodules, diffuse leptomeningeal lesions, or ependymal lesions. Cerebrospinal fluid (CSF) drop metastasis of glioma is not well-recognized in dogs. Ten dogs with at least two anatomically distinct and histologically confirmed foci of glioma were included in this study. The 10 dogs underwent 28 magnetic resonance imaging (MRI) examinations, with distant CSF drop metastasis revealed in 13 MRIs. The CSF drop metastases appeared as leptomeningeal nodules in four dogs, diffuse leptomeningeal lesions in six dogs, and ependymal lesions in seven dogs; six dogs had a combination of lesion types. Primary tumors were generally T2-heterogeneous and contrast-enhancing. Many metastases were T2-homogeneous and non-enhancing. Diffuse leptomeningeal lesions were seen as widespread extra-axial contrast-enhancement, again very dissimilar to the intra-axial primary mass. Primary masses were rostrotentorial, whereas metastases generally occurred in the direction of CSF flow, in ventricles, CSF cisterns, and the central canal or leptomeninges of the cervical or thoracolumbar spinal cord. Seven of the dogs had received therapy limited to the primary mass, such as surgery or stereotactic radiation, then developed metastasis in the following months. CSF drop metastasis of glioma may take a very different appearance on MRI to the primary mass, including periventricular lesions that are more homogeneous and less contrast-enhancing, rostral horn signal changes, or leptomeningeal enhancement ventral to the brainstem or encircling the spinal cord.

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“…The sequence coding for a single-chain protein consisting of two N-terminal diphtheria toxin domains (DT390) fused to IL-13 was expressed under T7 constitutive promoter in plasmid pWD-MCS in strain BL21(DE3) (New England Biolabs, Ipswich, MA, USA). The expression plasmid was constructed in the Waldemar Dębiński lab (Wake Forest University Health Sciences, Winston-Salem, NC, USA) (details can be found here [ 29 ]). Sequence identity of the full-length plasmid was confirmed by MiSeq Illumina sequencing (Genomed SA, Warsaw, Poland).…”

Section: Methodsmentioning

confidence: 99%

Structure–Activity Relationship of the Dimeric and Oligomeric Forms of a Cytotoxic Biotherapeutic Based on Diphtheria Toxin

et al. 2022

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Protein aggregation is a well-recognized problem in industrial preparation, including biotherapeutics. These low-energy states constantly compete with a native-like conformation, which is more pronounced in the case of macromolecules of low stability in the solution. A better understanding of the structure and function of such aggregates is generally required for the more rational development of therapeutic proteins, including single-chain fusion cytotoxins to target specific receptors on cancer cells. Here, we identified and purified such particles as side products of the renaturation process of the single-chain fusion cytotoxin, composed of two diphtheria toxin (DT) domains and interleukin 13 (IL-13), and applied various experimental techniques to comprehensively understand their molecular architecture and function. Importantly, we distinguished soluble purified dimeric and fractionated oligomeric particles from aggregates. The oligomers are polydisperse and multimodal, with a distribution favoring lower and even stoichiometries, suggesting they are composed of dimeric building units. Importantly, all these oligomeric particles and the monomer are cystine-dependent as their innate disulfide bonds have structural and functional roles. Their reduction triggers aggregation. Presumably the dimer and lower oligomers represent the metastable state, retaining the native disulfide bond. Although significantly reduced in contrast to the monomer, they preserve some fraction of bioactivity, manifested by their IL-13RA2 receptor affinity and selective cytotoxic potency towards the U-251 glioblastoma cell line. These molecular assemblies probably preserve structural integrity and native-like fold, at least to some extent. As our study demonstrated, the dimeric and oligomeric cytotoxin may be an exciting model protein, introducing a new understanding of its monomeric counterpart’s molecular characteristics.

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Multireceptor targeting of glioblastoma

Cited by 10 publications

References 49 publications

Comparison of linear and volumetric criteria for the determination of therapeutic response in dogs with intracranial gliomas

Comparison of linear and volumetric criteria for the determination of therapeutic response in dogs with intracranial gliomas

Cerebrospinal Fluid Drop Metastases of Canine Glioma: Magnetic Resonance Imaging Classification

Structure–Activity Relationship of the Dimeric and Oligomeric Forms of a Cytotoxic Biotherapeutic Based on Diphtheria Toxin

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