Targeting Glioblastoma Using a Novel Peptide Specific to a Deglycosylated Isoform of Brevican

Spreckelsen, Niklas von; Fadzen, Colin M.; Hartrampf, Nina; Ghotmi, Yarah; Wolfe, Justin M.; Dubey, Sarvesh; Yang, Bo; Kijewski, Marie Foley; Wang, Shuyan; Farquhar, Charlotte E.; Bergmann, Sonja; Zdioruk, Mykola; Wasserburg, J Roscoe; Scott, Benjamin B.; Murrell, Emily; Bononi, Fernanda; Luyt, Leonard G.; DiCarli, Marcelo F.; Lamfers, Martine L.M.; Ligon, Keith L.; Chiocca, E. Antonio; Viapiano, Mariano S.; Pentelute, Bradley L.; Lawler, Sean E.; Cho, Choi-Fong

doi:10.1002/adtp.202000244

Cited by 16 publications

(26 citation statements)

References 38 publications

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“…3 F ). Another criterion for our candidate selection was that EGFR and TF are currently explored as ADC targets in clinical trials, and previous studies pointed at their potential as treatment targets in cancer ( 26 – 31 ). We next performed immunofluorescence stainings of available matched patient tumors for EGFR, TF, BCAN, CD81, and MCT2.…”

Section: Resultsmentioning

confidence: 99%

Landscape of surfaceome and endocytome in human glioma is divergent and depends on cellular spatial organization

Governa

Talbot

Oliveira

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Therapeutic strategies directed at the tumor surfaceome (TS), including checkpoint inhibitor blocking antibodies, antibody drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cells, provide a new armament to fight cancer. However, a remaining bottleneck is the lack of strategies to comprehensively interrogate patient tumors for potential TS targets. Here, we have developed a platform (tumor surfaceome mapping [TS-MAP]) integrated with a newly curated TS classifier (SURFME) that allows profiling of primary 3D cultures and intact patient glioma tumors with preserved tissue architecture. Moreover, TS-MAP specifically identifies proteins capable of endocytosis as tractable targets for ADCs and other modalities requiring toxic payload internalization. In high-grade gliomas that remain among the most aggressive forms of cancer, we show that cellular spatial organization (2D vs. 3D) fundamentally transforms the surfaceome and endocytome (e.g., integrins, proteoglycans, semaphorins, and cancer stem cell markers) with general implications for target screening approaches, as exemplified by an ADC targeting EGFR. The TS-MAP platform was further applied to profile the surfaceome and endocytome landscape in a cohort of freshly resected gliomas. We found a highly diverse TS repertoire between patient tumors, not directly associated with grade and histology, which highlights the need for individualized approaches. Our data provide additional layers of understanding fundamental to the future development of immunotherapy strategies, as well as procedures for proteomics-based target identification and selection. The TS-MAP platform should be widely applicable in efforts aiming at a better understanding of how to harness the TS for personalized immunotherapy.

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Section: Resultsmentioning

confidence: 99%

Landscape of surfaceome and endocytome in human glioma is divergent and depends on cellular spatial organization

Governa

Talbot

Oliveira

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, high levels of HA receptors including epican ( CD44 ) were correlated with poor prognosis in cancer patients ( Yan and Wang, 2020 ). RNA levels for fibronectin ( FN1 ), brevican ( BCAN ), versican ( VCAN ), perlecan ( HSPG2 ), and several laminins were high in glioblastomas compared with in the normal brain ( Dzikowski et al, 2021 ; von Spreckelsen et al, 2021 ). A high level of CD74 was expressed in the monocytic subset of immune suppressive myeloid-derived suppressor cells and localized in the tumor microenvironment ( Alban et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Novel Insight Into Glycosaminoglycan Biosynthesis Based on Gene Expression Profiles

Huang

Mizumoto²,

Fujita³

2021

Front. Cell Dev. Biol.

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Glycosaminoglycans (GAGs) including chondroitin sulfate, dermatan sulfate, heparan sulfate, and keratan sulfate, except for hyaluronan that is a free polysaccharide, are covalently attached to core proteins to form proteoglycans. More than 50 gene products are involved in the biosynthesis of GAGs. We recently developed a comprehensive glycosylation mapping tool, GlycoMaple, for visualization and estimation of glycan structures based on gene expression profiles. Using this tool, the expression levels of GAG biosynthetic genes were analyzed in various human tissues as well as tumor tissues. In brain and pancreatic tumors, the pathways for biosynthesis of chondroitin and dermatan sulfate were predicted to be upregulated. In breast cancerous tissues, the pathways for biosynthesis of chondroitin and dermatan sulfate were predicted to be up- and down-regulated, respectively, which are consistent with biochemical findings published in the literature. In addition, the expression levels of the chondroitin sulfate-proteoglycan versican and the dermatan sulfate-proteoglycan decorin were up- and down-regulated, respectively. These findings may provide new insight into GAG profiles in various human diseases including cancerous tumors as well as neurodegenerative disease using GlycoMaple analysis.

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“…An ECM glycoprotein expressed exclusively in the central nervous system (CNS) called brevican (Bcan) is upregulated in GBM [9][10][11], and is linked to increased tumor invasion and aggressiveness [12]. The deglycosylated isoform, called dg-Bcan is only found in human high-grade glioma tissue samples [10,13], making it an attractive GBM-specific marker for the development of novel therapeutic targeting strategies. Previously, we have screened a combinatorial D-amino acid peptide library to identify an octameric dg-Bcan-Targeting Peptide, called BTP-7, that is stable in serum, binds dg-Bcan specifically, crosses the BBB, and preferentially homes to intracranial GBM xenografts in mice established using patient-derived GBM stem cells (GSC) [13].…”

Section: Introductionmentioning

confidence: 99%

“…The deglycosylated isoform, called dg-Bcan is only found in human high-grade glioma tissue samples [10,13], making it an attractive GBM-specific marker for the development of novel therapeutic targeting strategies. Previously, we have screened a combinatorial D-amino acid peptide library to identify an octameric dg-Bcan-Targeting Peptide, called BTP-7, that is stable in serum, binds dg-Bcan specifically, crosses the BBB, and preferentially homes to intracranial GBM xenografts in mice established using patient-derived GBM stem cells (GSC) [13]. Positron emission tomography (PET) imaging using [ 18 F]-radiolabeled BTP-7 reveals higher tumor-to-brain uptake ratio (sustained over several hours) in comparison to values reported from similar studies evaluating clinical radiotracers such as [ 18 F]FDG and [ 18 F]FET [13].…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we have screened a combinatorial D-amino acid peptide library to identify an octameric dg-Bcan-Targeting Peptide, called BTP-7, that is stable in serum, binds dg-Bcan specifically, crosses the BBB, and preferentially homes to intracranial GBM xenografts in mice established using patient-derived GBM stem cells (GSC) [13]. Positron emission tomography (PET) imaging using [ 18 F]-radiolabeled BTP-7 reveals higher tumor-to-brain uptake ratio (sustained over several hours) in comparison to values reported from similar studies evaluating clinical radiotracers such as [ 18 F]FDG and [ 18 F]FET [13]. These studies highlight BTP-7 as a promising tumor-specific agent for delivering functional cargoes to GBM, warranting further investigation and development.…”

Section: Introductionmentioning

confidence: 99%

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A Tumor-Homing Peptide Platform Enhances Drug Solubility, Improves Blood–Brain Barrier Permeability and Targets Glioblastoma

Cho

Farquhar

Fadzen

et al. 2022

Cancers

Self Cite

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Background: Glioblastoma (GBM) is the most common and deadliest malignant primary brain tumor, contributing significant morbidity and mortality among patients. As current standard-of-care demonstrates limited success, the development of new efficacious GBM therapeutics is urgently needed. Major challenges in advancing GBM chemotherapy include poor bioavailability, lack of tumor selectivity leading to undesired side effects, poor permeability across the blood–brain barrier (BBB), and extensive intratumoral heterogeneity. Methods: We have previously identified a small, soluble peptide (BTP-7) that is able to cross the BBB and target the human GBM extracellular matrix (ECM). Here, we covalently attached BTP-7 to an insoluble anti-cancer drug, camptothecin (CPT). Results: We demonstrate that conjugation of BTP-7 to CPT improves drug solubility in aqueous solution, retains drug efficacy against patient-derived GBM stem cells (GSC), enhances BBB permeability, and enables therapeutic targeting to intracranial GBM, leading to higher toxicity in GBM cells compared to normal brain tissues, and ultimately prolongs survival in mice bearing intracranial patient-derived GBM xenograft. Conclusion: BTP-7 is a new modality that opens the door to possibilities for GBM-targeted therapeutic approaches.

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Targeting Glioblastoma Using a Novel Peptide Specific to a Deglycosylated Isoform of Brevican

Cited by 16 publications

References 38 publications

Landscape of surfaceome and endocytome in human glioma is divergent and depends on cellular spatial organization

Landscape of surfaceome and endocytome in human glioma is divergent and depends on cellular spatial organization

Novel Insight Into Glycosaminoglycan Biosynthesis Based on Gene Expression Profiles

A Tumor-Homing Peptide Platform Enhances Drug Solubility, Improves Blood–Brain Barrier Permeability and Targets Glioblastoma

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