Increased apoptotic priming of glioblastoma enables therapeutic targeting by BH3-mimetics

Koessinger, Anna L.; Koessinger, Dominik; Kinch, Kevin; Martínez-Escardó, Laura; Paul, Nikki R.; Elmasry, Yassmin; Malviya, Gaurav; Cloix, Catherine; Campbell, Kirsteen J.; Bock, Florian; O’Prey, Jim; Stevenson, Katrina H.; Nixon, Colin; Jackson, Mark R.; Ichim, Gabriel; Stewart, William; Blyth, Karen; Ryan, Kevin M.; Aj, Chalmers; Norman, Jim C.; Tait, Stephen W.G.

doi:10.1101/2021.06.13.448232

Cited by 4 publications

(2 citation statements)

References 61 publications

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“…Previously, it was demonstrated that TRAIL receptor agonists have broad efficacy against GBM cells alone or in combination with sensitisers [35,[45][46][47][48][49]. Beyond GBM, the CNS is also a frequent secondary site for many cancer metastases, including lung cancer, breast cancer and melanoma, consequently leading to lower treatment responses and poor patient outcomes [50,51].…”

Section: Discussionmentioning

confidence: 99%

Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma

et al. 2021

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Glioblastoma (GBM) is the most malignant and aggressive form of glioma and is associated with a poor survival rate. Latest generation Tumour Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL)-based therapeutics potently induce apoptosis in cancer cells, including GBM cells, by binding to death receptors. However, the blood–brain barrier (BBB) is a major obstacle for these biologics to enter the central nervous system (CNS). We therefore investigated if antibody-based fusion proteins that combine hexavalent TRAIL and angiopep-2 (ANG2) moieties can be developed, with ANG2 promoting receptor-mediated transcytosis (RMT) across the BBB. We demonstrate that these fusion proteins retain the potent apoptosis induction of hexavalent TRAIL-receptor agonists. Importantly, blood–brain barrier cells instead remained highly resistant to this fusion protein. Binding studies indicated that ANG2 is active in these constructs but that TRAIL-ANG2 fusion proteins bind preferentially to BBB endothelial cells via the TRAIL moiety. Consequently, transport studies indicated that TRAIL-ANG2 fusion proteins can, in principle, be shuttled across BBB endothelial cells, but that low TRAIL receptor expression on BBB endothelial cells interferes with efficient transport. Our work therefore demonstrates that TRAIL-ANG2 fusion proteins remain highly potent in inducing apoptosis, but that therapeutic avenues will require combinatorial strategies, such as TRAIL-R masking, to achieve effective CNS transport.

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Section: Discussionmentioning

confidence: 99%

Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma

et al. 2021

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“…The underlying reason for this toxicity is most likely because neuronal development and survival is based on BCL-XL activity ( 66 ). Additionally, navitoclax is almost impenetrable to the blood brain barrier, thus, the current drugs are not able to reach the brain parenchyma ( 67 ). Thus, despite the demonstrated senolytic effects of BCL-2 family inhibitors, their clinical translation is limited due to potential side effects, off-target effects on platelets and poor central nervous system (CNS) penetrance.…”

Section: Cellular Senescencementioning

confidence: 99%

Translating the Biology of Aging into New Therapeutics for Alzheimer’s Disease: Senolytics

Riessland,

Orr

2023

J Prev Alz Dis

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The recent FDA-approval for amyloid lowering therapies reflects an unwavering commitment from the Alzheimer’s disease (AD) research community to identify treatments for this leading cause of dementia. The clinical benefits achieved by reducing amyloid, though modest, provide evidence that disease modification is possible. Expanding the same tenacity to interventions targeting upstream drivers of AD pathogenesis could significantly impact the disease course. Advanced age is the greatest risk factor for developing AD. Interventions targeting biological aging offer the possibility of disrupting a foundational cause of AD. Senescent cells accumulate with age and contribute to inflammation and age-related diseases like AD. Senolytic drugs that clear senescent cells improve healthy aging, halt AD disease progression in animal models and are undergoing clinical testing. This review explores the biology of aging, the role of senescent cells in AD pathology, and various senotherapeutic approaches such as senolytics, dampening the SASP (senescence associated secretory phenotype), senescence pathway inhibition, vaccines, and prodrugs. We highlight ongoing clinical trials evaluating the safety and efficacy of the most advanced senolytic approach, dasatinib and quercetin (D+Q), including an ongoing Phase II senolytic trial supported by the Alzheimer’s Drug Discovery Foundation (ADDF). Challenges in the field of senotherapy for AD, including target engagement and biomarker development, are addressed. Ultimately, this research pursuit may lead to an effective treatment for AD and provide the field with another disease-modifying therapy to be used, alone or in combination, with other emerging treatment options.

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Ex-vivo models of post-surgical residual disease in human glioblastoma

Rominiyi,

McGarrity-Cottrell,

Myers

et al. 2024

F1000Res

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Background Glioblastoma is a highly infiltrative, currently incurable brain cancer. To date, translation of novel therapies for glioblastoma from the laboratory into clinical trials has relied heavily on in vitro cell culture and murine (subcutaneous and orthotopic) xenograft models using cells derived from the main bulk of patient tumours. However, it is the residual cells left-behind after surgery that are responsible for disease progression and death in the clinic. A lack of substantial improvements in patient survival for decades suggests commonly used murine xenograft models, a key step before clinical trials, do not reflect the biology of residual disease in patients. Methods To address this, we have developed the ‘Sheffield Protocol’ to generate ex vivo models that reflect both resected, and post-surgical residual disease from the same patient. The protocol leverages parallel derivation of inherently treatment-resistant glioblastoma stem cells (GSCs) from ‘core’ and distant ‘edge’ regions through careful macrodissection of a large en bloc specimen, such as from a partial lobectomy for tumour, followed by tissue dissociation and propagation in serum-free media. Opportunistic en bloc specimen use can liberate the most distant infiltrative cells feasibly accessible from living patients. Results We provide an example illustrating that resected and residual disease models represent spatially divergent tumour subpopulations harbouring distinct transcriptomic and cancer stem cell marker expression profiles. We also introduce the ‘Sheffield Living Biobank’ of glioma models (SLB) that incorporates over 150 GSC lines from 60+ patients, including 44+ resected and residual models, which are available for academic use via MTA. Conclusions These models provide a novel tool to reduce animal xenograft usage by improving candidate drug triage in early preclinical studies and directly replacing animal studies for some therapies that are post-Phase 1+ clinical trial for other cancers/conditions to, ultimately, deliver more effective treatments for post-surgical residual disease in glioblastoma.

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Increased apoptotic priming of glioblastoma enables therapeutic targeting by BH3-mimetics

Cited by 4 publications

References 61 publications

Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma

Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma

Translating the Biology of Aging into New Therapeutics for Alzheimer’s Disease: Senolytics

Ex-vivo models of post-surgical residual disease in human glioblastoma

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