Abstract
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.
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.
| Original language | English |
|---|---|
| Article number | 1316 |
| Number of pages | 29 |
| Journal | F1000Research |
| Volume | 13 |
| DOIs | |
| Publication status | Published - 30 Nov 2024 |
Funding
This work was supported by Expanding Theories grant awarded to OR, DW & SJC by The Brain Tumour Charity (ET_2019/1_10403) and PhD Studentship (CMG) awarded to SJC & OR by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) (NC/T001895/1). OR & SJC also acknowledge funding support from the Royal College of Surgeons, Neurocare and Yorkshire’s Brain Tumour Charity (formerly BTRS) which helped to develop the initial concept for these models. OR is supported by an NIHR Clinical Lectureship and Future Leaders funding by The Brain Tumour Charity (FL_2021_/1_10610). OR, AV, YAT & SJC are supported by the NIHR Sheffield Biomedical Research Centre and/or NIHR Sheffield Clinical Research Facility.
Keywords
- ex-vivo
- glioblastoma
- post-surgical
- human
