PO.CL07.01 · 临床研究
In silico screening of therapeutics candidates targeting minimal residual disease in glioblastoma
作者与单位
摘要 Abstract
Background : Glioblastoma recurrence is inevitable despite aggressive surgical resection of contrast enhancing (CE) tumor. Unlike the deep molecular characterization of CE glioblastoma, unresected infiltrating tumor, representing minimal residual disease (MRD) has not been well profiled. Increasingly, clinical trials are being conducted in the MRD setting for glioblastoma patients, necessitating understanding of unresected infiltrating tumor for targeted therapeutic development.
Methods : Visium HD spatial transcriptomics was used to profile a cohort of newly diagnosed, treatment-naïve glioblastoma patients that underwent supramaximal resection, with both core and infiltrating in situ components. Spatial profiles generated expression signatures of infiltrative and CE tumor. For i n silico prediction of therapeutics targeting the MRD, expression signatures of infiltrative and CE tumor were compared with drug perturbation signatures from the NIH L1000 database using the sRGES method to predict reversal of disease expression patterns. IC 50 data from human cell lines were aggregated from the Genomics of Drug Sensitivity in Cancer or individual study data while blood-brain barrier (BBB) penetrance was predicted using the CNS-MPO approach.
Findings : Infiltrative tumor expression profiles were enriched for genes corresponding to neural and oligodendrocyte progenitor like cells. In contrast CE glioblastoma displayed mesenchymal and astrocytic programs, suggesting spatial concentration of glioblastoma states within MRD and CE tumor. For CE glioblastoma, proteasome inhibitors and glucocorticoid receptor agonists were predicted to have the highest antitumor activity. In contrast, histone deacetylase inhibitors (HDACi) were highly ranked for MRD while exhibiting low predicted efficacy in CE tumor. Synergy analysis of drug candidates provided multiple dual treatment options for both the CE and MRD contexts.
Conclusions : Cumulatively, these data indicate that the resected tumor does not reflect the MRD state, providing clarity on why targeted therapeutics for glioblastoma have not been particularly successful. Spatial profiling of the MRD demonstrates vulnerability to unique drug targets, which if utilized in the correct setting could confer greater survival benefit.
利益披露 Disclosure
H. Congivaram,
Lunaphore ).
S. Tripathi, None..
M. Gomez, None..
K. McCortney, None..
C. Wai, None..
R. Du, None..
T. K. Sears, None..
J. Zhang, None..
C. M. Horbinski, None..
M. W. Youngblood, None..
J. T. Ahrendsen, None..
A. M. Sonabend, None.
S. T. Magill,
Stryker ).
Black Forest Medical Group ).
Stanford University Other, honoraria.
M. C. Tate, None..
M. S. Lesniak, None.
S. Sachdev,
Servier g., Board of Directors, non-salaried role), ).
T. Sita, None.
P. Kumthekar,
Belay Diagnostics ).
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Biodexa ).
Bioclinica ).
Janssen ).
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Autem ).
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Pfizer (Seagen) Other, honoraria.
Servier Other, honoraria.
K. Dixit,
Servier Other, honoraria.
R. Buerki,
Guidepoint ).
Techspert ).
Servier ).
Sapience Pharmeceuticals Other, honoraria.
Monteris Medical Other, honoraria.
D. Primdahl,
Servier g., Board of Directors, non-salaried role).
Catalyst g., Board of Directors, non-salaried role).
M. Khasraw,
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Immvira ).
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CNS Pharmeceuticals ).
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Jakscon Laboratory honoraria.
Johnson and Johnson Other, honoraria.
Voyager Therapeutics Other, honoraria.
George Clinical Other, honoraria.
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Daiichi Sankyo ), honoraria.
Siren Therapeutics honoraria.
Menarini Therapeutics honoraria.
J. de Groot,
Kintara ).
Kazia ).
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DSP Pharma ).
Telix ).
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Alpha Pharmeceuticals ).
Capital One ).
Nuvation ).
Ariceum ).
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Stoked Bio ).
GBM AGILE Agent Selection Committee ).
D. A. Reardon,
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Ashvattha Therapeutics ).
Boehringer Ingelheim ).
Bristol Myers Squibb ).
Corbus Pharmeceuticals ).
EMD Serono ).
Enterome ).
InvivO Therapeutics ).
Medicenna Therapeutics ).
Mogling Bio ).
NeoTx ).
Numiera Therapeutics ).
Sapience Pharmeceuticals ).
SphereBio ).
Vaccinex ).
AnHeart Pharmeceuticals ).
BlueRock Therapeutics ).
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R. V. Lukas,
Merck g., Board of Directors, non-salaried role).
Novocure g., Board of Directors, non-salaried role), Other, honoraria.
Servier g., Board of Directors, non-salaried role), Other, honoraria.
Telix g., Board of Directors, non-salaried role).
Bristol Myers Squibb ).
Novocure ), Other, honoraria.
EBSCO Other, honoraria.
Elsevier ), Other, honoraria.
Medlink Neurology ), Other, honoraria.
Oxford University Press ), Other, honoraria.
R. Stupp,
Agenus ).
Bristol Myers Squibb ).
Carthera ).
Alpheus ).
Carthera ).
G Medical ).
Novocure Other, honoraria.
ZaiLab Other, honoraria.
Sapience Pharmeceuticals g., Board of Directors, non-salaried role).
Ipsen g., Board of Directors, non-salaried role).
AiMED Bio g., Board of Directors, non-salaried role).
Hemispherian g., Board of Directors, non-salaried role).
Carthera Stock, Stock Option.
Alpheus Stock, Stock Option.
Modifi Bio Stock.
A. B. Heimberger,
WCG Oncology g., Board of Directors, non-salaried role).
Moleculin ).
AbbVie ).
Alnylam ).
Caris Life Sciences g., Board of Directors, non-salaried role).
ImmunoGenesis g., Board of Directors, non-salaried role).