Longitudinal Drug Synergy Assessment Using Convolutional Neural Network Image-decoding of Glioblastoma Single-spheroid Cultures

Overview

Journal Neurooncol Adv

Publisher Oxford University Press

Date 2023 Dec 4

PMID 38047207

Authors

Anna Giczewska

Krzysztof Pastuszak

Megan Houweling

Kulsoom U Abdul

Noa Faaij

Laurine Wedekind

David Noske

Thomas Wurdinger

Anna Supernat

Bart A Westerman

Affiliations

Soon will be listed here.

Abstract

Background: In recent years, drug combinations have become increasingly popular to improve therapeutic outcomes in various diseases, including difficult to cure cancers such as the brain cancer glioblastoma. Assessing the interaction between drugs over time is critical for predicting drug combination effectiveness and minimizing the risk of therapy resistance. However, as viability readouts of drug combination experiments are commonly performed as an endpoint where cells are lysed, longitudinal drug-interaction monitoring is currently only possible through combined endpoint assays.

Methods: We provide a method for massive parallel monitoring of drug interactions for 16 drug combinations in 3 glioblastoma models over a time frame of 18 days. In our assay, viabilities of single neurospheres are to be estimated based on image information taken at different time points. Neurosphere images taken on the final day (day 18) were matched to the respective viability measured by CellTiter-Glo 3D on the same day. This allowed to use of machine learning to decode image information to viability values on day 18 as well as for the earlier time points (on days 8, 11, and 15).

Results: Our study shows that neurosphere images allow us to predict cell viability from extrapolated viabilities. This enables to assess of the drug interactions in a time window of 18 days. Our results show a clear and persistent synergistic interaction for several drug combinations over time.

Conclusions: Our method facilitates longitudinal drug-interaction assessment, providing new insights into the temporal-dynamic effects of drug combinations in 3D neurospheres which can help to identify more effective therapies against glioblastoma.

Citing Articles

Artificial Intelligence-Assisted Drug and Biomarker Discovery for Glioblastoma: A Scoping Review of the Literature.

Conte L, Caruso G, Philip A, Cucci F, De Nunzio G, Cascio D Cancers (Basel). 2025; 17(4).

PMID: 40002166 PMC: 11852502. DOI: 10.3390/cancers17040571.

References

Shin S, Park C, Kwon H, Lee K . Erlotinib plus gemcitabine versus gemcitabine for pancreatic cancer: real-world analysis of Korean national database. BMC Cancer. 2016; 16:443. PMC: 4940912. DOI: 10.1186/s12885-016-2482-z. View

Newlands E, Stevens M, Wedge S, Wheelhouse R, Brock C . Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev. 1997; 23(1):35-61. DOI: 10.1016/s0305-7372(97)90019-0. View

Malarikova D, Jorda R, Kupcova K, Senavova J, Dolnikova A, Pokorna E . Cyclin dependent kinase 4/6 inhibitor palbociclib synergizes with BCL2 inhibitor venetoclax in experimental models of mantle cell lymphoma without RB1 deletion. Exp Hematol Oncol. 2024; 13(1):34. PMC: 10962182. DOI: 10.1186/s40164-024-00499-2. View

Ahmed Alamoudi W, Ahmad F, Acharya S, Haque S, Alsamman K, Herzallah H . A simplified colorimetric method for rapid detection of cell viability and toxicity in adherent cell culture systems. J BUON. 2018; 23(5):1505-1513. View

Chen X, Li Y, Wyman N, Zhang Z, Fan H, Le M . Deep learning provides high accuracy in automated chondrocyte viability assessment in articular cartilage using nonlinear optical microscopy. Biomed Opt Express. 2021; 12(5):2759-2772. PMC: 8176803. DOI: 10.1364/BOE.417478. View

Stathias V, Jermakowicz A, Maloof M, Forlin M, Walters W, Suter R . Drug and disease signature integration identifies synergistic combinations in glioblastoma. Nat Commun. 2018; 9(1):5315. PMC: 6294341. DOI: 10.1038/s41467-018-07659-z. View

Brat D, Aldape K, Colman H, Holland E, Louis D, Jenkins R . cIMPACT-NOW update 3: recommended diagnostic criteria for "Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV". Acta Neuropathol. 2018; 136(5):805-810. PMC: 6204285. DOI: 10.1007/s00401-018-1913-0. View

Houweling M, Abdul U, Brahm C, Lagerweij T, Heukelom S, Koken P . Radio-sensitizing effect of MEK inhibition in glioblastoma in vitro and in vivo. J Cancer Res Clin Oncol. 2022; 149(1):297-305. DOI: 10.1007/s00432-022-04483-3. View

Narayan R, Gasol A, Slangen P, Cornelissen F, Lagerweij T, Veldman H . Identification of MEK162 as a Radiosensitizer for the Treatment of Glioblastoma. Mol Cancer Ther. 2017; 17(2):347-354. DOI: 10.1158/1535-7163.MCT-17-0480. View

10.

Di Veroli G, Fornari C, Wang D, Mollard S, Bramhall J, Richards F . Combenefit: an interactive platform for the analysis and visualization of drug combinations. Bioinformatics. 2016; 32(18):2866-8. PMC: 5018366. DOI: 10.1093/bioinformatics/btw230. View

11.

Nichols J, Herbert Chan H, Baker M . Machine learning: applications of artificial intelligence to imaging and diagnosis. Biophys Rev. 2018; 11(1):111-118. PMC: 6381354. DOI: 10.1007/s12551-018-0449-9. View

12.

Stupp R, Mason W, van den Bent M, Weller M, Fisher B, Taphoorn M . Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352(10):987-96. DOI: 10.1056/NEJMoa043330. View

13.

Jiang P, Mukthavaram R, Mukthavavam R, Chao Y, Bharati I, Fogal V . Novel anti-glioblastoma agents and therapeutic combinations identified from a collection of FDA approved drugs. J Transl Med. 2014; 12:13. PMC: 3898565. DOI: 10.1186/1479-5876-12-13. View

14.

Kagawa K, Sato S, Koyama K, Imakura T, Murakami K, Yamashita Y . The lymphocyte-specific protein tyrosine kinase-specific inhibitor A-770041 attenuates lung fibrosis via the suppression of TGF-β production in regulatory T-cells. PLoS One. 2022; 17(10):e0275987. PMC: 9612470. DOI: 10.1371/journal.pone.0275987. View

15.

Martin A, Mitchell C, Rahmani M, Nephew K, Grant S, Dent P . Inhibition of MCL-1 enhances lapatinib toxicity and overcomes lapatinib resistance via BAK-dependent autophagy. Cancer Biol Ther. 2009; 8(21):2084-96. PMC: 3887451. DOI: 10.4161/cbt.8.21.9895. View

16.

Whitaker R, Placzek W . MCL1 binding to the reverse BH3 motif of P18INK4C couples cell survival to cell proliferation. Cell Death Dis. 2020; 11(2):156. PMC: 7048787. DOI: 10.1038/s41419-020-2351-1. View

17.

Park S, Veluvolu V, Martin W, Nguyen T, Park J, Sackett D . Label-free, non-invasive, and repeatable cell viability bioassay using dynamic full-field optical coherence microscopy and supervised machine learning. Biomed Opt Express. 2022; 13(6):3187-3194. PMC: 9208588. DOI: 10.1364/BOE.452471. View

18.

Hutoczki G, Virga J, Birko Z, Klekner A . Novel Concepts of Glioblastoma Therapy Concerning Its Heterogeneity. Int J Mol Sci. 2021; 22(18). PMC: 8470251. DOI: 10.3390/ijms221810005. View

19.

McHugh L, Kriajevska M, Mellon J, Griffiths T . Combined treatment of bladder cancer cell lines with lapatinib and varying chemotherapy regimens--evidence of schedule-dependent synergy. Urology. 2007; 69(2):390-4. DOI: 10.1016/j.urology.2006.12.003. View

20.

Cruickshanks N, Hamed H, Bareford M, Poklepovic A, Fisher P, Grant S . Lapatinib and obatoclax kill tumor cells through blockade of ERBB1/3/4 and through inhibition of BCL-XL and MCL-1. Mol Pharmacol. 2012; 81(5):748-58. PMC: 3336802. DOI: 10.1124/mol.112.077586. View