High-Content Drug Discovery Targeting Molecular Bladder Cancer Subtypes

Sébastien Rinaldetti; Qiong Zhou; Joshua M. Abbott; Florus C. de Jong; Hector Esquer; James C. Costello; Dan Theodorescu; Daniel V. LaBarbera

doi:10.3390/ijms231810605

High-Content Drug Discovery Targeting Molecular Bladder Cancer Subtypes

Sébastien Rinaldetti, Qiong Zhou, Joshua M. Abbott, Florus C. de Jong, Hector Esquer, James C. Costello, Dan Theodorescu, Daniel V. LaBarbera^*

^*Corresponding author for this work

Urology

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Abstract

Molecular subtypes of muscle-invasive bladder cancer (MIBC) display differential survival and drug sensitivities in clinical trials. To date, they have not been used as a paradigm for phenotypic drug discovery. This study aimed to discover novel subtype-stratified therapy approaches based on high-content screening (HCS) drug discovery. Transcriptome expression data of CCLE and BLA-40 cell lines were used for molecular subtype assignment in basal, luminal, and mesenchymal-like cell lines. Two independent HCSs, using focused compound libraries, were conducted to identify subtype-specific drug leads. We correlated lead drug sensitivity data with functional genomics, regulon analysis, and in-vitro drug response-based enrichment analysis. The basal MIBC subtype displayed sensitivity to HDAC and CHK inhibitors, while the luminal subtype was sensitive to MDM2 inhibitors. The mesenchymal-like cell lines were exclusively sensitive to the ITGAV inhibitor SB273005. The role of integrins within this mesenchymal-like MIBC subtype was confirmed via its regulon activity and gene essentiality based on CRISPR–Cas9 knock-out data. Patients with high ITGAV expression showed a significant decrease in the median overall survival. Phenotypic high-content drug screens based on bladder cancer cell lines provide rationales for novel stratified therapeutic approaches as a framework for further prospective validation in clinical trials.

Original language	English
Article number	10605
Number of pages	15
Journal	International Journal of Molecular Sciences
Volume	23
Issue number	18
DOIs	https://doi.org/10.3390/ijms231810605
Publication status	Published - 14 Sept 2022

Bibliographical note

Funding Information:
This research was supported in part by grants awarded to D.V.L. from the U.S. Department of Defense Peer-Reviewed Cancer Research Program (W81XWH-18-1-0142) and the Colorado Cancer Translational Research Accelerator. The research was also supported in part by a fellowship grant awarded to S.R. by the Cancer Foundation of Luxembourg. We thank the Drug Discovery and Development Shared Resource (D3SR, RRID:SCR_021986). The D3SSR is part of the CU AMC Center for Drug Discovery, which was established with a generous grant from The ALSAM Foundation and with CU Anschutz institutional support. We also thank the Biostatistics and Bioinformatics Shared Resource (BBSR, RRID:SCR_021983). The D3SR and BBSR are also supported in part by the University of Colorado Cancer Center, an NIH NCI designated center (P30CA046934).

Publisher Copyright:
© 2022 by the authors.

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title = "High-Content Drug Discovery Targeting Molecular Bladder Cancer Subtypes",

abstract = "Molecular subtypes of muscle-invasive bladder cancer (MIBC) display differential survival and drug sensitivities in clinical trials. To date, they have not been used as a paradigm for phenotypic drug discovery. This study aimed to discover novel subtype-stratified therapy approaches based on high-content screening (HCS) drug discovery. Transcriptome expression data of CCLE and BLA-40 cell lines were used for molecular subtype assignment in basal, luminal, and mesenchymal-like cell lines. Two independent HCSs, using focused compound libraries, were conducted to identify subtype-specific drug leads. We correlated lead drug sensitivity data with functional genomics, regulon analysis, and in-vitro drug response-based enrichment analysis. The basal MIBC subtype displayed sensitivity to HDAC and CHK inhibitors, while the luminal subtype was sensitive to MDM2 inhibitors. The mesenchymal-like cell lines were exclusively sensitive to the ITGAV inhibitor SB273005. The role of integrins within this mesenchymal-like MIBC subtype was confirmed via its regulon activity and gene essentiality based on CRISPR–Cas9 knock-out data. Patients with high ITGAV expression showed a significant decrease in the median overall survival. Phenotypic high-content drug screens based on bladder cancer cell lines provide rationales for novel stratified therapeutic approaches as a framework for further prospective validation in clinical trials.",

author = "S{\'e}bastien Rinaldetti and Qiong Zhou and Abbott, {Joshua M.} and {de Jong}, {Florus C.} and Hector Esquer and Costello, {James C.} and Dan Theodorescu and LaBarbera, {Daniel V.}",

note = "Funding Information: This research was supported in part by grants awarded to D.V.L. from the U.S. Department of Defense Peer-Reviewed Cancer Research Program (W81XWH-18-1-0142) and the Colorado Cancer Translational Research Accelerator. The research was also supported in part by a fellowship grant awarded to S.R. by the Cancer Foundation of Luxembourg. We thank the Drug Discovery and Development Shared Resource (D3SR, RRID:SCR_021986). The D3SSR is part of the CU AMC Center for Drug Discovery, which was established with a generous grant from The ALSAM Foundation and with CU Anschutz institutional support. We also thank the Biostatistics and Bioinformatics Shared Resource (BBSR, RRID:SCR_021983). The D3SR and BBSR are also supported in part by the University of Colorado Cancer Center, an NIH NCI designated center (P30CA046934). Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2022",

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doi = "10.3390/ijms231810605",

language = "English",

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AU - Rinaldetti, Sébastien

AU - Zhou, Qiong

AU - Abbott, Joshua M.

AU - de Jong, Florus C.

AU - Esquer, Hector

AU - Costello, James C.

AU - Theodorescu, Dan

AU - LaBarbera, Daniel V.

N1 - Funding Information: This research was supported in part by grants awarded to D.V.L. from the U.S. Department of Defense Peer-Reviewed Cancer Research Program (W81XWH-18-1-0142) and the Colorado Cancer Translational Research Accelerator. The research was also supported in part by a fellowship grant awarded to S.R. by the Cancer Foundation of Luxembourg. We thank the Drug Discovery and Development Shared Resource (D3SR, RRID:SCR_021986). The D3SSR is part of the CU AMC Center for Drug Discovery, which was established with a generous grant from The ALSAM Foundation and with CU Anschutz institutional support. We also thank the Biostatistics and Bioinformatics Shared Resource (BBSR, RRID:SCR_021983). The D3SR and BBSR are also supported in part by the University of Colorado Cancer Center, an NIH NCI designated center (P30CA046934). Publisher Copyright: © 2022 by the authors.

PY - 2022/9/14

Y1 - 2022/9/14

N2 - Molecular subtypes of muscle-invasive bladder cancer (MIBC) display differential survival and drug sensitivities in clinical trials. To date, they have not been used as a paradigm for phenotypic drug discovery. This study aimed to discover novel subtype-stratified therapy approaches based on high-content screening (HCS) drug discovery. Transcriptome expression data of CCLE and BLA-40 cell lines were used for molecular subtype assignment in basal, luminal, and mesenchymal-like cell lines. Two independent HCSs, using focused compound libraries, were conducted to identify subtype-specific drug leads. We correlated lead drug sensitivity data with functional genomics, regulon analysis, and in-vitro drug response-based enrichment analysis. The basal MIBC subtype displayed sensitivity to HDAC and CHK inhibitors, while the luminal subtype was sensitive to MDM2 inhibitors. The mesenchymal-like cell lines were exclusively sensitive to the ITGAV inhibitor SB273005. The role of integrins within this mesenchymal-like MIBC subtype was confirmed via its regulon activity and gene essentiality based on CRISPR–Cas9 knock-out data. Patients with high ITGAV expression showed a significant decrease in the median overall survival. Phenotypic high-content drug screens based on bladder cancer cell lines provide rationales for novel stratified therapeutic approaches as a framework for further prospective validation in clinical trials.

AB - Molecular subtypes of muscle-invasive bladder cancer (MIBC) display differential survival and drug sensitivities in clinical trials. To date, they have not been used as a paradigm for phenotypic drug discovery. This study aimed to discover novel subtype-stratified therapy approaches based on high-content screening (HCS) drug discovery. Transcriptome expression data of CCLE and BLA-40 cell lines were used for molecular subtype assignment in basal, luminal, and mesenchymal-like cell lines. Two independent HCSs, using focused compound libraries, were conducted to identify subtype-specific drug leads. We correlated lead drug sensitivity data with functional genomics, regulon analysis, and in-vitro drug response-based enrichment analysis. The basal MIBC subtype displayed sensitivity to HDAC and CHK inhibitors, while the luminal subtype was sensitive to MDM2 inhibitors. The mesenchymal-like cell lines were exclusively sensitive to the ITGAV inhibitor SB273005. The role of integrins within this mesenchymal-like MIBC subtype was confirmed via its regulon activity and gene essentiality based on CRISPR–Cas9 knock-out data. Patients with high ITGAV expression showed a significant decrease in the median overall survival. Phenotypic high-content drug screens based on bladder cancer cell lines provide rationales for novel stratified therapeutic approaches as a framework for further prospective validation in clinical trials.

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DO - 10.3390/ijms231810605

M3 - Article

C2 - 36142576

SN - 1661-6596

VL - 23

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 18

M1 - 10605

ER -

High-Content Drug Discovery Targeting Molecular Bladder Cancer Subtypes

Abstract

Bibliographical note

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