Identifying biomarkers of differential chemotherapy response in TNBC patient-derived xenografts with a CTD/WGCNA approach

Varduhi Petrosyan; Lacey E. Dobrolecki; Lillian Thistlethwaite; Alaina N. Lewis; Christina Sallas; Ramakrishnan R. Srinivasan; Jonathan T. Lei; Vladimir Kovacevic; Predrag Obradovic; Matthew J. Ellis; C. Kent Osborne; Mothaffar F. Rimawi; Anne Pavlick; Maryam Nemati Shafaee; Heidi Dowst; Antrix Jain; Alexander B. Saltzman; Anna Malovannaya; Elisabetta Marangoni; Alana L. Welm; Bryan E. Welm; Shunqiang Li; Gerburg M. Wulf; Olmo Sonzogni; Chen Huang; Suhas Vasaikar; Susan G. Hilsenbeck; Bing Zhang; Aleksandar Milosavljevic; Michael T. Lewis

doi:10.1016/j.isci.2022.105799

Identifying biomarkers of differential chemotherapy response in TNBC patient-derived xenografts with a CTD/WGCNA approach

Varduhi Petrosyan, Lacey E. Dobrolecki, Lillian Thistlethwaite, Alaina N. Lewis, Christina Sallas, Ramakrishnan R. Srinivasan, Jonathan T. Lei, Vladimir Kovacevic, Predrag Obradovic, Matthew J. Ellis, C. Kent Osborne, Mothaffar F. Rimawi, Anne Pavlick, Maryam Nemati Shafaee, Heidi Dowst, Antrix Jain, Alexander B. Saltzman, Anna Malovannaya, Elisabetta Marangoni, Alana L. WelmBryan E. Welm, Shunqiang Li, Gerburg M. Wulf, Olmo Sonzogni, Chen Huang, Suhas Vasaikar, Susan G. Hilsenbeck, Bing Zhang, Aleksandar Milosavljevic, Michael T. Lewis

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Although systemic chemotherapy remains the standard of care for TNBC, even combination chemotherapy is often ineffective. The identification of biomarkers for differential chemotherapy response would allow for the selection of responsive patients, thus maximizing efficacy and minimizing toxicities. Here, we leverage TNBC PDXs to identify biomarkers of response. To demonstrate their ability to function as a preclinical cohort, PDXs were characterized using DNA sequencing, transcriptomics, and proteomics to show consistency with clinical samples. We then developed a network-based approach (CTD/WGCNA) to identify biomarkers of response to carboplatin (MSI1, TMSB15A, ARHGDIB, GGT1, SV2A, SEC14L2, SERPINI1, ADAMTS20, DGKQ) and docetaxel (c, MAGED4, CERS1, ST8SIA2, KIF24, PARPBP). CTD/WGCNA multigene biomarkers are predictive in PDX datasets (RNAseq and Affymetrix) for both taxane- (docetaxel or paclitaxel) and platinum-based (carboplatin or cisplatin) response, thereby demonstrating cross-expression platform and cross-drug class robustness. These biomarkers were also predictive in clinical datasets, thus demonstrating translational potential.

Original language	English
Article number	105799
Journal	iScience
Volume	26
Issue number	1
DOIs	https://doi.org/10.1016/j.isci.2022.105799
State	Published - Jan 20 2023

Keywords

Cancer
Immune response
Omics

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10.1016/j.isci.2022.105799

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Petrosyan, V., Dobrolecki, L. E., Thistlethwaite, L., Lewis, A. N., Sallas, C., Srinivasan, R. R., Lei, J. T., Kovacevic, V., Obradovic, P., Ellis, M. J., Osborne, C. K., Rimawi, M. F., Pavlick, A., Shafaee, M. N., Dowst, H., Jain, A., Saltzman, A. B., Malovannaya, A., Marangoni, E., ... Lewis, M. T. (2023). Identifying biomarkers of differential chemotherapy response in TNBC patient-derived xenografts with a CTD/WGCNA approach. iScience, 26(1), [105799]. https://doi.org/10.1016/j.isci.2022.105799

@article{f763d58fe23245f1b2a407739d7130a3,

title = "Identifying biomarkers of differential chemotherapy response in TNBC patient-derived xenografts with a CTD/WGCNA approach",

abstract = "Although systemic chemotherapy remains the standard of care for TNBC, even combination chemotherapy is often ineffective. The identification of biomarkers for differential chemotherapy response would allow for the selection of responsive patients, thus maximizing efficacy and minimizing toxicities. Here, we leverage TNBC PDXs to identify biomarkers of response. To demonstrate their ability to function as a preclinical cohort, PDXs were characterized using DNA sequencing, transcriptomics, and proteomics to show consistency with clinical samples. We then developed a network-based approach (CTD/WGCNA) to identify biomarkers of response to carboplatin (MSI1, TMSB15A, ARHGDIB, GGT1, SV2A, SEC14L2, SERPINI1, ADAMTS20, DGKQ) and docetaxel (c, MAGED4, CERS1, ST8SIA2, KIF24, PARPBP). CTD/WGCNA multigene biomarkers are predictive in PDX datasets (RNAseq and Affymetrix) for both taxane- (docetaxel or paclitaxel) and platinum-based (carboplatin or cisplatin) response, thereby demonstrating cross-expression platform and cross-drug class robustness. These biomarkers were also predictive in clinical datasets, thus demonstrating translational potential.",

keywords = "Cancer, Immune response, Omics",

author = "Varduhi Petrosyan and Dobrolecki, {Lacey E.} and Lillian Thistlethwaite and Lewis, {Alaina N.} and Christina Sallas and Srinivasan, {Ramakrishnan R.} and Lei, {Jonathan T.} and Vladimir Kovacevic and Predrag Obradovic and Ellis, {Matthew J.} and Osborne, {C. Kent} and Rimawi, {Mothaffar F.} and Anne Pavlick and Shafaee, {Maryam Nemati} and Heidi Dowst and Antrix Jain and Saltzman, {Alexander B.} and Anna Malovannaya and Elisabetta Marangoni and Welm, {Alana L.} and Welm, {Bryan E.} and Shunqiang Li and Wulf, {Gerburg M.} and Olmo Sonzogni and Chen Huang and Suhas Vasaikar and Hilsenbeck, {Susan G.} and Bing Zhang and Aleksandar Milosavljevic and Lewis, {Michael T.}",

note = "Funding Information: This work was supported by NIH / NCI grants U54 CA224076 (to A.L.W, B.E.W, and M.T.L.), U24 CA226110 , (to M.T.L.), P50 CA186784 (to C.K.O and M.T.L.), Dan L. Duncan Cancer Center (P30 Cancer Center Support Grant NCI-CA125123 ) (to C.K.O.), a grant from the Common Fund of the National Institutes of Health (NIH) ( 5U54 DA036134 ) (to A.M) and the Henry and Emma Meyer Chair in Molecular Genetics (to A.M), and by grant T32 CA203690 from the Translational Breast Cancer Research Training Program (to J.T.L.). This work was also supported by a Core Facility grant from the Cancer Prevention and Research Institute of Texas (CPRIT Core Facilities Support Grant RP170691 ), a grant from the V Foundation , and a generous gift from the Korell family for the study of triple-negative breast cancer. B.Z. is a CPRIT Scholar in Cancer Research, and this work was supported by CPRIT award RR160027 . This work was further supported by the Stand Up to Cancer Dream Team Translational Research Grant (SU2C-AACR-DT0209 (GMW)), DF/HCC Specialized Program of Research Excellence (SPORE) in Breast Cancer, NIH Grant P50 CA168504 (GMW) and the Breast Cancer Research Foundation . Work performed by BCM Mass Spectrometry Proteomics Core was supported by the Dan L. Duncan Comprehensive Cancer Center Award ( P30 CA125123 ) and CPRIT Core Facility Awards ( RP170005 and RP210227 ). Funding Information: M.T.L is a Founder of, and an uncompensated Limited Partner in, StemMed Ltd., and an uncompensated Manager in StemMed Holdings L.L.C., its General Partner. MTL is also a Founder of, and equity stake holder in, Tvardi Therapeutics Inc. L.E.D. is a compensated employee of StemMed Ltd. Selected BCM PDX models described herein are exclusively licensed to StemMed Ltd., resulting in tangible property royalties to M.T.L. and L.E.D. University of Utah may license the HCI PDX models described herein to for-profit companies, which may result in tangible property royalties to A.L.W. and B.E.W. Washington University has licensed selected PDX to Envigo, which results in tangible property royalties to S.L. He also received research funding from Pfizer, Takeda Oncology, and Zenopharm, independent of this project. S.L. has received license fees from Envigo. He received research funding from Pfizer, Takeda Oncology, and Zenopharm, outside of this project. O.S, is a compensated employee of, and equity stake holder in, Bluebird Bio. M.J.E. received consulting fees from Abbvie, Sermonix, Pfizer, AstraZeneca, Celgene, NanoString, Puma, Veracyte, Eli Lilly, and Novartis, and he is an equity stockholder and Board of Directors member of BioClassifier. M.J.E. is an inventor on a patent for the Breast Cancer PAM50-based assay, Prosigna, which is marketed by Veracyte. M.J.E. also receives royalties from Washington University in St Louis when the WHIM PDX lines are licensed to for-profit companies. Publisher Copyright: {\textcopyright} 2022",

year = "2023",

month = jan,

day = "20",

doi = "10.1016/j.isci.2022.105799",

language = "English",

volume = "26",

journal = "iScience",

issn = "2589-0042",

number = "1",

}

Petrosyan, V, Dobrolecki, LE, Thistlethwaite, L, Lewis, AN, Sallas, C, Srinivasan, RR, Lei, JT, Kovacevic, V, Obradovic, P, Ellis, MJ, Osborne, CK, Rimawi, MF, Pavlick, A, Shafaee, MN, Dowst, H, Jain, A, Saltzman, AB, Malovannaya, A, Marangoni, E, Welm, AL, Welm, BE, Li, S, Wulf, GM, Sonzogni, O, Huang, C, Vasaikar, S, Hilsenbeck, SG, Zhang, B, Milosavljevic, A & Lewis, MT 2023, 'Identifying biomarkers of differential chemotherapy response in TNBC patient-derived xenografts with a CTD/WGCNA approach', iScience, vol. 26, no. 1, 105799. https://doi.org/10.1016/j.isci.2022.105799

TY - JOUR

T1 - Identifying biomarkers of differential chemotherapy response in TNBC patient-derived xenografts with a CTD/WGCNA approach

AU - Petrosyan, Varduhi

AU - Dobrolecki, Lacey E.

AU - Thistlethwaite, Lillian

AU - Lewis, Alaina N.

AU - Sallas, Christina

AU - Srinivasan, Ramakrishnan R.

AU - Lei, Jonathan T.

AU - Kovacevic, Vladimir

AU - Obradovic, Predrag

AU - Ellis, Matthew J.

AU - Osborne, C. Kent

AU - Rimawi, Mothaffar F.

AU - Pavlick, Anne

AU - Shafaee, Maryam Nemati

AU - Dowst, Heidi

AU - Jain, Antrix

AU - Saltzman, Alexander B.

AU - Malovannaya, Anna

AU - Marangoni, Elisabetta

AU - Welm, Alana L.

AU - Welm, Bryan E.

AU - Li, Shunqiang

AU - Wulf, Gerburg M.

AU - Sonzogni, Olmo

AU - Huang, Chen

AU - Vasaikar, Suhas

AU - Hilsenbeck, Susan G.

AU - Zhang, Bing

AU - Milosavljevic, Aleksandar

AU - Lewis, Michael T.

N1 - Funding Information: This work was supported by NIH / NCI grants U54 CA224076 (to A.L.W, B.E.W, and M.T.L.), U24 CA226110 , (to M.T.L.), P50 CA186784 (to C.K.O and M.T.L.), Dan L. Duncan Cancer Center (P30 Cancer Center Support Grant NCI-CA125123 ) (to C.K.O.), a grant from the Common Fund of the National Institutes of Health (NIH) ( 5U54 DA036134 ) (to A.M) and the Henry and Emma Meyer Chair in Molecular Genetics (to A.M), and by grant T32 CA203690 from the Translational Breast Cancer Research Training Program (to J.T.L.). This work was also supported by a Core Facility grant from the Cancer Prevention and Research Institute of Texas (CPRIT Core Facilities Support Grant RP170691 ), a grant from the V Foundation , and a generous gift from the Korell family for the study of triple-negative breast cancer. B.Z. is a CPRIT Scholar in Cancer Research, and this work was supported by CPRIT award RR160027 . This work was further supported by the Stand Up to Cancer Dream Team Translational Research Grant (SU2C-AACR-DT0209 (GMW)), DF/HCC Specialized Program of Research Excellence (SPORE) in Breast Cancer, NIH Grant P50 CA168504 (GMW) and the Breast Cancer Research Foundation . Work performed by BCM Mass Spectrometry Proteomics Core was supported by the Dan L. Duncan Comprehensive Cancer Center Award ( P30 CA125123 ) and CPRIT Core Facility Awards ( RP170005 and RP210227 ). Funding Information: M.T.L is a Founder of, and an uncompensated Limited Partner in, StemMed Ltd., and an uncompensated Manager in StemMed Holdings L.L.C., its General Partner. MTL is also a Founder of, and equity stake holder in, Tvardi Therapeutics Inc. L.E.D. is a compensated employee of StemMed Ltd. Selected BCM PDX models described herein are exclusively licensed to StemMed Ltd., resulting in tangible property royalties to M.T.L. and L.E.D. University of Utah may license the HCI PDX models described herein to for-profit companies, which may result in tangible property royalties to A.L.W. and B.E.W. Washington University has licensed selected PDX to Envigo, which results in tangible property royalties to S.L. He also received research funding from Pfizer, Takeda Oncology, and Zenopharm, independent of this project. S.L. has received license fees from Envigo. He received research funding from Pfizer, Takeda Oncology, and Zenopharm, outside of this project. O.S, is a compensated employee of, and equity stake holder in, Bluebird Bio. M.J.E. received consulting fees from Abbvie, Sermonix, Pfizer, AstraZeneca, Celgene, NanoString, Puma, Veracyte, Eli Lilly, and Novartis, and he is an equity stockholder and Board of Directors member of BioClassifier. M.J.E. is an inventor on a patent for the Breast Cancer PAM50-based assay, Prosigna, which is marketed by Veracyte. M.J.E. also receives royalties from Washington University in St Louis when the WHIM PDX lines are licensed to for-profit companies. Publisher Copyright: © 2022

PY - 2023/1/20

Y1 - 2023/1/20

N2 - Although systemic chemotherapy remains the standard of care for TNBC, even combination chemotherapy is often ineffective. The identification of biomarkers for differential chemotherapy response would allow for the selection of responsive patients, thus maximizing efficacy and minimizing toxicities. Here, we leverage TNBC PDXs to identify biomarkers of response. To demonstrate their ability to function as a preclinical cohort, PDXs were characterized using DNA sequencing, transcriptomics, and proteomics to show consistency with clinical samples. We then developed a network-based approach (CTD/WGCNA) to identify biomarkers of response to carboplatin (MSI1, TMSB15A, ARHGDIB, GGT1, SV2A, SEC14L2, SERPINI1, ADAMTS20, DGKQ) and docetaxel (c, MAGED4, CERS1, ST8SIA2, KIF24, PARPBP). CTD/WGCNA multigene biomarkers are predictive in PDX datasets (RNAseq and Affymetrix) for both taxane- (docetaxel or paclitaxel) and platinum-based (carboplatin or cisplatin) response, thereby demonstrating cross-expression platform and cross-drug class robustness. These biomarkers were also predictive in clinical datasets, thus demonstrating translational potential.

AB - Although systemic chemotherapy remains the standard of care for TNBC, even combination chemotherapy is often ineffective. The identification of biomarkers for differential chemotherapy response would allow for the selection of responsive patients, thus maximizing efficacy and minimizing toxicities. Here, we leverage TNBC PDXs to identify biomarkers of response. To demonstrate their ability to function as a preclinical cohort, PDXs were characterized using DNA sequencing, transcriptomics, and proteomics to show consistency with clinical samples. We then developed a network-based approach (CTD/WGCNA) to identify biomarkers of response to carboplatin (MSI1, TMSB15A, ARHGDIB, GGT1, SV2A, SEC14L2, SERPINI1, ADAMTS20, DGKQ) and docetaxel (c, MAGED4, CERS1, ST8SIA2, KIF24, PARPBP). CTD/WGCNA multigene biomarkers are predictive in PDX datasets (RNAseq and Affymetrix) for both taxane- (docetaxel or paclitaxel) and platinum-based (carboplatin or cisplatin) response, thereby demonstrating cross-expression platform and cross-drug class robustness. These biomarkers were also predictive in clinical datasets, thus demonstrating translational potential.

KW - Cancer

KW - Immune response

KW - Omics

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U2 - 10.1016/j.isci.2022.105799

DO - 10.1016/j.isci.2022.105799

M3 - Article

C2 - 36619972

AN - SCOPUS:85144867364

SN - 2589-0042

VL - 26

JO - iScience

JF - iScience

IS - 1

M1 - 105799

ER -

Identifying biomarkers of differential chemotherapy response in TNBC patient-derived xenografts with a CTD/WGCNA approach

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