Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer

Jamie M. Sperger; Kyle T. Helzer; Charlotte N. Stahlfeld; Dawei Jiang; Anupama Singh; Katherine R. Kaufmann; David J. Niles; Erika Heninger; Nicholas R. Rydzewski; Liguo Wang; Liewei Wang; Rendong Yang; Yanan Ren; Jonathan W. Engle; Peng Huang; Christos E. Kyriakopoulos; Susan F. Slovin; Howard R. Soule; Shuang G. Zhao; Manish Kohli; Scott T. Tagawa; Weibo Cai; Scott M. Dehm; Joshua M. Lang

doi:10.1158/1078-0432.CCR-22-1305

Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer

Jamie M. Sperger, Kyle T. Helzer, Charlotte N. Stahlfeld, Dawei Jiang, Anupama Singh, Katherine R. Kaufmann, David J. Niles, Erika Heninger, Nicholas R. Rydzewski, Liguo Wang, Liewei Wang, Rendong Yang, Yanan Ren, Jonathan W. Engle, Peng Huang, Christos E. Kyriakopoulos, Susan F. Slovin, Howard R. Soule, Shuang G. Zhao, Manish KohliScott T. Tagawa, Weibo Cai, Scott M. Dehm, Joshua M. Lang

Urology

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

Abstract

PURPOSE: Men with metastatic castration-resistant prostate cancer (mCRPC) frequently develop resistance to androgen receptor signaling inhibitor (ARSI) treatment; therefore, new therapies are needed. Trophoblastic cell-surface antigen (TROP-2) is a transmembrane protein identified in prostate cancer and overexpressed in multiple malignancies. TROP-2 is a therapeutic target for antibody-drug conjugates (ADC). EXPERIMENTAL DESIGN: TROP-2 gene (TACSTD2) expression and markers of treatment resistance from prostate biopsies were analyzed using data from four previously curated cohorts of mCRPC (n = 634) and the PROMOTE study (dbGaP accession phs001141.v1.p1, n = 88). EPCAM or TROP-2-positive circulating tumor cells (CTC) were captured from peripheral blood for comparison of protein (n = 15) and gene expression signatures of treatment resistance (n = 40). We assessed the efficacy of TROP-2-targeting agents in a mouse xenograft model generated from prostate cancer cell lines. RESULTS: We demonstrated that TACSTD2 is expressed in mCRPC from luminal and basal tumors but at lower levels in patients with neuroendocrine prostate cancer. Patients previously treated with ARSI showed no significant difference in TACSTD2 expression, whereas patients with detectable AR-V7 expression showed increased expression. We observed that TROP-2 can serve as a cell surface target for isolating CTCs, which may serve as a predictive biomarker for ADCs. We also demonstrated that prostate cancer cell line xenografts can be targeted specifically by labeled anti-TROP-2 agents in vivo. CONCLUSIONS: These results support further studies on TROP-2 as a therapeutic and diagnostic target for mCRPC.

Original language	English (US)
Pages (from-to)	2324-2335
Number of pages	12
Journal	Clinical cancer research : an official journal of the American Association for Cancer Research
Volume	29
Issue number	12
DOIs	https://doi.org/10.1158/1078-0432.CCR-22-1305
State	Published - Jun 13 2023

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Medicine(all)

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10.1158/1078-0432.CCR-22-1305

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Sperger, J. M., Helzer, K. T., Stahlfeld, C. N., Jiang, D., Singh, A., Kaufmann, K. R., Niles, D. J., Heninger, E., Rydzewski, N. R., Wang, L., Wang, L., Yang, R., Ren, Y., Engle, J. W., Huang, P., Kyriakopoulos, C. E., Slovin, S. F., Soule, H. R., Zhao, S. G., ... Lang, J. M. (2023). Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 29(12), 2324-2335. https://doi.org/10.1158/1078-0432.CCR-22-1305

@article{c75a0cbf35394e11855c6d978e5cff39,

title = "Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer",

abstract = "PURPOSE: Men with metastatic castration-resistant prostate cancer (mCRPC) frequently develop resistance to androgen receptor signaling inhibitor (ARSI) treatment; therefore, new therapies are needed. Trophoblastic cell-surface antigen (TROP-2) is a transmembrane protein identified in prostate cancer and overexpressed in multiple malignancies. TROP-2 is a therapeutic target for antibody-drug conjugates (ADC). EXPERIMENTAL DESIGN: TROP-2 gene (TACSTD2) expression and markers of treatment resistance from prostate biopsies were analyzed using data from four previously curated cohorts of mCRPC (n = 634) and the PROMOTE study (dbGaP accession phs001141.v1.p1, n = 88). EPCAM or TROP-2-positive circulating tumor cells (CTC) were captured from peripheral blood for comparison of protein (n = 15) and gene expression signatures of treatment resistance (n = 40). We assessed the efficacy of TROP-2-targeting agents in a mouse xenograft model generated from prostate cancer cell lines. RESULTS: We demonstrated that TACSTD2 is expressed in mCRPC from luminal and basal tumors but at lower levels in patients with neuroendocrine prostate cancer. Patients previously treated with ARSI showed no significant difference in TACSTD2 expression, whereas patients with detectable AR-V7 expression showed increased expression. We observed that TROP-2 can serve as a cell surface target for isolating CTCs, which may serve as a predictive biomarker for ADCs. We also demonstrated that prostate cancer cell line xenografts can be targeted specifically by labeled anti-TROP-2 agents in vivo. CONCLUSIONS: These results support further studies on TROP-2 as a therapeutic and diagnostic target for mCRPC.",

author = "Sperger, {Jamie M.} and Helzer, {Kyle T.} and Stahlfeld, {Charlotte N.} and Dawei Jiang and Anupama Singh and Kaufmann, {Katherine R.} and Niles, {David J.} and Erika Heninger and Rydzewski, {Nicholas R.} and Liguo Wang and Liewei Wang and Rendong Yang and Yanan Ren and Engle, {Jonathan W.} and Peng Huang and Kyriakopoulos, {Christos E.} and Slovin, {Susan F.} and Soule, {Howard R.} and Zhao, {Shuang G.} and Manish Kohli and Tagawa, {Scott T.} and Weibo Cai and Dehm, {Scott M.} and Lang, {Joshua M.}",

note = "Publisher Copyright: {\textcopyright}2023 The Authors; Published by the American Association for Cancer Research.",

year = "2023",

month = jun,

day = "13",

doi = "10.1158/1078-0432.CCR-22-1305",

language = "English (US)",

volume = "29",

pages = "2324--2335",

journal = "Clinical cancer research : an official journal of the American Association for Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "12",

}

Sperger, JM, Helzer, KT, Stahlfeld, CN, Jiang, D, Singh, A, Kaufmann, KR, Niles, DJ, Heninger, E, Rydzewski, NR, Wang, L, Wang, L, Yang, R, Ren, Y, Engle, JW, Huang, P, Kyriakopoulos, CE, Slovin, SF, Soule, HR, Zhao, SG, Kohli, M, Tagawa, ST, Cai, W, Dehm, SM & Lang, JM 2023, 'Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer', Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 29, no. 12, pp. 2324-2335. https://doi.org/10.1158/1078-0432.CCR-22-1305

TY - JOUR

T1 - Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer

AU - Sperger, Jamie M.

AU - Helzer, Kyle T.

AU - Stahlfeld, Charlotte N.

AU - Jiang, Dawei

AU - Singh, Anupama

AU - Kaufmann, Katherine R.

AU - Niles, David J.

AU - Heninger, Erika

AU - Rydzewski, Nicholas R.

AU - Wang, Liguo

AU - Wang, Liewei

AU - Yang, Rendong

AU - Ren, Yanan

AU - Engle, Jonathan W.

AU - Huang, Peng

AU - Kyriakopoulos, Christos E.

AU - Slovin, Susan F.

AU - Soule, Howard R.

AU - Zhao, Shuang G.

AU - Kohli, Manish

AU - Tagawa, Scott T.

AU - Cai, Weibo

AU - Dehm, Scott M.

AU - Lang, Joshua M.

PY - 2023/6/13

Y1 - 2023/6/13

N2 - PURPOSE: Men with metastatic castration-resistant prostate cancer (mCRPC) frequently develop resistance to androgen receptor signaling inhibitor (ARSI) treatment; therefore, new therapies are needed. Trophoblastic cell-surface antigen (TROP-2) is a transmembrane protein identified in prostate cancer and overexpressed in multiple malignancies. TROP-2 is a therapeutic target for antibody-drug conjugates (ADC). EXPERIMENTAL DESIGN: TROP-2 gene (TACSTD2) expression and markers of treatment resistance from prostate biopsies were analyzed using data from four previously curated cohorts of mCRPC (n = 634) and the PROMOTE study (dbGaP accession phs001141.v1.p1, n = 88). EPCAM or TROP-2-positive circulating tumor cells (CTC) were captured from peripheral blood for comparison of protein (n = 15) and gene expression signatures of treatment resistance (n = 40). We assessed the efficacy of TROP-2-targeting agents in a mouse xenograft model generated from prostate cancer cell lines. RESULTS: We demonstrated that TACSTD2 is expressed in mCRPC from luminal and basal tumors but at lower levels in patients with neuroendocrine prostate cancer. Patients previously treated with ARSI showed no significant difference in TACSTD2 expression, whereas patients with detectable AR-V7 expression showed increased expression. We observed that TROP-2 can serve as a cell surface target for isolating CTCs, which may serve as a predictive biomarker for ADCs. We also demonstrated that prostate cancer cell line xenografts can be targeted specifically by labeled anti-TROP-2 agents in vivo. CONCLUSIONS: These results support further studies on TROP-2 as a therapeutic and diagnostic target for mCRPC.

AB - PURPOSE: Men with metastatic castration-resistant prostate cancer (mCRPC) frequently develop resistance to androgen receptor signaling inhibitor (ARSI) treatment; therefore, new therapies are needed. Trophoblastic cell-surface antigen (TROP-2) is a transmembrane protein identified in prostate cancer and overexpressed in multiple malignancies. TROP-2 is a therapeutic target for antibody-drug conjugates (ADC). EXPERIMENTAL DESIGN: TROP-2 gene (TACSTD2) expression and markers of treatment resistance from prostate biopsies were analyzed using data from four previously curated cohorts of mCRPC (n = 634) and the PROMOTE study (dbGaP accession phs001141.v1.p1, n = 88). EPCAM or TROP-2-positive circulating tumor cells (CTC) were captured from peripheral blood for comparison of protein (n = 15) and gene expression signatures of treatment resistance (n = 40). We assessed the efficacy of TROP-2-targeting agents in a mouse xenograft model generated from prostate cancer cell lines. RESULTS: We demonstrated that TACSTD2 is expressed in mCRPC from luminal and basal tumors but at lower levels in patients with neuroendocrine prostate cancer. Patients previously treated with ARSI showed no significant difference in TACSTD2 expression, whereas patients with detectable AR-V7 expression showed increased expression. We observed that TROP-2 can serve as a cell surface target for isolating CTCs, which may serve as a predictive biomarker for ADCs. We also demonstrated that prostate cancer cell line xenografts can be targeted specifically by labeled anti-TROP-2 agents in vivo. CONCLUSIONS: These results support further studies on TROP-2 as a therapeutic and diagnostic target for mCRPC.

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UR - http://www.scopus.com/inward/citedby.url?scp=85163252635&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-22-1305

DO - 10.1158/1078-0432.CCR-22-1305

M3 - Article

C2 - 36939530

AN - SCOPUS:85163252635

SN - 1078-0432

VL - 29

SP - 2324

EP - 2335

JO - Clinical cancer research : an official journal of the American Association for Cancer Research

JF - Clinical cancer research : an official journal of the American Association for Cancer Research

IS - 12

ER -

Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer

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