Expression and therapeutic targeting of Trop-2 in treatment resistant prostate cancer.

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 (ADCs).

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 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.

We demonstrated 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 circulating tumor cells, 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.

These results support further studies on Trop-2 as a therapeutic and diagnostic target for mCRPC.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2023 Mar 20 [Epub ahead of print]

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

University of Wisconsin-Madison, Madison, WISCONSIN, United States., University of Wisconsin-Madison, Madison, Wisconsin, United States., Wuhan Union Hospital, Wuhan, Hubei, China., University of Wisconsin-Madison, Madison, WI, United States., Mayo Clinic, Rochester, MN, United States., University of Minnesota, Austin, United States., University of Minnesota, AUSTIN, MN, United States., Shenzhen University, Shenzhen, China., Memorial Sloan Kettering Cancer Center, New York, NY, United States., Prostate Cancer Foundation, Santa Monica, CA, United States., Huntsman Cancer Institute, Salt Lake City, UT, United States., Weill Cornell Medicine, New York, NY, United States., University of Minnesota, Minneapolis, MN, United States.