Neuroendocrine differentiation of prostate cancer leads to PSMA suppression.

Keon Wook Kang,Abdulkadir Hussein,So Won Oh,Chang Wook Jeong,Hyewon Youn,Alastair D Lamb,Yuzhuo Wang,Mark Dunning,Keith F Stringer,Yinan Li,Gi Jeong Cheon,Rosa-Maria Ferraiuolo,Lisa A Porter,Cheol Kwak,Xuesen Dong,Martin K Bakht,Iulian Derecichei

doi:10.1530/erc-18-0226

Abstract

Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate adenocarcinoma (AdPC) cells and acts as a target for molecular imaging. However, some case reports indicate that PSMA-targeted imaging could be ineffectual for delineation of neuroendocrine (NE) prostate cancer (NEPC) lesions due to the suppression of the PSMA gene (FOLH1). These same reports suggest that targeting somatostatin receptor type 2 (SSTR2) could be an alternative diagnostic target for NEPC patients. This study evaluates the correlation between expression of FOLH1, NEPC marker genes and SSTR2. We evaluated the transcript abundance for FOLH1 and SSTR2 genes as well as NE markers across 909 tumors. A significant suppression of FOLH1 in NEPC patient samples and AdPC samples with high expression of NE marker genes was observed. We also investigated protein alterations of PSMA and SSTR2 in an NE-induced cell line derived by hormone depletion and lineage plasticity by loss of p53. PSMA is suppressed following NE induction and cellular plasticity in p53-deficient NEPC model. The PSMA-suppressed cells have more colony formation ability and resistance to enzalutamide treatment. Conversely, SSTR2 was only elevated following hormone depletion. In 18 NEPC patient-derived xenograft (PDX) models we find a significant suppression of FOLH1 and amplification of SSTR2 expression. Due to the observed FOLH1-supressed signature of NEPC, this study cautions on the reliability of using PMSA as a target for molecular imaging of NEPC. The observed elevation of SSTR2 in NEPC supports the possible ability of SSTR2-targeted imaging for follow-up imaging of low PSMA patients and monitoring for NEPC development.

Highlights

The main treatment protocol for patients suffering from castration-resistant prostate cancer (CRPC) is androgen receptor pathway inhibition (ARPI)
The use of potent antiandrogens and lineage plasticity may contribute to the increasing prevalence of neuroendocrine prostate cancer (NEPC), an aggressive and hormone-resistant form of AdPC
While prostatespecific membrane antigen (PSMA) targeting is a promising approach for the nuclear imaging and therapy of many forms of aggressive AdPC, our data based on transcriptome analysis of tumor samples, cell line models and patient-derived xenograft (PDX) mice models supports that PSMA (FOLH1 gene) levels are not consistent with all forms of high-grade CRPC

Summary

Introduction

The main treatment protocol for patients suffering from castration-resistant prostate cancer (CRPC) is androgen receptor pathway inhibition (ARPI). Despite the positive implications of PSMA for many forms of advanced AdPC there are clinical reports supporting that PSMA-targeted imaging is not able to delineate NEPC tumors (Parimi et al 2014, Chakraborty et al 2015, Sheikhbahaei et al 2017, Tosoian et al 2017, Usmani et al 2017). NEPC patients did not show substantial PSMA-radioligand uptake, in one case, this was described due to a downregulation of PSMA (Chakraborty et al 2015, Tosoian et al 2017, Usmani et al 2017, Parida et al 2018). The relevance of these clinical reports has not been investigated

Methods

Results

Discussion

Conclusion