Abstract 818: New targets in prostate cancer: Nuclear localization of galectin-1 in androgen receptor indifferent prostate cancer

Abstract

Abstract Currently, no morphological characteristics have been described in clinical specimens to delineate an androgen receptor (AR)-active from an AR-inactive phenotype in AR-expressing aggressive variant prostate cancer (AVPC). 36 localized and 51 metastatic prostate cancer (CaP) samples were analyzed - 19 (37.3%) of the metastases were in the bone, 20 (39.2%) were in the lung, while the rest were in other areas such as brain, lymph node, bladder, etc). Expression level of Gal-1 was graded individually in the nucleus and the cytoplasm of both primary and metastatic tissues. Very low Gal-1 expression was observed in epithelial cells of benign prostate, while stromal staining was strong. Localized prostate tumors obtained from prostatectomy samples showed strong gal-1 expression in the epithelial cells, but remarkably the Gal-1 staining was confined to the cytoplasm. In contrast, in metastatic tumors many nuclei stained for Gal-1. Among localized tumors, Kaplan-Meier curves showed a significant increase in metastasis formation (p=0.022) and decreased overall survival (p=0.015) among those expressing nuclear Gal-1 (n=16) compared to those with no nuclear Gal-1 (n=20). Whereas cytoplasmic Gal-1 negatively correlated with patient age (R=-0.51, p=0.008) and PSA (R=-0.41, p=0.006), and positively correlated with Ki67 (R=0.35, p=0.014), the expression of nuclear Gal-1 correlated strongly with the expression of NE markers including chromogranin A (R=0.32, p=0.031). Significantly, nuclear Gal-1 was expressed in AVPC models but not in those derived from localized tissues. Significantly, androgen deprivation, including treatment with AR antagonists, resulted in nuclear localization of Gal-1. We adapted the powerful one-bead-two-compound (OB2C) combinatorial library method for the discovery of synthetic small molecule death ligands against cancer cells in an ultra-high throughput fashion. One of these benzimidazole-based ligands, LLS80, was active against tumor cells at low micromolar IC50. Pull-down assay followed by LC MS/MS indicated that galectin-1 is the target protein of LLS80, which induced apoptosis preferentially in AVPC cells expressing high level of Gal-1. LLS80 has all the indicators of being a good therapeutic agent: (i) LLS80 has a low in vitro IC50 in AVPC cells, (ii) it shows significant in vivo anti-tumor efficacy using xenograft models, (iii) it is a novel small molecule that can penetrate AVPC cells, (iv) it can synergize with enzalutamide in vivo and in vitro, (v) it inhibits a known therapeutic target, Gal-1, and (vi) low toxicity. Treatment with LLS80 (2 µM) prevented AR antagonist-induced Gal-1 nuclear localization, and also downregulated NE markers in AVPC models of CaP progression. We conclude that nuclear Gal-1 is a novel marker of AVPC. Citation Format: Maria Malvina Tsamouri, Salma Siddiqui, Blythe P. Durbin-Johnson, Kit S. Lam, Ruiwu Liu, Paramita M. Ghosh. New targets in prostate cancer: Nuclear localization of galectin-1 in androgen receptor indifferent prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 818.