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Predictive and targeting value of IGFBP-3 in therapeutically resistant prostate cancer
Patrick J Hensley1, Zheng Cao1,2, Hong Pu1
1Department of Urology, University of Kentucky Lexington, KY, USA.
Background:
Our previous studies demonstrated that a novel quinazoline derivative, DZ-50, inhibited prostate cancer epithelial cell invasion and survival by targeting insulin-like-growth factor binding protein-3 (IGFBP-3) and mediating epithelial-mesenchymal transition (EMT) conversion to mesenchymal-epithelial transition (MET). This study investigated the therapeutic value of DZ-50 agent in in vitro and in vivo models of advanced prostate cancer and the ability of the compound to overcome resistance to antiandrogen (enzalutamide) in prostate tumors.
Approach:
LNCaP and LNCaP-enzalutamide resistant human prostate cancer (LNCaP-ER) cells, as well as 22Rv1 and enzalutamide resistant, 22Rv1-ER were used as cell models. The effects of DZ-50 and the antiandrogen, enzalutamide (as single agents or in combination) on cell death, EMT-MET interconversion, and expression of IGFBP3 and the androgen receptor (AR), were examined. The TRAMP mouse model of prostate cancer progression was used as a pre-clinical model. Transgenic mice (20-wks of age) were treated with DZ-50 (100 mg/kg for 2 wks, oral gavage daily) and prostate tumors were subjected to immunohistochemical assessment of apoptosis, cell proliferation, markers of EMT and differentiation and IGFBP-3 and AR expression. A tissue microarray (TMA) was analyzed for expression of IGBP-3, the target of DZ-50 and its association with tumor progression and biochemical recurrence.
Results:
We found that treatment with DZ-50 enhanced the anti-tumor response to the antiandrogen via promoting EMT to MET interconversion, in vitro. This DZ-50-mediated phenotypic reversal to MET leads to prostate tumor re-differentiation in vivo, by targeting nuclear IGFBP-3 expression (without affecting AR). Analysis of human prostate cancer specimens and TCGA patient cohorts revealed that overexpression of IGBP-3 protein correlated with tumor recurrence and poor patient survival.
Conclusions:
These findings provide significant new insights into (a) the predictive value of IGFBP-3 in prostate cancer progression and (b) the antitumor action of DZ-50, [in combination or sequencing with enzalutamide] as a novel approach for the treatment of therapeutically resistant prostate cancer.
Insights
The novel agent DZ-50 enhances anti-androgen therapy in prostate cancer by reversing epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET). This approach targets insulin-like growth factor binding protein-3 (IGFBP-3) to overcome treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Previous studies identified DZ-50, a quinazoline derivative, as an inhibitor of prostate cancer cell invasion and survival.
- DZ-50 targets insulin-like growth factor binding protein-3 (IGFBP-3) and mediates epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET).
Purpose of the Study:
- To investigate the therapeutic potential of DZ-50 in advanced prostate cancer models.
- To evaluate DZ-50's ability to overcome enzalutamide resistance in prostate tumors.
Main Methods:
- Utilized LNCaP and 22Rv1 cell lines, including enzalutamide-resistant variants (LNCaP-ER, 22Rv1-ER).
- Assessed effects of DZ-50 and enzalutamide on cell death, EMT-MET interconversion, IGFBP-3, and androgen receptor (AR) expression.
- Employed the TRAMP mouse model for in vivo studies, including immunohistochemical analysis of tumors and tissue microarrays.
Main Results:
- DZ-50 enhanced anti-tumor response to enzalutamide by promoting EMT to MET interconversion in vitro.
- DZ-50 induced prostate tumor redifferentiation in vivo by targeting nuclear IGFBP-3 expression.
- Overexpression of IGFBP-3 correlated with tumor recurrence and poor survival in human prostate cancer specimens and TCGA cohorts.
Conclusions:
- IGFBP-3 holds predictive value for prostate cancer progression.
- DZ-50, alone or in combination with enzalutamide, represents a novel therapeutic strategy for treatment-resistant prostate cancer.
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