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Background <p>Advanced prostate cancer (PCa), particularly enzalutamide-resistant, bone-metastatic castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC), remains an intractable clinical challenge due to oncogenic crosstalk across multiple pathways and tumor microenvironment (TME) heterogeneity. Given these unmet clinical needs, novel targeted therapeutics are urgently required to improve advanced PCa patient outcomes.</p> Methods <p>In this study, we examined the expression of integrin subtypes, particularly pan-αv integrins and α5β1, in prostate cancertumor samples and cell lines using immunohistochemistry (IHC) and Western blotting. Based on rational drug design, we synthesized a first-in-class, orally bioavailable, non-RGD pan-αv/α5β1 integrin antagonist, C19-9N, and characterized it through homology modeling, molecular docking, surface plasmon resonance (SPR), and microscale thermophoresis (MST). The antitumor activity of C19-9N was evaluated in vitro (via assays of cell viability, migration and invasion) and in vivo using multiple models, including subcutaneous xenografts of CRPC, bone-metastatic xenograft models established by intratibial and intracardiac injection, and patient-derived xenografts (PDXs) of NEPC. The in vivo safety and pharmacokinetic profile of C19-9N were also assessed. Mechanistically, single-cell RNA sequencing (scRNA-seq) was employed to uncover the regulatory effects of C19-9N on infiltrating immune cells within the tumor microenvironment, which were further validated through multiplex immunofluorescence and bone marrow-derived macrophage-mediated phagocytosis assays.</p> Results <p>C19-9N targeting pan-αv and α5β1 integrin circumvented potential compensatory resistance mediated by integrin subtype switching. C19-9N disrupted extracellular matrix (ECM)-integrin biochemical and mechanical signaling, thereby suppressing cancer stem cell (CSC) self-renewal and epithelial-to-mesenchymal transition (EMT). Mechanistically, C19-9N inhibited PI3K/AKT and STAT3 signaling pathways to block alternative splicing of AR-V7, and modulated Survivin and c-Myc to enhance enzalutamide sensitivity. Additionally, it remodeled TME by repolarizing tumor-associated macrophages (TAMs) toward a pro-inflammatory phenotype and downregulating CD47-mediated immune escape. In preclinical models, C19-9N overcame enzalutamide resistance in CRPC xenografts, suppressed bone metastatic progression, and exhibited superior efficacy to platinum/taxane therapies in NEPC.</p> Conclusion <p>Collectively, by co-targeting oncogenic drivers and TME vulnerabilities, C19-9N heralds a transformative therapeutic paradigm with profound clinical potential for aggressive PCa.</p>

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An orally bioavailable pan-αv/α5β1 integrin antagonist prevents aggressive prostate cancer progression via suppressing both oncogenic signals and CD47-mediated immune escape

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Yanlun Gu,
  • Bingqi Dong,
  • Xia Teng,
  • Lin Chen,
  • Yang Yang,
  • Xiaojiao Sun,
  • Song Song,
  • Binzhi Qian,
  • Yufang Sun,
  • Jixin Zhang,
  • Zhigang Zheng,
  • Yuke Chen,
  • Yimin Cui,
  • Zhuona Rong,
  • Xiaocong Pang

摘要

Background

Advanced prostate cancer (PCa), particularly enzalutamide-resistant, bone-metastatic castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC), remains an intractable clinical challenge due to oncogenic crosstalk across multiple pathways and tumor microenvironment (TME) heterogeneity. Given these unmet clinical needs, novel targeted therapeutics are urgently required to improve advanced PCa patient outcomes.

Methods

In this study, we examined the expression of integrin subtypes, particularly pan-αv integrins and α5β1, in prostate cancertumor samples and cell lines using immunohistochemistry (IHC) and Western blotting. Based on rational drug design, we synthesized a first-in-class, orally bioavailable, non-RGD pan-αv/α5β1 integrin antagonist, C19-9N, and characterized it through homology modeling, molecular docking, surface plasmon resonance (SPR), and microscale thermophoresis (MST). The antitumor activity of C19-9N was evaluated in vitro (via assays of cell viability, migration and invasion) and in vivo using multiple models, including subcutaneous xenografts of CRPC, bone-metastatic xenograft models established by intratibial and intracardiac injection, and patient-derived xenografts (PDXs) of NEPC. The in vivo safety and pharmacokinetic profile of C19-9N were also assessed. Mechanistically, single-cell RNA sequencing (scRNA-seq) was employed to uncover the regulatory effects of C19-9N on infiltrating immune cells within the tumor microenvironment, which were further validated through multiplex immunofluorescence and bone marrow-derived macrophage-mediated phagocytosis assays.

Results

C19-9N targeting pan-αv and α5β1 integrin circumvented potential compensatory resistance mediated by integrin subtype switching. C19-9N disrupted extracellular matrix (ECM)-integrin biochemical and mechanical signaling, thereby suppressing cancer stem cell (CSC) self-renewal and epithelial-to-mesenchymal transition (EMT). Mechanistically, C19-9N inhibited PI3K/AKT and STAT3 signaling pathways to block alternative splicing of AR-V7, and modulated Survivin and c-Myc to enhance enzalutamide sensitivity. Additionally, it remodeled TME by repolarizing tumor-associated macrophages (TAMs) toward a pro-inflammatory phenotype and downregulating CD47-mediated immune escape. In preclinical models, C19-9N overcame enzalutamide resistance in CRPC xenografts, suppressed bone metastatic progression, and exhibited superior efficacy to platinum/taxane therapies in NEPC.

Conclusion

Collectively, by co-targeting oncogenic drivers and TME vulnerabilities, C19-9N heralds a transformative therapeutic paradigm with profound clinical potential for aggressive PCa.