Targeting Hypoxic Prostate Tumors Using the Novel Hypoxia-Activated Prodrug OCT1002 Inhibits Expression of Genes Associated with Malignant Progression

Heather Nesbitt, Niall M. Byrne, S. Nicole Williams, Louise Ming, Jenny Worthington, Rachel J. Errington, Laurence H. Patterson, Paul J. Smith, Stephanie McKeown, Declan McKenna

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Abstract

Purpose To understand the role of hypoxia in prostate tumor progression, and to evaluate the ability of the novel unidirectional hypoxia-activated prodrug OCT1002 to enhance the anti-tumor effect of bicalutamide. Experimental Design The effect of OCT1002 on prostate cancer cells (LNCaP, 22Rv1, PC3) was measured in normoxia and hypoxia in vitro. In vivo, tumor growth and lung metastases were measured in mice treated with bicalutamide, OCT1002, or a combination. Dorsal skin fold chambers were used to image tumor vasculature in vivo. Longitudinal gene expression changes in tumors were analysed using PCR. Results Reduction of OCT1002 to its active form (OCT1001) decreased prostate cancer cell viability. In LNCaP-luc spheroids, OCT1002 caused increased apoptosis and decreased clonogenicity. In vivo, treatment with OCT1002 alone, or with bicalutamide, showed significantly greater tumor growth control and reduced lung metastases compared to controls. Re-establishment of the tumor microvasculature following bicalutamide-induced vascular collapse is inhibited by OCT1002. Significantly, the up-regulation of RUNX2 and its targets caused by bicalutamide alone were blocked by OCT1002. Conclusions OCT1002 selectively targets hypoxic tumor cells and enhances the anti-tumor efficacy of bicalutamide. Furthermore, bicalutamide caused changes in gene expression which indicated progression to a more malignant genotype; OCT1002 blocked these effects, emphasising that more attention should be attached to understanding genetic changes that may occur during treatment. Early targeting of hypoxic cells with OCT1002 can provide a means of inhibiting prostate tumor growth and malignant progression. This is of importance for the design and refinement of existing androgen-deprivation regimens in the clinic.
Original languageEnglish
Pages (from-to)1797-1808
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number7
Early online date3 Oct 2016
DOIs
Publication statusPublished - 30 Apr 2017

Keywords

  • OCT1002
  • tumor hypoxia
  • hypoxia-activated prodrug
  • prostate
  • bicalutamide

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