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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.
LanguageEnglish
Pages1797-1808
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number7
Early online date3 Oct 2016
DOIs
Publication statusPublished - Apr 2017

Fingerprint

Prodrugs
Prostate
Gene Expression
Neoplasms
Prostatic Neoplasms
Growth
Hypoxia
Neoplasm Metastasis
Lung
Microvessels
bicalutamide
Androgens
Blood Vessels
Cell Survival
Research Design
Up-Regulation
Genotype
Apoptosis
Polymerase Chain Reaction
Skin

Keywords

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

Cite this

Nesbitt, Heather ; Byrne, Niall M. ; Williams, S. Nicole ; Ming, Louise ; Worthington, Jenny ; Errington, Rachel J. ; Patterson, Laurence H. ; Smith, Paul J. ; McKeown, Stephanie ; McKenna, Declan. / Targeting Hypoxic Prostate Tumors Using the Novel Hypoxia-Activated Prodrug OCT1002 Inhibits Expression of Genes Associated with Malignant Progression. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 7. pp. 1797-1808.
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title = "Targeting Hypoxic Prostate Tumors Using the Novel Hypoxia-Activated Prodrug OCT1002 Inhibits Expression of Genes Associated with Malignant Progression",
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.",
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author = "Heather Nesbitt and Byrne, {Niall M.} and Williams, {S. Nicole} and Louise Ming and Jenny Worthington and Errington, {Rachel J.} and Patterson, {Laurence H.} and Smith, {Paul J.} and Stephanie McKeown and Declan McKenna",
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Targeting Hypoxic Prostate Tumors Using the Novel Hypoxia-Activated Prodrug OCT1002 Inhibits Expression of Genes Associated with Malignant Progression. / Nesbitt, Heather; Byrne, Niall M.; Williams, S. Nicole; Ming, Louise; Worthington, Jenny; Errington, Rachel J.; Patterson, Laurence H.; Smith, Paul J.; McKeown, Stephanie; McKenna, Declan.

In: Clinical Cancer Research, Vol. 23, No. 7, 04.2017, p. 1797-1808.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Targeting Hypoxic Prostate Tumors Using the Novel Hypoxia-Activated Prodrug OCT1002 Inhibits Expression of Genes Associated with Malignant Progression

AU - Nesbitt, Heather

AU - Byrne, Niall M.

AU - Williams, S. Nicole

AU - Ming, Louise

AU - Worthington, Jenny

AU - Errington, Rachel J.

AU - Patterson, Laurence H.

AU - Smith, Paul J.

AU - McKeown, Stephanie

AU - McKenna, Declan

PY - 2017/4

Y1 - 2017/4

N2 - 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.

AB - 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.

KW - OCT1002

KW - tumor hypoxia

KW - hypoxia-activated prodrug

KW - prostate

KW - bicalutamide

U2 - 10.1158/1078-0432.CCR-16-1361

DO - 10.1158/1078-0432.CCR-16-1361

M3 - Article

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JO - Clinical Cancer Research

T2 - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

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