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Androgen deprivation therapy potentiates the efficacy of vascular targeted photodynamic therapy of prostate cancer xenografts

Kim, Kwanghee ; Watson, Philip A. ; Lebdai, Souhil ; Jebiwott, Sylvia ; Somma, Alexander J. ; Rosa, Stephen La ; Mehta, Dipti ; Murray, Katie S. ; Lilja, Hans LU orcid and Ulmert, David LU , et al. (2018) In Clinical Cancer Research 24(10). p.2408-2416
Abstract

Purpose: WST11 vascular targeted photodynamic therapy (VTP) is a local ablation approach relying upon rapid, free radical-mediated destruction of tumor vasculature. A phase III trial showed that VTP significantly reduced disease progression when compared with active surveillance in patients with low-risk prostate cancer. The aim of this study was to identify a druggable pathway that could be combined with VTP to improve its efficacy and applicability to higher risk prostate cancer tumors. Experimental Design: Transcriptome analysis of VTP-treated tumors (LNCaP-AR xenografts) was used to identify a candidate pathway for combination therapy. The efficacy of the combination therapy was assessed in mice bearing LNCaP-AR or VCaP tumors.... (More)

Purpose: WST11 vascular targeted photodynamic therapy (VTP) is a local ablation approach relying upon rapid, free radical-mediated destruction of tumor vasculature. A phase III trial showed that VTP significantly reduced disease progression when compared with active surveillance in patients with low-risk prostate cancer. The aim of this study was to identify a druggable pathway that could be combined with VTP to improve its efficacy and applicability to higher risk prostate cancer tumors. Experimental Design: Transcriptome analysis of VTP-treated tumors (LNCaP-AR xenografts) was used to identify a candidate pathway for combination therapy. The efficacy of the combination therapy was assessed in mice bearing LNCaP-AR or VCaP tumors. Results: Gene set enrichment analysis identifies the enrichment of androgen-responsive gene sets within hours after VTP treatment, suggesting that the androgen receptor (AR) may be a viable target in combination with VTP. We tested this hypothesis in mice bearing LNCaP-AR xenograft tumors by using androgen deprivation therapy (ADT), degarelix, in combination with VTP. Compared with either ADT or VTP alone, a single dose of degarelix in concert with VTP significantly inhibited tumor growth. A sharp decline in serum prostate-specific antigen (PSA) confirmed AR inhibition in this group. Tumors treated by VTP and degarelix displayed intense terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining 7 days after treatment, supporting an increased apoptotic frequency underlying the effect on tumor inhibition. Conclusions: Improvement of local tumor control following androgen deprivation combined with VTP provides the rationale and preliminary protocol parameters for clinical trials in patients presented with locally advanced prostate cancer.

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publishing date
type
Contribution to journal
publication status
published
in
Clinical Cancer Research
volume
24
issue
10
pages
2408 - 2416
publisher
American Association for Cancer Research
external identifiers
  • pmid:29463549
  • scopus:85047832934
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-17-3474
language
English
LU publication?
no
additional info
Publisher Copyright: © 2018 American Association for Cancer Research.
id
71b3e8bd-7278-4c39-8d57-0f429d887512
date added to LUP
2022-12-06 14:11:24
date last changed
2024-04-04 13:47:42
@article{71b3e8bd-7278-4c39-8d57-0f429d887512,
  abstract     = {{<p>Purpose: WST11 vascular targeted photodynamic therapy (VTP) is a local ablation approach relying upon rapid, free radical-mediated destruction of tumor vasculature. A phase III trial showed that VTP significantly reduced disease progression when compared with active surveillance in patients with low-risk prostate cancer. The aim of this study was to identify a druggable pathway that could be combined with VTP to improve its efficacy and applicability to higher risk prostate cancer tumors. Experimental Design: Transcriptome analysis of VTP-treated tumors (LNCaP-AR xenografts) was used to identify a candidate pathway for combination therapy. The efficacy of the combination therapy was assessed in mice bearing LNCaP-AR or VCaP tumors. Results: Gene set enrichment analysis identifies the enrichment of androgen-responsive gene sets within hours after VTP treatment, suggesting that the androgen receptor (AR) may be a viable target in combination with VTP. We tested this hypothesis in mice bearing LNCaP-AR xenograft tumors by using androgen deprivation therapy (ADT), degarelix, in combination with VTP. Compared with either ADT or VTP alone, a single dose of degarelix in concert with VTP significantly inhibited tumor growth. A sharp decline in serum prostate-specific antigen (PSA) confirmed AR inhibition in this group. Tumors treated by VTP and degarelix displayed intense terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining 7 days after treatment, supporting an increased apoptotic frequency underlying the effect on tumor inhibition. Conclusions: Improvement of local tumor control following androgen deprivation combined with VTP provides the rationale and preliminary protocol parameters for clinical trials in patients presented with locally advanced prostate cancer.</p>}},
  author       = {{Kim, Kwanghee and Watson, Philip A. and Lebdai, Souhil and Jebiwott, Sylvia and Somma, Alexander J. and Rosa, Stephen La and Mehta, Dipti and Murray, Katie S. and Lilja, Hans and Ulmert, David and Monette, Sebastien and Scherz, Avigdor and Coleman, Jonathan A.}},
  issn         = {{1078-0432}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{10}},
  pages        = {{2408--2416}},
  publisher    = {{American Association for Cancer Research}},
  series       = {{Clinical Cancer Research}},
  title        = {{Androgen deprivation therapy potentiates the efficacy of vascular targeted photodynamic therapy of prostate cancer xenografts}},
  url          = {{http://dx.doi.org/10.1158/1078-0432.CCR-17-3474}},
  doi          = {{10.1158/1078-0432.CCR-17-3474}},
  volume       = {{24}},
  year         = {{2018}},
}