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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Small Molecule Therapeutics

A Multifunctional Therapy Approach for Cancer: Targeting Raf1- Mediated Inhibition of Cell Motility, Growth, and Interaction with the Microenvironment

Limin Zhang, Abhinandan Pattanayak, Wenqi Li, Hyun-Kyung Ko, Graham Fowler, Ryan Gordon and Raymond Bergan
Limin Zhang
1Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
2Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
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  • ORCID record for Limin Zhang
Abhinandan Pattanayak
1Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
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Wenqi Li
1Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
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Hyun-Kyung Ko
1Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
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Graham Fowler
1Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
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Ryan Gordon
1Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
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Raymond Bergan
1Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
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  • ORCID record for Raymond Bergan
  • For correspondence: bergan@ohsu.edu
DOI: 10.1158/1535-7163.MCT-19-0222 Published January 2020
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Abstract

Prostate cancer cells move from their primary site of origin, interact with a distant microenvironment, grow, and thereby cause death. It had heretofore not been possible to selectively inhibit cancer cell motility. Our group has recently shown that inhibition of intracellular activation of Raf1 with the small-molecule therapeutic KBU2046 permits, for the first time, selective inhibition of cell motility. We hypothesized that simultaneous disruption of multiple distinct functions that drive progression of prostate cancer to induce death would result in advanced disease control. Using a murine orthotopic implantation model of human prostate cancer metastasis, we demonstrate that combined treatment with KBU2046 and docetaxel retains docetaxel's antitumor action, but provides improved inhibition of metastasis, compared with monotherapy. KBU2046 does not interfere with hormone therapy, inclusive of enzalutamide-mediated inhibition of androgen receptor (AR) function and cell growth inhibition, and inclusive of the ability of castration to inhibit LNCaP-AR cell outgrowth in mice. Cell movement is necessary for osteoclast-mediated bone degradation. KBU2046 inhibits Raf1 and its downstream activation of MEK1/2 and ERK1/2 in osteoclasts, inhibiting cytoskeleton rearrangement, resorptive cavity formation, and bone destruction in vitro, with improved effects observed when the bone microenvironment is chemically modified by pretreatment with zoledronic acid. Using a murine cardiac injection model of human prostate cancer bone destruction quantified by CT, KBU2046 plus zoledronic exhibit improved inhibitory efficacy, compared with monotherapy. The combined disruption of pathways that drive cell movement, interaction with bone, and growth constitutes a multifunctional targeting strategy that provides advanced disease control.

This article is featured in Highlights of This Issue, p. 1

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:39–51

  • Received March 2, 2019.
  • Revision received May 17, 2019.
  • Accepted September 26, 2019.
  • Published first October 3, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (1)
January 2020
Volume 19, Issue 1
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A Multifunctional Therapy Approach for Cancer: Targeting Raf1- Mediated Inhibition of Cell Motility, Growth, and Interaction with the Microenvironment
Limin Zhang, Abhinandan Pattanayak, Wenqi Li, Hyun-Kyung Ko, Graham Fowler, Ryan Gordon and Raymond Bergan
Mol Cancer Ther January 1 2020 (19) (1) 39-51; DOI: 10.1158/1535-7163.MCT-19-0222

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A Multifunctional Therapy Approach for Cancer: Targeting Raf1- Mediated Inhibition of Cell Motility, Growth, and Interaction with the Microenvironment
Limin Zhang, Abhinandan Pattanayak, Wenqi Li, Hyun-Kyung Ko, Graham Fowler, Ryan Gordon and Raymond Bergan
Mol Cancer Ther January 1 2020 (19) (1) 39-51; DOI: 10.1158/1535-7163.MCT-19-0222
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Molecular Cancer Therapeutics
eISSN: 1538-8514
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