SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer

Meghan A Rice; Vineet Kumar; Dhanir Tailor; Fernando Jose Garcia-Marques; En-Chi Hsu; Shiqin Liu; Abel Bermudez; Vijayalakshmi Kanchustambham; Vishnu Shankar; Zintis Inde; Busola Ruth Alabi; Arvind Muruganantham; Michelle Shen; Mallesh Pandrala; Rosalie Nolley; Merve Aslan; Ali Ghoochani; Arushi Agarwal; Mark Buckup; Manoj Kumar; Catherine C Going; Donna M Peehl; Scott J Dixon; Richard N Zare; James D Brooks; Sharon J Pitteri; Sanjay V Malhotra; Tanya Stoyanova

doi:10.1016/j.xcrm.2021.100502

SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer

Cell Rep Med. 2022 Feb 2;3(2):100502. doi: 10.1016/j.xcrm.2021.100502. eCollection 2022 Feb 15.

Authors

Meghan A Rice^{1

2}, Vineet Kumar³, Dhanir Tailor^{3

4

5}, Fernando Jose Garcia-Marques^{1

2}, En-Chi Hsu^{1

2}, Shiqin Liu^{1

2}, Abel Bermudez^{1

2}, Vijayalakshmi Kanchustambham⁶, Vishnu Shankar⁶, Zintis Inde⁷, Busola Ruth Alabi^{1

2}, Arvind Muruganantham^{1

2}, Michelle Shen^{1

2}, Mallesh Pandrala^{3

4

5}, Rosalie Nolley⁸, Merve Aslan^{1

2}, Ali Ghoochani^{1

2}, Arushi Agarwal^{1

2}, Mark Buckup^{1

2}, Manoj Kumar^{1

2}, Catherine C Going^{1

2}, Donna M Peehl^{8

9}, Scott J Dixon⁷, Richard N Zare⁶, James D Brooks^{2

8}, Sharon J Pitteri^{1

2}, Sanjay V Malhotra^{3

4

5}, Tanya Stoyanova^{1

2}

Affiliations

¹ Department of Radiology, Stanford University, Stanford, CA 94305, USA.
² Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, CA 94305, USA.
³ Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
⁴ Department of Cell, Development and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
⁵ Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
⁶ Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
⁷ Department of Biology, Stanford University, Stanford, CA 94305, USA.
⁸ Department of Urology, Stanford University, Stanford, CA 94305, USA.
⁹ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA.

Abstract

Among men, prostate cancer is the second leading cause of cancer-associated mortality, with advanced disease remaining a major clinical challenge. We describe a small molecule, SU086, as a therapeutic strategy for advanced prostate cancer. We demonstrate that SU086 inhibits the growth of prostate cancer cells in vitro, cell-line and patient-derived xenografts in vivo, and ex vivo prostate cancer patient specimens. Furthermore, SU086 in combination with standard of care second-generation anti-androgen therapies displays increased impairment of prostate cancer cell and tumor growth in vitro and in vivo. Cellular thermal shift assay reveals that SU086 binds to heat shock protein 90 (HSP90) and leads to a decrease in HSP90 levels. Proteomic profiling demonstrates that SU086 binds to and decreases HSP90. Metabolomic profiling reveals that SU086 leads to perturbation of glycolysis. Our study identifies SU086 as a treatment for advanced prostate cancer as a single agent or when combined with second-generation anti-androgens.

Keywords: HSP90; combination therapy; glycolysis; metabolism; prostate cancer; therapeutics; therapy.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Proliferation
Glycolysis
HSP90 Heat-Shock Proteins / metabolism
Humans
Male
Prostatic Neoplasms* / drug therapy
Proteomics*

Substances

HSP90 Heat-Shock Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding