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

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 KumarCatherine C. Going, Donna M. Peehl, Scott J. Dixon, Richard N. Zare, James D. Brooks, Sharon J. Pitteri, Sanjay V. Malhotra, Tanya Stoyanova

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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.

Original language	English (US)
Article number	100502
Journal	Cell Reports Medicine
Volume	3
Issue number	2
DOIs	https://doi.org/10.1016/j.xcrm.2021.100502
State	Published - Feb 15 2022

Keywords

HSP90
combination therapy
glycolysis
metabolism
prostate cancer
therapeutics
therapy

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Rice, M. A., Kumar, V., Tailor, D., Garcia-Marques, F. J., Hsu, E. C., Liu, S., Bermudez, A., Kanchustambham, V., Shankar, V., Inde, Z., Alabi, B. R., Muruganantham, A., Shen, M., Pandrala, M., Nolley, R., Aslan, M., Ghoochani, A., Agarwal, A., Buckup, M., ... Stoyanova, T. (2022). SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer. Cell Reports Medicine, 3(2), Article 100502. https://doi.org/10.1016/j.xcrm.2021.100502

Rice, MA, Kumar, V, Tailor, D, Garcia-Marques, FJ, Hsu, EC, Liu, S, Bermudez, A, Kanchustambham, V, Shankar, V, Inde, Z, Alabi, BR, Muruganantham, A, Shen, M, Pandrala, M, Nolley, R, Aslan, M, Ghoochani, A, Agarwal, A, Buckup, M, Kumar, M, Going, CC, Peehl, DM, Dixon, SJ, Zare, RN, Brooks, JD, Pitteri, SJ, Malhotra, SV & Stoyanova, T 2022, 'SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer', Cell Reports Medicine, vol. 3, no. 2, 100502. https://doi.org/10.1016/j.xcrm.2021.100502

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

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",

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

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day = "15",

doi = "10.1016/j.xcrm.2021.100502",

language = "English (US)",

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T1 - SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer

AU - Rice, Meghan A.

AU - Kumar, Vineet

AU - Tailor, Dhanir

AU - Garcia-Marques, Fernando Jose

AU - Hsu, En Chi

AU - Liu, Shiqin

AU - Bermudez, Abel

AU - Kanchustambham, Vijayalakshmi

AU - Shankar, Vishnu

AU - Inde, Zintis

AU - Alabi, Busola Ruth

AU - Muruganantham, Arvind

AU - Shen, Michelle

AU - Pandrala, Mallesh

AU - Nolley, Rosalie

AU - Aslan, Merve

AU - Ghoochani, Ali

AU - Agarwal, Arushi

AU - Buckup, Mark

AU - Kumar, Manoj

AU - Going, Catherine C.

AU - Peehl, Donna M.

AU - Dixon, Scott J.

AU - Zare, Richard N.

AU - Brooks, James D.

AU - Pitteri, Sharon J.

AU - Malhotra, Sanjay V.

AU - Stoyanova, Tanya

PY - 2022/2/15

Y1 - 2022/2/15

N2 - 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.

AB - 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.

KW - HSP90

KW - combination therapy

KW - glycolysis

KW - metabolism

KW - prostate cancer

KW - therapeutics

KW - therapy

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ER -

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

Abstract

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