1. SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer
- Author
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Rice, Meghan A, Kumar, Vineet, Tailor, Dhanir, Garcia-Marques, Fernando Jose, Hsu, En-Chi, Liu, Shiqin, Bermudez, Abel, Kanchustambham, Vijayalakshmi, Shankar, Vishnu, Inde, Zintis, Alabi, Busola Ruth, Muruganantham, Arvind, Shen, Michelle, Pandrala, Mallesh, Nolley, Rosalie, Aslan, Merve, Ghoochani, Ali, Agarwal, Arushi, Buckup, Mark, Kumar, Manoj, Going, Catherine C, Peehl, Donna M, Dixon, Scott J, Zare, Richard N, Brooks, James D, Pitteri, Sharon J, Malhotra, Sanjay V, and Stoyanova, Tanya
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Prostate Cancer ,Biotechnology ,Aging ,Clinical Research ,Cancer ,Urologic Diseases ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Cell Proliferation ,Glycolysis ,HSP90 Heat-Shock Proteins ,Humans ,Male ,Prostatic Neoplasms ,Proteomics ,HSP90 ,combination therapy ,glycolysis ,metabolism ,prostate cancer ,therapeutics ,therapy ,Biomedical and clinical sciences - 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.
- Published
- 2022