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  3. A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice

A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice

  • Sci Transl Med. 2021 Jul 21;13(603):eabf1383. doi: 10.1126/scitranslmed.abf1383.
Matthew W Boudreau 1 2,  Darjan Duraki 3,  Lawrence Wang 3,  Chengjian Mao 3,  Ji Eun Kim 3,  Madeline A Henn 4,  Bingtao Tang 4,  Sean W Fanning 5,  Jeffrey Kiefer 6,  Theodore M Tarasow 6,  Elizabeth M Bruckheimer 6,  Ramon Moreno 6,  Spyro Mousses 6,  Geoffrey L Greene 5,  Edward J Roy 4 7,  Ben Ho Park 8,  Timothy M Fan 2 4 7 9,  Erik R Nelson 2 4 7 10 11,  Paul J Hergenrother 12 2 7,  David J Shapiro 13 7
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • 2 Carl R. Woese Institute for Genomic Biology University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • 3 Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • 4 Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • 5 Ben May Department of Cancer Research, University of Chicago, Chicago, IL 60637, USA.
  • 6 Systems Oncology, Scottsdale, AZ 85255, USA.
  • 7 Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • 8 Department of Medicine, Division of Heme/Onc, Vanderbilt Ingram Cancer Center, Nashville, TN 37232, USA.
  • 9 Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA.
  • 10 Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • 11 University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA.
  • 12 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. djshapir@illinois.edu hergenro@illinois.edu.
  • 13 Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. djshapir@illinois.edu hergenro@illinois.edu.
PMID: 34290053 DOI: 10.1126/scitranslmed.abf1383
Abstract

Metastatic Estrogen Receptor α (ERα)-positive breast Cancer is presently incurable. Seeking to target these drug-resistant cancers, we report the discovery of a compound, called ErSO, that activates the anticipatory unfolded protein response (a-UPR) and induces rapid and selective necrosis of ERα-positive breast Cancer cell lines in vitro. We then tested ErSO in vivo in several preclinical orthotopic and metastasis mouse models carrying different xenografts of human breast Cancer lines or patient-derived breast tumors. In multiple orthotopic models, ErSO treatment given either orally or intraperitoneally for 14 to 21 days induced tumor regression without recurrence. In a cell line tail vein metastasis model, ErSO was also effective at inducing regression of most lung, bone, and liver metastases. ErSO treatment induced almost complete regression of brain metastases in mice carrying intracranial human breast Cancer cell line xenografts. Tumors that did not undergo complete regression and regrew remained sensitive to retreatment with ErSO. ErSO was well tolerated in mice, rats, and dogs at doses above those needed for therapeutic responses and had little or no effect on normal ERα-expressing murine tissues. ErSO mediated its Anticancer effects through activation of the a-UPR, suggesting that activation of a tumor protective pathway could induce tumor regression.

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