A necrosis inducer promotes an immunogenic response and destroys ovarian cancers in mouse xenografts and patient ascites organoids

Darjan Duraki; Musarrat Jabeen; Chengjian Mao; Lawrence Wang; Santanu Ghosh; Xinyi Dai; Junyao Zhu; Matthew W. Boudreau; Erik Nelson; Paul J. Hergenrother; Georgina Cheng; David J. Shapiro

doi:10.1016/j.canlet.2025.217738

A necrosis inducer promotes an immunogenic response and destroys ovarian cancers in mouse xenografts and patient ascites organoids

Darjan Duraki, Musarrat Jabeen, Chengjian Mao, Lawrence Wang, Santanu Ghosh, Xinyi Dai, Junyao Zhu, Matthew W. Boudreau, Erik Nelson, Paul J. Hergenrother, Georgina Cheng, David J. Shapiro

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

Abstract

Most ovarian cancer patients present with advanced disease and there are few targeted therapies; consequently, five-year survival for ovarian cancer remains below 50%. We described the anticipatory unfolded protein response (a-UPR) hyperactivator, ErSO, which induced profound and often complete regression of breast cancer in mouse models. Here we explore the effectiveness of ErSO against ovarian cancer. ErSO induced death of human PEO4 and Caov-3 ovarian cancer cells in vitro. In mouse xenografts, injected ErSO induced rapid complete, or near complete, regression of orthotopic metastatic PEO4 tumors and of Caov-3 ovarian tumors. Ovarian cancer patients often develop malignant ascites containing ovarian cancer organoids that drive metastasis. ErSO showed activity against 7/7 fresh patient derived ascites organoids (PDAOs). Low nanomolar ErSO destroyed 2/7 PDAOs. ErSO-mediated cell death in PDAOs occurred through the same a-UPR activation mechanism seen in cell culture. Moreover, ErSO family compound-induced a-UPR activation in ovarian cancer cells triggers necrotic cell death and release of damage associated molecular patterns (DAMPs), which strongly activated human macrophage and induced monocyte migration. These studies suggest ErSO has unusual potential for treatment of advanced ovarian cancer.

Original language	English (US)
Article number	217738
Journal	Cancer Letters
Volume	625
DOIs	https://doi.org/10.1016/j.canlet.2025.217738
State	Published - Aug 10 2025

Keywords

Immunogenic cell death
Organoid
Ovarian cancer
Patient ascites
Unfolded protein response

ASJC Scopus subject areas

Oncology
Cancer Research

Online availability

10.1016/j.canlet.2025.217738

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Duraki, D., Jabeen, M., Mao, C., Wang, L., Ghosh, S., Dai, X., Zhu, J., Boudreau, M. W., Nelson, E., Hergenrother, P. J., Cheng, G., & Shapiro, D. J. (2025). A necrosis inducer promotes an immunogenic response and destroys ovarian cancers in mouse xenografts and patient ascites organoids. Cancer Letters, 625, Article 217738. https://doi.org/10.1016/j.canlet.2025.217738

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title = "A necrosis inducer promotes an immunogenic response and destroys ovarian cancers in mouse xenografts and patient ascites organoids",

abstract = "Most ovarian cancer patients present with advanced disease and there are few targeted therapies; consequently, five-year survival for ovarian cancer remains below 50%. We described the anticipatory unfolded protein response (a-UPR) hyperactivator, ErSO, which induced profound and often complete regression of breast cancer in mouse models. Here we explore the effectiveness of ErSO against ovarian cancer. ErSO induced death of human PEO4 and Caov-3 ovarian cancer cells in vitro. In mouse xenografts, injected ErSO induced rapid complete, or near complete, regression of orthotopic metastatic PEO4 tumors and of Caov-3 ovarian tumors. Ovarian cancer patients often develop malignant ascites containing ovarian cancer organoids that drive metastasis. ErSO showed activity against 7/7 fresh patient derived ascites organoids (PDAOs). Low nanomolar ErSO destroyed 2/7 PDAOs. ErSO-mediated cell death in PDAOs occurred through the same a-UPR activation mechanism seen in cell culture. Moreover, ErSO family compound-induced a-UPR activation in ovarian cancer cells triggers necrotic cell death and release of damage associated molecular patterns (DAMPs), which strongly activated human macrophage and induced monocyte migration. These studies suggest ErSO has unusual potential for treatment of advanced ovarian cancer.",

keywords = "Immunogenic cell death, Organoid, Ovarian cancer, Patient ascites, Unfolded protein response",

author = "Darjan Duraki and Musarrat Jabeen and Chengjian Mao and Lawrence Wang and Santanu Ghosh and Xinyi Dai and Junyao Zhu and Boudreau, {Matthew W.} and Erik Nelson and Hergenrother, {Paul J.} and Georgina Cheng and Shapiro, {David J.}",

note = "This study was supported by National Institutes of Health grants RO1DKO71909 (DJS) RO1CA265333 (DJS); RO1CA258746 (PJH), R35CA283859 (PJH), an unrestricted donation from Systems Oncology (DJS, PJH) , University of Illinois (PJH) , RO1 CA234025 (ERN); Carle Stephens Family Clinical Research Institute (GC) . predoctoral fellowships and traineeships: DD and SG, Dept of Biochemistry, Univ. Illinois, MWB: Chemistry-Biology Interface Training Program ( T32-GM1336629 ), ACS Medicinal Chemistry , NCI F99 ( F99-CA253731 ). We are grateful to Dr. M. Livezey for preliminary studies using ovarian cancer cell lines, to the University of Illinois Cell/Media facility for preparation of cell culture medium and to the ovarian cancer patients who consented to use of samples for this study.",

year = "2025",

month = aug,

day = "10",

doi = "10.1016/j.canlet.2025.217738",

language = "English (US)",

volume = "625",

journal = "Cancer Letters",

issn = "0304-3835",

publisher = "Elsevier Ireland Ltd",

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TY - JOUR

T1 - A necrosis inducer promotes an immunogenic response and destroys ovarian cancers in mouse xenografts and patient ascites organoids

AU - Duraki, Darjan

AU - Jabeen, Musarrat

AU - Mao, Chengjian

AU - Wang, Lawrence

AU - Ghosh, Santanu

AU - Dai, Xinyi

AU - Zhu, Junyao

AU - Boudreau, Matthew W.

AU - Nelson, Erik

AU - Hergenrother, Paul J.

AU - Cheng, Georgina

AU - Shapiro, David J.

N1 - This study was supported by National Institutes of Health grants RO1DKO71909 (DJS) RO1CA265333 (DJS); RO1CA258746 (PJH), R35CA283859 (PJH), an unrestricted donation from Systems Oncology (DJS, PJH) , University of Illinois (PJH) , RO1 CA234025 (ERN); Carle Stephens Family Clinical Research Institute (GC) . predoctoral fellowships and traineeships: DD and SG, Dept of Biochemistry, Univ. Illinois, MWB: Chemistry-Biology Interface Training Program ( T32-GM1336629 ), ACS Medicinal Chemistry , NCI F99 ( F99-CA253731 ). We are grateful to Dr. M. Livezey for preliminary studies using ovarian cancer cell lines, to the University of Illinois Cell/Media facility for preparation of cell culture medium and to the ovarian cancer patients who consented to use of samples for this study.

PY - 2025/8/10

Y1 - 2025/8/10

N2 - Most ovarian cancer patients present with advanced disease and there are few targeted therapies; consequently, five-year survival for ovarian cancer remains below 50%. We described the anticipatory unfolded protein response (a-UPR) hyperactivator, ErSO, which induced profound and often complete regression of breast cancer in mouse models. Here we explore the effectiveness of ErSO against ovarian cancer. ErSO induced death of human PEO4 and Caov-3 ovarian cancer cells in vitro. In mouse xenografts, injected ErSO induced rapid complete, or near complete, regression of orthotopic metastatic PEO4 tumors and of Caov-3 ovarian tumors. Ovarian cancer patients often develop malignant ascites containing ovarian cancer organoids that drive metastasis. ErSO showed activity against 7/7 fresh patient derived ascites organoids (PDAOs). Low nanomolar ErSO destroyed 2/7 PDAOs. ErSO-mediated cell death in PDAOs occurred through the same a-UPR activation mechanism seen in cell culture. Moreover, ErSO family compound-induced a-UPR activation in ovarian cancer cells triggers necrotic cell death and release of damage associated molecular patterns (DAMPs), which strongly activated human macrophage and induced monocyte migration. These studies suggest ErSO has unusual potential for treatment of advanced ovarian cancer.

AB - Most ovarian cancer patients present with advanced disease and there are few targeted therapies; consequently, five-year survival for ovarian cancer remains below 50%. We described the anticipatory unfolded protein response (a-UPR) hyperactivator, ErSO, which induced profound and often complete regression of breast cancer in mouse models. Here we explore the effectiveness of ErSO against ovarian cancer. ErSO induced death of human PEO4 and Caov-3 ovarian cancer cells in vitro. In mouse xenografts, injected ErSO induced rapid complete, or near complete, regression of orthotopic metastatic PEO4 tumors and of Caov-3 ovarian tumors. Ovarian cancer patients often develop malignant ascites containing ovarian cancer organoids that drive metastasis. ErSO showed activity against 7/7 fresh patient derived ascites organoids (PDAOs). Low nanomolar ErSO destroyed 2/7 PDAOs. ErSO-mediated cell death in PDAOs occurred through the same a-UPR activation mechanism seen in cell culture. Moreover, ErSO family compound-induced a-UPR activation in ovarian cancer cells triggers necrotic cell death and release of damage associated molecular patterns (DAMPs), which strongly activated human macrophage and induced monocyte migration. These studies suggest ErSO has unusual potential for treatment of advanced ovarian cancer.

KW - Immunogenic cell death

KW - Organoid

KW - Ovarian cancer

KW - Patient ascites

KW - Unfolded protein response

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U2 - 10.1016/j.canlet.2025.217738

DO - 10.1016/j.canlet.2025.217738

M3 - Article

C2 - 40311911

AN - SCOPUS:105004804257

SN - 0304-3835

VL - 625

JO - Cancer Letters

JF - Cancer Letters

M1 - 217738

ER -

A necrosis inducer promotes an immunogenic response and destroys ovarian cancers in mouse xenografts and patient ascites organoids

Abstract

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