{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/115860"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/115860","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Small molecule leveraging of the anticipatory unfolded protein response to induce marked regression in multiple human cancers","abstract":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-08-01","abstract_html":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-08-01","abstract_has_math":false,"creators":["Duraki, Darjan"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Biochemistry","degree_department":null,"school":null,"contributors":["Shapiro, David","Hergenrother, Paul","Nelson, Erik","Kalsotra, Auinash"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-08","date_published":"2022-08","updated_at":"2026-07-22T22:24:55Z","subjects":["Cancer","ErSO"],"languages":["en","eng"],"rights":["Copyright 2022 Darjan Duraki"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/115860","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Shapiro, David","Hergenrother, Paul","Nelson, Erik","Kalsotra, Auinash"]},{"key":"dc:creator","label":"Author","values":["Duraki, Darjan"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2022-08","2022-06-01"]},{"key":"dc:type","label":"Dc Type","values":["text","Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biochemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Cancer","ErSO"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en","eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2022 Darjan Duraki"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/115860"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-08-01","The student, Darjan Duraki, accepted the attached license on 2022-05-18 at 20:36.","The student, Darjan Duraki, submitted this Dissertation for approval on 2022-05-18 at 20:42.","This Dissertation was approved for publication on 2022-06-01 at 15:58.","DSpace SAF Submission Ingestion Package generated from Vireo submission #18037 on 2022-11-16 at 10:16:12","The role of estrogen receptor  (ER) in cancer varies depending on the type of cancer. The use of therapeutics that target the ER has seen successful in breast cancer where estrogen acts through ER to drive proliferation. While treatment with endocrine therapies to target ER-positive breast cancers is initially successful, resistance often occurs. Metastatic (ER)-positive breast cancer is presently incurable and most patients die within 7 years. From a medicinal chemistry program, we identified a novel small molecule that acts through ER to kill breast cancer cells and often induces complete regression without recurrence of large, therapy-resistant primary breast tumors and of lung, bone, and liver metastases. To target metastatic ER positive breast cancer, we exploited our finding that estrogen-ER activates an extranuclear tumor-protective, signaling pathway, the anticipatory unfolded protein response (a-UPR). We repurposed this tumor protective pathway by targeting it with the small molecule, ErSO. ErSO kills cancer cells by acting non-competitively through ERa to induce lethal hyperactivation of the anticipatory UPR, triggering rapid necrotic cell death. Using luciferase to image primary tumors and metastases containing lethal ERD538G and ERY537S mutations seen in metastatic breast cancer, oral and injected ErSO exhibited unprecedented antitumor activity. Consistent with the essential nature of the UPR pathway targeted by ErSO, in more than 100 tumor-bearing mice, we have never seen an ErSO-resistant tumor. In just 7 days, oral ErSO induced complete regression of most lung, bone, and liver metastases. ErSO is well-tolerated in mice and blood-brain-barrier penetrant. Injected ErSO induced profound regression of challenging brain tumors. Moreover, use of ErSO is not limited to breast cancer. ErSO rapidly kills ER positive ovarian and endometrial cancer cells that do not require estrogen for growth. We tested ErSO in multiple orthotopic mouse ovarian and endometrial xenograft models. ErSO treatment by intraperitoneal administration for 14 days led to near complete tumor regression. Tumors that did not completely regress to undetectable and regrew remained completely sensitive to second treatment cycle of ErSO. ErSO treatment induced substantial cell death in human ovarian cancer patient ascites. ErSO mediated cell death in patient ascites occurred through the same a-UPR activation mechanism seern in cell culture. To further test the ability of ErSO and its ability to induce marked regression by leveraging the ER-mediated a-UPR, we evaluated ErSO efficacy in cell line cancer models not traditionally associated with ER dependence. ErSO treatment was able to induce cytotoxicity in pancreatic, colorectal, prostate, urothelial, esophageal, glioblastoma, and lung cancer models in vitro. Because lung cancer is the leading cause of cancer death with approximately 25% of all cancer deaths occurring because of it, we further evaluated the effects of ErSO in the context of lung cancer utilizing metastatic xenograft models. Mice bearing human lung cancer tumors that received ErSO treatment regressed over 99% in 7 days, as quantified by bioluminescent imaging. Tumors that did not completely regress to undetectable and regrew remained completely sensitive to a second treatment cycle of ErSO. ErSO’s unique ability to induce targeted regression in a variety of cancer models independent of the role of ER highlights the benefits of unique a-UPR leveraging mechanisms and offers a promising prospect for future therapeutic use."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Small molecule leveraging of the anticipatory unfolded protein response to induce marked regression in multiple human cancers"]}]}],"canonical_facts":{"dc:contributor":["Shapiro, David","Hergenrother, Paul","Nelson, Erik","Kalsotra, Auinash"],"dc:creator":["Duraki, Darjan"],"dc:date":["2022-08","2022-06-01"],"dc:description":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-08-01","The student, Darjan Duraki, accepted the attached license on 2022-05-18 at 20:36.","The student, Darjan Duraki, submitted this Dissertation for approval on 2022-05-18 at 20:42.","This Dissertation was approved for publication on 2022-06-01 at 15:58.","DSpace SAF Submission Ingestion Package generated from Vireo submission #18037 on 2022-11-16 at 10:16:12","The role of estrogen receptor  (ER) in cancer varies depending on the type of cancer. The use of therapeutics that target the ER has seen successful in breast cancer where estrogen acts through ER to drive proliferation. While treatment with endocrine therapies to target ER-positive breast cancers is initially successful, resistance often occurs. Metastatic (ER)-positive breast cancer is presently incurable and most patients die within 7 years. From a medicinal chemistry program, we identified a novel small molecule that acts through ER to kill breast cancer cells and often induces complete regression without recurrence of large, therapy-resistant primary breast tumors and of lung, bone, and liver metastases. To target metastatic ER positive breast cancer, we exploited our finding that estrogen-ER activates an extranuclear tumor-protective, signaling pathway, the anticipatory unfolded protein response (a-UPR). We repurposed this tumor protective pathway by targeting it with the small molecule, ErSO. ErSO kills cancer cells by acting non-competitively through ERa to induce lethal hyperactivation of the anticipatory UPR, triggering rapid necrotic cell death. Using luciferase to image primary tumors and metastases containing lethal ERD538G and ERY537S mutations seen in metastatic breast cancer, oral and injected ErSO exhibited unprecedented antitumor activity. Consistent with the essential nature of the UPR pathway targeted by ErSO, in more than 100 tumor-bearing mice, we have never seen an ErSO-resistant tumor. In just 7 days, oral ErSO induced complete regression of most lung, bone, and liver metastases. ErSO is well-tolerated in mice and blood-brain-barrier penetrant. Injected ErSO induced profound regression of challenging brain tumors. Moreover, use of ErSO is not limited to breast cancer. ErSO rapidly kills ER positive ovarian and endometrial cancer cells that do not require estrogen for growth. We tested ErSO in multiple orthotopic mouse ovarian and endometrial xenograft models. ErSO treatment by intraperitoneal administration for 14 days led to near complete tumor regression. Tumors that did not completely regress to undetectable and regrew remained completely sensitive to second treatment cycle of ErSO. ErSO treatment induced substantial cell death in human ovarian cancer patient ascites. ErSO mediated cell death in patient ascites occurred through the same a-UPR activation mechanism seern in cell culture. To further test the ability of ErSO and its ability to induce marked regression by leveraging the ER-mediated a-UPR, we evaluated ErSO efficacy in cell line cancer models not traditionally associated with ER dependence. ErSO treatment was able to induce cytotoxicity in pancreatic, colorectal, prostate, urothelial, esophageal, glioblastoma, and lung cancer models in vitro. Because lung cancer is the leading cause of cancer death with approximately 25% of all cancer deaths occurring because of it, we further evaluated the effects of ErSO in the context of lung cancer utilizing metastatic xenograft models. Mice bearing human lung cancer tumors that received ErSO treatment regressed over 99% in 7 days, as quantified by bioluminescent imaging. Tumors that did not completely regress to undetectable and regrew remained completely sensitive to a second treatment cycle of ErSO. ErSO’s unique ability to induce targeted regression in a variety of cancer models independent of the role of ER highlights the benefits of unique a-UPR leveraging mechanisms and offers a promising prospect for future therapeutic use."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/115860"],"dc:language":["en","eng"],"dc:rights":["Copyright 2022 Darjan Duraki"],"dc:subject":["Cancer","ErSO"],"dc:title":["Small molecule leveraging of the anticipatory unfolded protein response to induce marked regression in multiple human cancers"],"dc:type":["text","Thesis"],"thesis:degree_discipline":["Biochemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:24:55Z"}