{"id":{"repo_id":"nus","oai_identifier":"oai:scholarbank.nus.edu.sg:10635/317678"},"canonical_url":"https://search.dev.ndltd.org/etd/nus/oai:scholarbank.nus.edu.sg:10635/317678","repository":{"repo_id":"nus","name":"National University of Singapore","base_url":"https://scholarbank.nus.edu.sg/oai/request"},"display":{"title":"CHARACTERISATION OF A NOVEL SMALL MOLECULE INHIBITOR FOR IMMUNE ACTIVATION IN TRIPLE NEGATIVE BREAST CANCER","abstract":"Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor prognosis and limited treatment options. Our group has previously identified a novel small molecule inhibitor, CHL-4, whose anti-tumour effects function through Lyn kinase, a member of the Src family kinases. This current study characterised a novel immunomodulatory role for CHL-4, which is able to increase gene and protein expression of Type I/III IFNs in TNBC cell lines. This signalling is dependent on the RIG/MAVS cytosolic RNA-sensing pathway, and is possibly triggered by increased cytosolic localisation of mitochondrial dsRNA. Using a 3D vascularised TNBC model, CHL-4 treatment increased peritumour accumulation of PBMCs compared to control treatment. Furthermore, combination treatment with anti-PD-L1 inhibitor Atezolizumab increased IFN-γ production by PBMCs. Interestingly, the immunomodulatory effects of CHL-4 are not mediated by Lyn kinase, but by another yet-to-be-identified target. Future work will focus on identification of novel targets for CHL-4 and further elucidation of its mechanism of action. Taken together, the identification of an additional mechanism of action of CHL-4 provides further support for its use as a therapeutic option in TNBC.","abstract_html":"Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor prognosis and limited treatment options. Our group has previously identified a novel small molecule inhibitor, CHL-4, whose anti-tumour effects function through Lyn kinase, a member of the Src family kinases. This current study characterised a novel immunomodulatory role for CHL-4, which is able to increase gene and protein expression of Type I/III IFNs in TNBC cell lines. This signalling is dependent on the RIG/MAVS cytosolic RNA-sensing pathway, and is possibly triggered by increased cytosolic localisation of mitochondrial dsRNA. Using a 3D vascularised TNBC model, CHL-4 treatment increased peritumour accumulation of PBMCs compared to control treatment. Furthermore, combination treatment with anti-PD-L1 inhibitor Atezolizumab increased IFN-γ production by PBMCs. Interestingly, the immunomodulatory effects of CHL-4 are not mediated by Lyn kinase, but by another yet-to-be-identified target. Future work will focus on identification of novel targets for CHL-4 and further elucidation of its mechanism of action. Taken together, the identification of an additional mechanism of action of CHL-4 provides further support for its use as a therapeutic option in TNBC.","abstract_has_math":false,"creators":["LEE E HUI CLARISSA"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-08-08","date_published":"2025-08-08","updated_at":"2026-07-24T03:32:43Z","subjects":["3D in-vitro model","RNA sensing","IFN signalling","cancer immunomodulation","small molecule inhibitor","Triple negative breast cancer"],"languages":[],"rights":[],"rights_urls":["https://scholarbank.nus.edu.sg/bitstreams/283c2859-4a36-4b90-a03a-0584e58be833/download"],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["LEE E HUI CLARISSA"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2025-08-08"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://scholarbank.nus.edu.sg/handle/10635/317678"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["3D in-vitro model","RNA sensing","IFN signalling","cancer immunomodulation","small molecule inhibitor","Triple negative breast cancer"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["https://scholarbank.nus.edu.sg/bitstreams/283c2859-4a36-4b90-a03a-0584e58be833/download"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://scholarbank.nus.edu.sg/bitstreams/730fb616-bc79-4f4a-bbf5-0828ef43c071/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor prognosis and limited treatment options. Our group has previously identified a novel small molecule inhibitor, CHL-4, whose anti-tumour effects function through Lyn kinase, a member of the Src family kinases. This current study characterised a novel immunomodulatory role for CHL-4, which is able to increase gene and protein expression of Type I/III IFNs in TNBC cell lines. This signalling is dependent on the RIG/MAVS cytosolic RNA-sensing pathway, and is possibly triggered by increased cytosolic localisation of mitochondrial dsRNA. Using a 3D vascularised TNBC model, CHL-4 treatment increased peritumour accumulation of PBMCs compared to control treatment. Furthermore, combination treatment with anti-PD-L1 inhibitor Atezolizumab increased IFN-γ production by PBMCs. Interestingly, the immunomodulatory effects of CHL-4 are not mediated by Lyn kinase, but by another yet-to-be-identified target. Future work will focus on identification of novel targets for CHL-4 and further elucidation of its mechanism of action. Taken together, the identification of an additional mechanism of action of CHL-4 provides further support for its use as a therapeutic option in TNBC."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["9f3c6f2aa8f96291ef77b0a18484521d","bf371782ee0e022b3c49d6eb01fffdf7","46641d1ef3812d825adb9cb4e3cc3df2"]},{"key":"dc:title","label":"Title","values":["CHARACTERISATION OF A NOVEL SMALL MOLECULE INHIBITOR FOR IMMUNE ACTIVATION IN TRIPLE NEGATIVE BREAST CANCER"]}]}],"canonical_facts":{"dc:creator":["LEE E HUI CLARISSA"],"dc:date.issued":["2025-08-08"],"dc:description.abstract":["Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor prognosis and limited treatment options. Our group has previously identified a novel small molecule inhibitor, CHL-4, whose anti-tumour effects function through Lyn kinase, a member of the Src family kinases. This current study characterised a novel immunomodulatory role for CHL-4, which is able to increase gene and protein expression of Type I/III IFNs in TNBC cell lines. This signalling is dependent on the RIG/MAVS cytosolic RNA-sensing pathway, and is possibly triggered by increased cytosolic localisation of mitochondrial dsRNA. Using a 3D vascularised TNBC model, CHL-4 treatment increased peritumour accumulation of PBMCs compared to control treatment. Furthermore, combination treatment with anti-PD-L1 inhibitor Atezolizumab increased IFN-γ production by PBMCs. Interestingly, the immunomodulatory effects of CHL-4 are not mediated by Lyn kinase, but by another yet-to-be-identified target. Future work will focus on identification of novel targets for CHL-4 and further elucidation of its mechanism of action. 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