{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T07:45:33Z","timestamp":1775979933198,"version":"3.50.1"},"posted":{"date-parts":[[2025,5,29]]},"group-title":"Cancer Biology","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T00:00:00Z","timestamp":1748476800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["1R21CA228099-01A1"],"award-info":[{"award-number":["1R21CA228099-01A1"]}]},{"name":"NIH","award":["P30 5P30CA062203"],"award-info":[{"award-number":["P30 5P30CA062203"]}]},{"name":"NIH","award":["T32CA009054"],"award-info":[{"award-number":["T32CA009054"]}]},{"DOI":"10.13039\/501100000735","name":"University of Cambridge","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000735","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100012357","name":"LifeArc","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012357","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Developing an efficient and safe therapy necessitates a mechanistic understanding of the complex underlying pathology and manipulation of the multiple pathways at the molecular and genetic level. Network-based simulation of chronic myeloid leukemia (CML), a relatively well-understood cancer model, revealed the dynamics of simultaneously expressing pro-apoptotic BIM and silencing pro-survival MCL-1 in combination with the BCR-ABL-targeted tyrosine kinase inhibitor dasatinib. Viral\/nonviral chimeric nanoparticles (ChNPs) composed of a BIM-expressing adeno-associated virus (AAV) core and a degradable polymeric shell that encapsulates MCL-1 siRNA (BIM\/MCL-1 ChNPs) synergistically and selectively killed BCR-ABL+ CML cells in combination with dasatinib. In a mouse CML model, the BIM\/MCL-1 ChNPs and dasatinib combination therapy suppressed proliferation of BCR-ABL+ hematopoietic cells and prevented leukemic infiltration of organs. The synergistic anti-leukemic effect was further pronounced in an acute phase model of the disease. This study investigated a strategy of developing a versatile and tunable multimodal therapy assisted by a computational toolset that analyzes the molecular foundation of a disease and predicts therapeutic response. The interdisciplinary approach developed and validated in this study can be used in discovering new therapies for cancer and other diseases.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Abstract Figure<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                    <jats:label>Graphical abstract<\/jats:label>\n                    <jats:caption>\n                      <jats:p>summarizing the study design and approach. A schematic representation of the integrated in silico and in vivo pipeline utilized in the study. The workflow begins with in silico simulations, including Boolean network modeling and protein-protein interaction (PPI) network analyses, leading to target discovery, optimized nanoparticle design, and validation in pathological contexts. This was followed by therapeutic efficacy assessments of BIM\/MCL-1 ChNPs and their combination with dasatinib in BCR-ABL+ leukemia models in vitro and in vivo.<\/jats:p>\n                    <\/jats:caption>\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"656072v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.26.656072","type":"posted-content","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T09:55:12Z","timestamp":1748512512000},"source":"Crossref","is-referenced-by-count":0,"title":["Multimodal gene and targeted drug therapy for chronic myelogenous leukemia: Computational target analysis and therapeutic validation"],"prefix":"10.64898","author":[{"given":"Margaret L.","family":"Lugin","sequence":"first","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, University of California, Irvine, CA 92697, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Winnie","family":"Lei","sequence":"additional","affiliation":[{"name":"The Milner Therapeutics Institute, University of Cambridge, Cambridge, United Kingdom, CB2 0AW"},{"name":"Department of Surgery, University of Cambridge, Cambridge, United Kingdom, CB2 0QQ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca T.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of California, Irvine, CA 92697"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jee Young","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0635-1712","authenticated-orcid":false,"given":"Nicholas M.","family":"Katritsis","sequence":"additional","affiliation":[{"name":"The Milner Therapeutics Institute, University of Cambridge, Cambridge, United Kingdom, CB2 0AW"},{"name":"Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom, CB3 0AS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Woochang","family":"Hwang","sequence":"additional","affiliation":[{"name":"The Milner Therapeutics Institute, University of Cambridge, Cambridge, United Kingdom, CB2 0AW"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela G.","family":"Fleischman","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, University of California, Irvine, CA 92697"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Namshik","family":"Han","sequence":"additional","affiliation":[{"name":"The Milner Therapeutics Institute, University of Cambridge, Cambridge, United Kingdom, CB2 0AW"},{"name":"Cambridge Centre for AI in Medicine, Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, United Kingdom, CB3 0WA"},{"name":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom, CB2 0AW"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young Jik","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, University of California, Irvine, CA 92697, United States"},{"name":"Department of Biomedical Engineering, University of California, Irvine, CA 92697"},{"name":"Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697"},{"name":"Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041200033685000_2025.05.26.656072v1.1","unstructured":"F. 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