Therapeutic Targeting of BET Proteins in Osteosarcoma

Date
2025-03
Language
American English
Embargo Lift Date
Department
Committee Chair
Degree
Ph.D.
Degree Year
2025
Department
Pharmacology & Toxicology
Grantor
Indiana University
Journal Title
Journal ISSN
Volume Title
Found At
Abstract

Osteosarcoma (OS) is an aggressive bone cancer in pediatric, adolescent, and young adult patients with an exceedingly poor prognosis. An area of therapeutic opportunity is that OS exhibits increased oncogenic replication stress (RS), augmenting genome instability and tumor progression. Exploiting RS provides a treatment intervention. Bromodomain and extra-terminal (BET) proteins regulate DNA transcription, replication, and repair. BET inhibitors create an imbalance between transcription and replication kinetics, exacerbating oncogenic RS and increasing cell death. We hypothesized that BET inhibition would decrease OS tumor growth via modulation of gene expression and increased RS. Bivalent BET inhibitor AZD5153 monotherapy significantly suppressed the growth of patient-derived xenografts (PDXs) established from treatment-naïve male and female OS patients. AZD5153-mediated anti-tumor effect correlated with increased γ-H2AX levels, indicative of elevated RS. RNA-sequencing and kinome profiling revealed intra- and inter-tumoral molecular response mechanisms attributable to therapeutic response and potential resistance in BET inhibitor-treated PDX and OS cell lines. Reprogramming of signaling networks involved in DNA damage response, apoptosis, invasion, and Wnt signaling were identified. Combining AZD5153 with salvage agents demonstrated additive-to-synergistic cell growth inhibition in vitro with drug combinations inducing apoptosis. AZD5153 increased DNA-strand breaks that was further enhanced by salvage therapy. In a PDX established from a metastatic lesion of a patient treated with frontline and salvage therapy, a combination of AZD5153 and topotecan was well tolerated and increased survival probability compared to each agent alone. These data suggest that AZD5153 alone or in combination with low-dose salvage therapy holds promise as an efficacious treatment strategy in OS.

Description
IUI
item.page.description.tableofcontents
item.page.relation.haspart
Cite As
ISSN
Publisher
Series/Report
Sponsorship
Major
Extent
Identifier
Relation
Journal
Source
Alternative Title
Type
Thesis
Number
Volume
Conference Dates
Conference Host
Conference Location
Conference Name
Conference Panel
Conference Secretariat Location
Version
Full Text Available at
This item is under embargo {{howLong}}