Browsing by Author "Angus, Steve"

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    A Mechanistic Approach to Identify Novel Therapeutic Drugs for Targeting FA-Disrupted Malignancies
    (2023-07) Sheth, Aditya Sukumar; Clapp, D. Wade; Vance, Gail; Angus, Steve; Herbert, Brittney-Shea
    The Fanconi anemia (FA) signaling network plays a critical role in maintaining genomic integrity during interphase and mitosis. Biallelic germline mutation of any of the 22 genes that constitute this pathway (FANCA-FANCW) results in Fanconi Anemia, a cancer predisposition syndrome characterized by congenital malformations, bone marrow failure, and pediatric acute myeloid leukemias (AMLs). Among the general population, acquired genetic disruptions of the FA pathway are found in 30% of all sporadic cancers and over 15% of sporadic pediatric AMLs underscoring the importance of this pathway in the prevention of malignant transformation. Therefore, the identification of precision therapies for FA-deficient AML is a critical need. The canonical tumor suppressive role of FA proteins in the repair of DNA damage during interphase is well established. We and others have uncovered the roles of FA proteins in mitotic regulation, suggesting additional mechanisms by which the FA pathway prevents genomic instability. Mutation of FANCA is the most common cause of FA and is one of the most frequently disrupted FA pathway genes in sporadic AML. To identify synthetic lethal targets of FANCA, we previously identified mitotic phospho-signaling pathways required for the survival of FANCA-/- patient-derived fibroblasts through a kinome-wide shRNA screen. We identified mitotic kinases CHEK1, PLK1, SLK, and TTK as potential targets, which suggests a mitosis-specific vulnerability of FA-deficient cells. These findings corroborate work by others who have identified synthetic lethal interactions between PLK1 and the FA pathway members, FANCG and BRCA1, suggesting that inactivation of the FA pathway may sensitize cancers to PLK1 inhibition. A more thorough understanding of FA pathway function in mitosis provides new insight into AML pathogenesis and suggests that genetic disruptions of the FA pathway may be predictive of sensitivity to PLK1 inhibition, providing a preclinical rationale for the development of precision therapies.
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    Therapeutic Targeting of BET Proteins in Osteosarcoma
    (2025-03) Riyahi, Niknam; Pollok, Karen; Angus, Steve; Fehrenbacher, Jill; Jerde, Travis; Yeh, Elizabeth
    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.