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Investigation of panobinostat differentiation therapy in SWI/SNF-deficient solid tumours.

thesis
posted on 12.10.2021, 14:51 by WAI CHIN CHONG
Mutations in SWI/SNF are associated with 20% of human malignancies. Among them, mutations in SWI/SNF subunits, SMARCA4 and SMARCB1, are recurrently mutated in Atypical teratoid rhabdoid tumour (ATRT) and lung adenocarcinoma (LUAD) and are associated with poor prognosis, implicating epigenetic dysregulation as an underlying pathogenic mechanism. Notably, SMARCB1- and SMARCA4-deficient cancers exhibit a hypoacetylated and primitive molecular and histological phenotype, suggestive poor cell development and differentiation within tumours due to a “closed” chromatin. Previous studies have demonstrated the therapeutic potential of HDACi potential to inhibit tumour growth and induce terminal differentiation in Malignant rhabdoid tumours. Here, we demonstrate efficacy of panobinostat ATRT and SMARCA4-deficient LUAD. Collectively, this study demonstrates the potential of panobinostat as differentiation therapy for ATRT and SMARCA4-deficient LUAD, and implicates SWI/SNF subunit mutations as genetic biomarkers of response to epigenetic differentiation therapy in a broader cancer context.

History

Principal supervisor

Jason Edward Cain

Additional supervisor 1

Associated Professor Elizabeth Algar

Year of Award

2021

Department, School or Centre

Molecular and Translational Sciences

Campus location

Australia

Course

Doctor of Philosophy

Degree Type

DOCTORATE

Faculty

Faculty of Medicine, Nursing and Health Sciences

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