Consequences of ARID1A Inactivation in Bladder Cancer

Research project

Description

There has been increasing number of molecular targeted drugs, such as multi kinase inhibitor and mTOR inhibitor. These drugs improved the survival of cancer patients, for example, those with kidney cancer and colorectal cancer. For years, however, the treatment of advanced bladder cancer has been limited to conventional modalities such as cisplatin-based chemotherapy, surgical intervention and radiotherapy. Recent progress in next generation sequencing technique identified novel somatic mutations in bladder cancer. ARID1a, the subunit of chromatin remodeling complex, is one such gene. To date, it remains unknown how ARID1a inactivation drives bladder tumorigenesis and which molecules could be targeted in ARID1a-mutated bladder cancer. In this proposal, we seek to elucidate the role of ARID1a in bladder cancer in vitro and in vivo. First, since ARID1a is a subunit of chromatin remodeling complex, loss of ARID1a could disrupt chromatin structure and then alter gene expression. We will assess this by identifying open (i.e. activated) chromatin region by Formaldehyde Assisted Identification of Regulatory Elements (FAIRE) and RNA-sequencing. The integration of these data sets will define gene expression alterations associated with ARID1a dependent changes in chromatin structure. Second, we will determine if the inhibition of PIK3CA, identified as promising target in other ARID1a-mutant cancers, is synthetic lethal in bladder cancer with ARID1a loss. Third, we will clarify whether loss of ARID1a’s function indeed drives the development of bladder cancer by using ARID1a conditional knockout mouse and PIK3CA mutant mouse. The goal of this proposal is to determine which genes are involved and targetable in ARID1a mutant bladder cancer and to start to devise treatment strategies targeting these pathways
StatusFinished
Effective start/end date7/15/147/14/16

Funding

  • Bladder Cancer Advocacy Network

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Urinary Bladder Neoplasms
Chromatin
Chromatin Assembly and Disassembly
Gene Expression
Pharmaceutical Preparations
Genes
Neoplasms
Therapeutics
RNA Sequence Analysis
Kidney Neoplasms
Knockout Mice
Formaldehyde
Cisplatin
Colorectal Neoplasms
Carcinogenesis
Urinary Bladder
Phosphotransferases
Radiotherapy
Drug Therapy
Mutation