Cholangiocarcinoma
Cancers of the liver and intrapehatic bile ducts are the fastest growing cancers in the United States. In order to address this growing menace, we have developed a robust panel of liver cancer model systems that properly reflect both the genetic and epigenetic diversity of these human diseases.
Our laboratory uses a combination of both functional genomic screens and small molecular inhibitors as chemical probes to identify previously unrecognized pathways and targets in these diseases with the hopes of translating our findings into new therapeutic avenues for patients. More fundamentally, our genetically engineered mouse models are used to elucidate pathogenic mechanisms driving liver cancer, including how these cancers so effectively evade our immunosurveillance mechanisms as well as how epigenetic dysregulation contributes to biological outcomes and impact therapeutic responses.
Specifically, our laboratory has three major areas of focus:
National Trends in Rates of New Cancer Cases
IDH mutations in intrahepatic cholangiocarcinoma (ICC)
While wild-type (WT) isocitrate dehydrogenase (IDH) catalyzes the reversible conversion from isocitrate to alpha-ketoglutarate (αKG) in the citric acid cycle, mutant IDH (found in ~25% of ICC tumors) takes on a ‘neomorphic’ enzymatic activity, resulting in the irreversible conversion of αKG to 2-hydroxyglutarate (2HG), a so-called ‘oncometabolite’. In turn, 2HG builds to millimolar levels within IDH mutant cancer cells, where it can theoretically act as a competitive inhibitor of a family of >70 dioxygenases, many of which act as epigenetic modifiers. Our work hopes to uncover the molecular mechanisms linking this aberrant metabolic pathway to tumorigenesis and drug response.
There are two main questions our work in this area is seeking to answer:
- What are the functionally relevant targets of 2HG in IDH mutant cancer?
This work is particularly relevant, as potent and specific mutant IDH inhibitors are currently being tested in phase III clinical trials for IDH mutant ICC, even though their mechanism of action is still unknown.
- What are the mechanisms underlying dasatinib hypersensitivity in IDH mutant ICC?
IDH mutant ICC cells are more sensitive than any other known solid tumor cells to SRC family kinase inhibitors such as dasatinib (Saha, et al. Cancer Discovery 2016). Our laboratory is currently uncovering a novel and unique pathway by which SRC itself maintains the survival of IDH mutant ICC cells.
Epigenetic Dysregulation in liver cancer
The SWI/SNF chromatin remodeling complexes form multisubunit structures capable of mobilizing nucleosomes by sliding, ejecting or inserting histone octamers in chromatin, presumably to regulate tissue- and lineage-specific gene regulation. Interestingly, frequent loss of function mutations are found in several SWI/SNF components, including PBRM1 and ARID1A, yet the role of these intriguing and complex molecular machines in suppressing tumorigenesis remains poorly understood. Our laboratory uses a robust panel of unique genetically-engineered mouse models to uncover how such mutations impact normal liver development, the liver regeneration, and ultimately the response of liver cancer cells to novel targeted therapies.
Overcoming immune evasion in liver cancer
Unfortunately, immunomodulatory therapies have demonstrated only limited success in a subset of liver cancer patients. Our laboratory is using a combination of multiplex immunohistochemistry, flow cytometry and unbiased proteomics to determine how various liver cancer mutations contribute to immune evasion mechanisms in liver cancer through the recruitment and activation of immunosuppressive cells and cytokines.
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