Developing Therapy for the Treatment of Cholangiocarcinoma

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 DESCRIPTION (provided by applicant): Cholangiocarcinoma (CCA) is a fatal disease, with a five year survival of 0-30%. For a majority of patients chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the frontline agent for treatment of CCA and the combination of gemcitabine and cisplatin is the current treatment standard. Neither gemcitabine alone or gemcitabine and cisplatin produce durable remissions. The molecular etiology of this disease is poorly understood, and tumors that respond initially uniformly relapse. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA. We propose to use these models to investigate the anti-tumor efficacy and mechanism of action of the novel compound JQ1, an agent that has not been evaluated for the treatment of CCA. Further, data in this application indicate that the combination of JQ1 + gemcitabine will produce synergistic cytotoxicity in CCA tumors; therefore, we will evaluate the anti-tumor efficacy of this combination using our unique panel of CCA models. JQ1 is an inhibitor of BET (bromodomain and extra-terminal domain) proteins, which regulate the association of transcriptional aggregates to acetylated lysine residues of histones at specific chromosomal loci. The rationale for combining JQ1 and gemcitabine is compelling. Firstly, JQ1 inhibits the activity of BET proteins and also inhibits expression of c-Myc, an oncogenic transcription factor that contributes to the tumorigenic phenotype of many solid tumors and likely plays a role in gemcitabine resistance. Secondly, data in this application document the novel finding that JQ1 down-regulates the DNA damage response protein Chk1. This finding is of particular relevance in that multiple studies in the literature demonstrate that inhibition of Chk1 sensitizes solid tumor cells to gemcitabine. Thirdly, unpublished data from our lab indicate that JQ1 induces DNA damage by a mechanism distinct from that of gemcitabine, suggesting the potential for at least additive induction of DNA damage by these two agents. Fourthly, our in vitro data show that JQ1 + gemcitabine are very strongly synergistic in pancreatic cancer cells, a cell type closely related to CCA. We hypothesize that JQ1 and gemcitabine will induce synergistic cytotoxicity in CCA tumors. We will evaluate the anti-tumor efficacy of this combination using our PDX CCA models, and determine if the observed downregulation of c-Myc and Chk1 is critical to the cytotoxicity of JQ1 and to the synergy of JQ1 and gemcitabine. We will also determine whether this combination produces synergistic anti-tumor cytotoxicity in gemcitabine-resistant as well as -sensitive tumors, and will generate expression profiles of gemcitabine-sensitive and -resistant CCA tumors, with a long-range goal of identifying biomarkers of sensitivity or resistance to gemcitabine and JQ1.