Mechanism-based combination therapy for cholangiocarcinoma

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PROJECT SUMMARY/ABSTRACT Cholangiocarcinoma (CCA) is an aggressive bile duct cancer. A majority of patients present with advanced disease and die within a year. For these patients, chemotherapy is the main therapeutic option. Current standards of care include gemcitabine-based regimens such as gemcitabine + cisplatin. However, the 5-year survival rate has not been improved for several decades; tumors that respond initially become resistant, and patients relapse. The literature documents that overexpression of DNA repair proteins contributes to resistance to DNA damaging agents such as gemcitabine and cisplatin, current frontline agents for CCA. This proposal seeks to identify gemcitabine-based combinations that overcome drug resistance and produce durable remissions for patients with CCA. To identify effective regimens and characterize molecular events that contribute to chemosensitivity or resistance, we developed a panel of patient-derived xenograft (PDX) CCA models: CCA1-5 and gemcitabine- resistant counterparts of CCA1 and CCA2 (CCA1.gemR and CCA2.gemR), with resistance acquired in vivo. We propose to use these models to identify effective treatments for CCA. Our data support the hypothesis that gemcitabine + a BET inhibitor (BETi) + a PARP inhibitor (PARPi) comprises effective treatment for this tumor type. Bromodomain and extra-terminal domain (BET) proteins regulate the association of transcription complexes to acetylated lysine residues of histones at specific chromosomal loci. BETi decrease expression of genes whose expression is BET-dependent. Multiple BETi are in clinical trial. Our data demonstrate: 1) that BETi + PARPi and also that BETi + gemcitabine are synergistic in vitro; 2) the novel finding that gemR cells are more sensitive to BETi + PARPi than to gemcitabine + cisplatin; and 3) that the BETi JQ1 + gemcitabine was more effective than gemcitabine as a single agent in the CCA1.gemR PDX in vivo model (P<0.001). Further, our data suggest that sequential administration of BETi → gemcitabine will produce BETi-mediated decreases in expression of DNA repair proteins and minimize gemcitabine resistance. Proposed work evaluates the anti-tumor efficacy of the clinical BETi OTX015 + the PARPi olaparib + gemcitabine, cisplatin, or gemcitabine + cisplatin in models of local and metastatic CCA. We will determine if any of these regimens is superior to current standard of care, and perform whole genome sequencing of all models to identify genetic and molecular characteristics associated with resistance. We will also generate expression profiles of treated vs control tumors and of primary vs metastatic tumors. These data will provide a basis for future work toward long-term goals of identifying gene products and pathways that contribute to drug resistance or metastasis of CCA, and to develop effective treatment regimens using targeted agents.