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Cholangiocarcinoma News

New Pathways and Molecular Targets in Cholangiocarcinoma

December 2021, Vol 2, No 4

Potential therapeutic targets for cholangiocarcinoma (CCA) include oncogenic pathways and other options, such as epigenetics, posttranslational modifications, and metabolism, according to presentations delivered during Session I, “Advances in Translational/Molecular Targets in CCA: New Molecular Targets/Pathways in CCA,” at the 3rd Annual CCA Summit.

Jesús M. Bañales, PhD, of Biodonostia Institute, San Sebastian, Spain, reviewed the classification, risk factors, cells of origin, and tumor features of CCA.

“CCA tumors are highly heterogeneous at the mutational level,” said Dr Bañales. “This is a limitation in order to find common and effective therapies for all cases, but this is a unique opportunity for personalized medicine and for targeted therapy, which is already a reality for patients with cholangiocarcinoma harboring FGFR fusion and IDH1 mutations.”

Dr Bañales discussed the molecular pathways beyond genes involved in the development, evolution, and progression of CCA, as well as key signaling pathways, including inflammatory cytokines, chemokines or growth factors, NOTCH, Wnt/β-catenin, Hippo (YAP or TAZ), and bile acids. He emphasized the therapeutic opportunities beyond genes.

Research is needed, he said, to identify key general pathways or mechanisms involved in cholangiocarcinogenesis that are amenable to available or to new drugs, which would potentially be beneficial for a high proportion of patients with CCA or for specific subgroups. He cited the 3 main areas of interest beyond genes for patients with CCA. “Epigenetics, posttranslational modifications, and metabolism represent general key signaling and molecular processes activated in CCA that could be targeted for therapy,” Dr Bañales suggested.

The G9a/DNMT1/UHRF1 epigenetic axis has been investigated. G9a, DNMT1, and UHRF1 are upregulated in human CCA compared with normal human cholangiocytes. Treatment with the CM-272 inhibitor has led to downregulation of the expression of these proteins.

The posttranslational modification of the neddylation pathway is upregulated in human CCA, as shown by increased expression of NAE1, particularly in moderate to poorly differentiated tumors. Pevonedistat, an NAE1 inhibitor, significantly reduces CCA cell proliferation and survival. Pevonedistat also halts cholangiocarcinogenesis in murine models.

Metabolic reprogramming is a hallmark of cancer. Increased lipid and lipoprotein uptake has been observed in CCA cells in vitro. Increased fatty acid oxidation promotes proliferation of CCA cells, which was significantly reduced after incubation with the inhibitor etomoxir.

Improved experimental models of CCA are needed to determine whether a drug works, and to further the development of new therapeutic options.

Nabeel El-Bardeesy, PhD, Harvard Medical School, Boston, MA, discussed oncogenic pathways in CCA. IDH1/2 mutations and FGFR2 fusions and mutations are frequently observed in patients with intrahepatic CCA. IDH1 inhibition with ivosidenib in intrahepatic CCA has resulted in clear survival benefits, which led to the FDA approval of the drug for CCA associated with IDH1 mutation. Inhibition of IDH1 mutation increases CD8-positive cytotoxic T-cell infiltration and effector function, and induces interferon-gamma response.

“The data suggest that mutated IDH has an important role in regulating tumor immune interplay in cholangiocarcinoma,” Dr El-Bardeesy said. “The initial benefit of this strong immune recruitment is offset by the gradual interferon-gamma–mediated recruitment and activation of the T-cell checkpoint, ultimately leading to treatment failure in our model systems. On the other hand, thwarting this immune checkpoint as well as Treg recruitment, using a CTLA antibody, we’ve been able to have very pronounced and durable responses that we are very excited to consider for further therapeutic development.”

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