Evaluation of voltage-gated calcium ion channels as a therapeutic target in intrahepatic cholangiocarcinoma

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Project Summary/Abstract Intrahepatic cholangiocarcinoma (ICC) is an aggressive primary liver cancer with a median overall survival of 11.7 months. The majority of patients present with unresectable disease, demonstrating a significant need for improved systemic therapies. Here, we use CRISPR/Cas9 screens to identify genes essential to ICC survival that could serve as novel therapeutic targets. We demonstrate that CACNA1A and CACNA1G, which encode the main pore-forming subunits of two voltage-gated calcium ion channels (VGCCs), are two genes of essentiality in five ICC cell lines. We hypothesize that aberrant expression of voltage-gated ion channels is essential to ICC survival and propose that existing FDA-approved calcium channel blockers could be repurposed to treat ICC. Our preliminary data demonstrate that not only are these two genes essential to ICC proliferation, but also that both antihypertensives and antipsychotics may be effective in decreasing ICC viability in vitro. To test our central hypothesis, we propose the following aims: 1) determine the effect of VGCC genetic knockdown and pharmacologic blockade on ICC cells in vitro, 2) investigate the mechanisms by which blockade of these calcium channels decreases ICC viability, and 3) determine whether calcium channel blockers can be used individually or to augment the effects of chemotherapy both in vivo and in novel patient- derived models.