Timeframe: 2019 – 2022
Goal: Investigate the potential of AURKA inhibitors for FLC treatment
Principal Investigator: John Gordan, MD, PhD, Assistant Professor, Department of Medicine, UCSF
Co-Investigator: Nabeel Bardeesy, Associate Professor, Massachusetts General Hospital, Harvard University
Even though the DNAJB1-PRKACA gene fusion (encoding a chimeric protein with a domain of heat shock protein 40, HSP40, fused to a majority of the enzymatically active subunit of protein kinase A, PKAc) is sufficient to trigger fibrolamellar liver cancer (FLC), no treatments directed at this target are clinically available. Most FLC patients receive chemotherapy and no PKA inhibitors are currently in clinical use.
Over the past two years, the study team has mapped the signaling cascade downstream of PRKACA in FLC and other tumors (see completed project below). This analysis highlights Aurora Kinase A (AURKA) as a key mediator of oncogenic growth. AURKA is best known for regulating the cell cycle, but also promotes cell survival and the expression of oncogenic genes (i.e., those that contribute to cancerous growth). Most conventional AURKA inhibitors fail to strongly inhibit the growth of human FLC cells. This finding is consistent with limited activity observed with such a drug in clinical trials. However, colleagues at UCSF described a novel class of AURKA inhibitors designed to disrupt its interaction with members of the MYC family of oncoproteins, which are critical drivers of many cancers. One of these new AURKA inhibitors does potently reduce the proliferation of FLC cells. The drug also reduces expression of MYC-family oncogenic transcription factors. The team hypothesizes that AURKA-mediated stabilization of MYC is necessary to maintain growth of FLC cancer cells. Although these new AURKA inhibitors are not yet ready for human use, the team will studying them to understand if they are likely to be effective for FLC and whether they work well in combination with other available drugs. They plan to assess the activity and mechanism of conformation disrupting AURKA inhibitors in FLC laboratory models, including human tumors grown in mice, with the goal of identifying a drug in this class that could be advanced to clinical testing in FLC patients.