Fibrolamellar hepatocellular carcinoma (FL-HCC) is a form of primary liver cancer that afflicts healthy children and young adults without underlying liver disease; approximately 90% of HCCs in this age group are FL-HCCs. HCC as a whole is a remarkably diverse disease from a histologic and molecular standpoint, and in the vast majority of adult cases arises in the setting of chronic liver injury and cirrhosis. Conversely, FL-HCCs display consistent clinical behavior and have a homogeneous histologic appearance, but there are no known risk factors. FL-HCC also differs from other subtypes of HCC in that it arises in normal liver, and since these patients are healthy at baseline, they tend to present with advanced disease, leaving no options for cure. Currently there are no effective non- surgical therapies for patients with FL-HCC. Therefore we aim to develop targeted therapies for FL- HCC patients through a detailed understanding of the molecular pathogenesis of this disease. Recently, a putative causative mutation in FL-HCC was reported, and results in a chimeric transcript consisting of the promoter region and first exon of a gene encoding a heat shock protein (DNAJB1) fused to the majority of the sequence for the gene encoding the catalytic subunit of protein kinase A (PRKACA). The mechanisms by which the resultant fusion protein drives carcinogenesis remain unknown, though we have recently demonstrated increased PKA activity in FL-HCCs compared to normal livers. The current proposal outlines experiments that will further investigate drivers of excess PKA signaling in FL-HCC, with focus on the role of a neuroendocrine hormone in this disease. Specifically, we will 1) evaluate the contribution of neurotensin to the development of FL-HCC, 2) investigate how the DNAJB1-PRKACA fusion leads to neuroendocrine activation in these cancers, and 3) define the oncologic effects of neurotensin/PKA signaling in the liver. In summary, we propose to investigate the mechanisms by which the DNAJB1-PRKACA protein product synergizes with neurotensin to drive carcinogenesis in FL-HCC, paving the way for the development of targeted therapies for this cancer.
Fibrolamellar hepatocellular carcinoma is a type of liver cancer that develops in healthy children and young adults; an underlying causative genetic mutation has just been discovered. The purpose of this proposal is to determine precisely how this mutation leads to the development of cancer in these patients, using a combination of patient samples and cell culture assays. Our overall goal is to develop targeted therapies to treat this cancer, for which no current non-surgical curative options exist.
|Sullivan, Kevin M; Kenerson, Heidi L; Pillarisetty, Venu G et al. (2018) Precision oncology in liver cancer. Ann Transl Med 6:285|