Novel Approach to Hepatocellular Carcinoma Treatment through Enhanced ER Stress

Project Summary Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death in the world and is the fastest growing cause of liver cancer death in the United States. The prognosis of advanced HCC is exceedingly dismal, with a median survival rate of about 10 months. Despite the administration of several surveillance programs to detect HCC at the earlier stages, most patients are diagnosed at the advanced stages where treatment options are limited. Thus, there is an unmet need to develop effective targeted therapies for the treatment of HCC. Specialized organelles like the endoplasmic reticulum (ER) fold and mature proteins. HCC cells develop rapidly, requiring de novo protein synthesis, folding, and maturation and this creates ER stress. Cells use the unfolded protein response (UPR) to combat ERS. UPR can resolve ERS and restore homeostasis. However, unresolved ERS can be lethal to cells via ERS-induced apoptosis. We reason that HCC's elevated basal level of ERS is a major weakness, and drugs that further activate this system can deplete the protective properties of cancer cells and trigger apoptosis. My mentor’s lab recently developed a small molecule, ERX-315, that promotes ERS in cancer cells with no effect on normal cells. Unbiased CRISPR knockout screens identified the lysosomal acid lipase A (LIPA) protein as the critical target of ERX-315. The rationale for this study is based on evolving findings and preliminary data that ERX-315’s target, LIPA, is highly expressed in HCC compared to normal liver tissue, ERX-315 reduced the growth of HCC cells and organoids, reduced clonogenicity of HCC cells, and reduced HCC progression xenograft models in vivo. The objective of this study is to test the therapeutic efficacy and establish the mechanism of ERX-315 in treating HCC. We hypothesize that LIPA plays a critical role in HCC progression, and binding of ERX-315 to LIPA enhances ERS and induces apoptosis of HCC cells. In aim1, we will evaluate the biological activity of ERX-315 and significance of LIPA using multiple HCC model cells, determine the efficacy of ERX-315 in blocking HCC progression in vivo using CDX models and test ERX-315 ability to induce ERS and apoptosis in PDOs in vitro and PDX in vivo. In Aim2, we will determine how ERX-315 promotes ERS in HCC using biochemical assays, define how ERX-315 binding to LIPA causes ER stress and define molecular correlates of ERX-315 activity in HCC cells using proteomics and transcriptomics. This study is significant as it will develop a novel approach to treating HCC patients and develop a new therapy strategy using ERX-315 for increasing ERS. The PI will be trained as a translational cancer scientist and learn essential tools including molecular biology, cancer biology, confocal and transmission microscopy, molecular imaging, proteomics, transcriptomics, bioinformatics, preclinical xenografts, organoids, PDX models, as well as oral, writing and communication abilities. Training will be conducted in UT Health San Antonio's collaborative, NCI designated cancer center and well-resourced research environment. Sponsor Dr. Ratna Vadlamudi, a renowned cancer molecular biologist, and co-sponsor Dr. LuZhe Sun, a liver cancer expert, will mentor the student.