Scientific Program

Abstract:

Hepatocellular carcinoma (HCC) is one of the most lethal cancers for humans. MAN2A1-FER is one of the most frequent oncogenic fusion genes in the HCC. In this report, we showed that MAN2A1-FER ectopically phosphorylated the extracellular domains of PDGFRA, MET, AXL, and N-cadherin. The ectopic phosphorylation of these transmembrane proteins led to the activation of their kinase activities and initiated the activation cascades of their downstream signaling molecules. A panel of mouse monoclonal antibodies was developed to recognize the ectopic phosphorylation sites of PDGFRA. The analyses showed that these antibodies bound to the specific phosphotyrosine epitopes in the extracellular domain of PDGFRA with high affinity and specificity. The treatment of MAN2A1-FER positive cancer HUH7 with one of the antibodies called 2-3B-G8 led to the deactivation of cell growth signaling pathways and cell growth arrest, while had minimal impact on HUH7ko cells where MAN2A1-FER expression was disrupted. The treatment of 2-3B-G8 antibody also led to a large number of cell deaths of MAN2A1-FER positive cancer cells such as HUH7, HEPG2, SNU449, etc., while the same treatment had no impact on HUH7ko cells. When severe combined-immunodeficiency mice xenografted with HEPG2 or HUH7 were treated with Monomethyl auristatin E (MMAE) conjugated 2-3B-G8 antibody, it slowed the progression of tumor growth, eliminated the metastasis, and reduced the mortality, in comparison with the controls. Targeting the cancer-specific ectopic phosphorylation sites of PDGFRA induced by MAN2A1-FER may hold promise as an effective treatment for liver cancer.

Audience Take Away Notes:

• Oncogenic fusion genes in human liver cancer is relatively new topics. It plays an important role in HCC development
• MAN2A1-FER has novel oncogenic signaling pathways that may not be easily intercepted by convention small molecule targeting
• New approaches can be developed to target these fusion genes in diagnostic and therapeutic schema
• Screening for HCC based on serum fusion test will be developed that may help primary care physician to detect HCC early and save lives. The antibodies described in the study can be utilized to target HCC cancer cells

Biography:

Dr. Luo has been studying molecular mechanisms of human malignancies in the last 35 years. Currently, he is a Professor of Pathology and Director of High Throughput Genome Center at University of Pittsburgh. In the last 29 years, Dr. Luo has been largely focusing on the genetic and molecular mechanism of human cancers such as prostate cancer. He is one of the pioneers in utilizing high throughput gene expression and genome analyses to analyze field effects in prostate cancer and liver cancer. He is also the first in using methylation array and whole genome methylation sequencing to analyze prostate cancer. He and his colleague helped to develop an ultra-low error synthetic long-read sequencing technology called LOOPSeq that can be utilized to quantify mRNA isoforms and mutation isoform distributions in single cell level. His group has discovered 21 novel fusion genes in prostate, liver and colon cancers. Subsequently, his group discovered that many of these fusion genes are recurrent in many other types of human cancers. His group also developed a genome intervention strategy targeting at the chromosomal breakpoint of fusion gene to treat cancers. Overall, these findings advance our understanding of how cancer develops and behaves, and lay down the foundation for better future diagnosis and treatment for human malignancies