A Novel Therapeutic Approach for Treating WNT-Driven Hepatocellular Carcinoma
Abstract
Hepatocellular carcinoma (HCC), the most common and a lethal form of liver cancer, accounting for more than 30,000 deaths each year in the United States alone. According to the estimates of the American Cancer Society, less than 18% patients diagnosed with HCC can expect to survive beyond 5 years. The survival rate drops even further when the disease spreads to distal organs such as lungs and bone, and in this scenario the 5-year survival rate drops below 3%. Due to higher hepatitis virus infection and exposure to several other chemicals that can cause HCC, the incidence of HCC is much higher in military personnel compared to the general population. This combined with very high mortality rate and lack of effective therapies makes HCC a high priority disease in urgent need for the development of effective treatment approaches. In recent years, studies have shown that in addition to direct changes in DNA sequences (genetic alterations), DNA, or proteins that wrap around DNA (known as histone) is also modified by a series of proteins that are collectively referred to as epigenetic regulators. The changes, caused by epigenetic regulators to the DNA or histone proteins are known as epigenetic alterations. New studies have now provided strong evidence for the important role of epigenetic regulators and epigenetic alterations in driving the growth and spread (also known as metastasis) of cancer cells, including HCC. WNT signaling pathway is an important cancer-promoting pathway that promotes cancer development and metastasis to different organs. DNA sequencing of large number of patient-derived HCC samples have identified that genes regulating WNT pathway are mutated in such a way that WNT signaling is always active in HCC and promotes its growth and metastasis to other organs. However, currently there is no specific treatment for effectively treating this subtype of HCC. Thus, treating WNT signaling-driven HCC is an unmet medical need. As mentioned above, epigenetic regulators are important drivers of tumor growth and progression. Therefore, we asked if WNT-driven HCCs depend upon any specific epigenetic regulator for their survival. To this end, we blocked the expression of all human genes that encode epigenetic regulators using an experimental approach of RNA interference. The RNA interference approach works by degrading the target gene using short stretches of RNAs known as small interfering RNA. This approached allowed us to identify a protein named SETD7 as being necessary for the growth of WNT-driven HCC tumors. We found that inhibiting SETD7 inhibited the growth of WNT-driven HCC. Thus, SETD7 represents a drug target for treating WNT-driven HCC that are highly aggressive and is associated with a significantly higher mortality rate. Based on these very encouraging results, the goal of this research proposal will be to rigorously test SETD7 targeting using genetic methods and, more importantly, using small molecule drugs, such as (R)-PFI-2, as an effective approach for treating WNT-driven HCC tumor growth and metastasis. Toward this end, we will use innovative and complementary mouse models of HCC that we have developed in our laboratory to accurately recapitulate characteristic features of human HCC. These pre-clinical mouse models will include a mouse model of liver fibrosis (also known as cirrhosis) and another mouse model that has transplanted human immune system, which allows the study of HCC growth and progression in the context of functional human immune system. The research in this proposal addresses the fiscal year 2018 (FY18) Peer Reviewed Cancer Research Program Topic Area of liver cancer. Additionally, our research proposal addresses both FY18 Military Relevance Focus Areas. First, our research proposal will address risk factor-associated cancer because the incidence of HCC is significantly higher in military personnel compared to general population due to the exposure to several liver carcinogens.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910480
Entities
People
- Narendra Wajapeyee
Organizations
- United States Army
- University of Alabama at Birmingham