A Druggable Epigenetic Vulnerability Pathway in p53-Deficient Hepatocellular Carcinoma
Abstract
Hepatocellular carcinoma (HCC), the most common and an often lethal form of liver cancer, accounts for more than 29,000 deaths 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 disease spread 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 different 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), modification of DNA or proteins that wraps around DNA (known as histone) can also get 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 important role of epigenetic regulators and epigenetic alterations in driving the growth and spread (also known as metastasis) of cancer cells, including HCC. Tumor suppressor p53 is an important protein that prevents tumor development and growth. DNA sequencing of large number of patient-derived HCC samples have identified that p53 gene is inactivated by gene deletion or mutations in p53 gene that makes it non-functional. The patients who have non-functional p53 (p53-deficient) HCCs are at a much higher risk of death (reduced overall survival) and also show reduced disease-free survival. Thus, p53-deficient HCC are highly aggressive subtype of HCC. However, currently there is no specific treatment for effectively treating this subtype of HCC. As mentioned above, epigenetic regulators are important drivers of tumor growth and progression. Therefore, we asked if p53-deficient 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 approach allowed us to identify a protein named DOT1L to be necessary for the growth of p53-deficient HCC tumors. We found that inhibiting DOT1L inhibited the growth of p53-deficient HCC. Thus, DOT1L represents a drug target for treating p53-deficient 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 DOT1L targeting using genetic methods and more importantly using small molecule drugs, such as EPZ-5676, as an effective approach for treating p53-deficient HCC tumor growth and metastasis. Towards this end, we will use innovative and complementary mouse models of HCC that we have developed in our laboratory to accurately recapitulate human HCC. These preclinical mouse models will include a mouse model of liver fibrosis (also known as cirrhosis) and another mouse model in which we have transplanted human immune system to study HCC development in the context of human immune system. The research in this proposal addresses the Fiscal Year 2017 (FY17) Peer Reviewed Cancer Research Program Topic Area of liver cancer. Additionally, our research proposal addresses both FY17 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 e
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810069
Entities
People
- Suresh Bugide
Organizations
- United States Army
- Yale University