TAF2: A Potential Oncogene for Hepatocellular Carcinoma (HCC)
Abstract
Hepatocellular carcinoma (HCC), the primary liver cancer arising from hepatocytes, the predominant cell constituting the liver, accounts for ~90% of all liver cancers. The present proposal focuses on HCC, a Fiscal Year 2017 (FY17) Peer Reviewed Cancer Research Program (PRCRP) Topic Area, and addresses gaps in biomedical knowledge in molecular pathogenesis of HCC and HCC treatment, FY17 PRCRP Military Relevance Focus Areas. The incidence of HCC is increasing in the West, and it is the fifth most common cancer and the second most common cause of cancer-related deaths globally. In the US, the estimated new HCC cases for 2017 are 40,710, out of which 28,920 are expected to die. Most HCC cases are diagnosed at advanced stages with a dismal prognosis owing to underlying liver disease, inherent resistance of HCC cells to conventional chemo- and radiotherapy, and lack of effective treatment options. Compromised liver function in HCC patients renders small molecule inhibitors either relatively ineffective or toxic because of improper metabolism. The most commonly used Food and Drug Administration (FDA)-approved drug, sorafenib, provides a survival benefit of only 2.8 months. This bleak scenario calls for better insights into the molecular mechanism of HCC initiation and progression and development and evaluation of novel, targeted therapeutic strategies. Our preliminary studies identify a new regulator of HCC and provide a clinically relevant approach to counteract it, and thereby might lead to promising benefits for general population as well as Veteran patients with HCC. Many oncogenes, genes that promote cancer, are transcription factors that regulate expression of genes. Overexpression of these transcription factors results in increased expression of genes that regulate the hallmarks of cancer, such as proliferation, invasion resulting in metastasis, resistance to therapy and new blood vessel formation. TATA-box binding protein (TBP) associated factor 2 (TAF2) is a transcription cofactor that helps the basal transcription factors to execute their function. Our preliminary studies document that TAF2 is overexpressed in human HCC and regulates proliferation and invasion of HCC cells. The hypothesis to be tested is that TAF2 exerts its oncogenic functions by modulating specific gene transcription and targeted inhibition of TAF2 might be an effective strategy to counteract HCC, thereby providing benefit not only to the general population but also to the military Service members and Veterans in whom both incidence and mortality of HCC are increasing alarmingly. The objectives of the proposal are to obtain in-depth understanding of the molecular mechanism by which TAF2 functions as an oncogene and evaluate a hepatocyte-specific nanoparticle formulation delivering TAF2 siRNA, which inhibits TAF2 function, as a potential anti-HCC approach. The role of TAF2 in HCC has not been studied before, and there is extreme paucity of studies analyzing the role of TAF2 in cancer in general. As such, our proposed studies are innovative and will provide novel insights. HCC develops on a cirrhotic background with compromised liver function that precludes efficient action of drugs and mandates alternate approaches. In clinical trials, nanoparticle-mediated delivery of siRNA targeting diverse oncogenes has provided significant objective response in HCC patients with complete regression of the disease. The nanoparticle formulation that we are using has been approved by FDA for clinical use. Additionally, we are working with Nanoparticle Characterization Laboratory (NCL) of the National Cancer Institute for in-depth characterization of our nanoparticle formulation. In view of this, successful completion of our proposed studies will facilitate accrual of baseline data for initiating an Investigational New Drug (IND) application to the FDA for a Phase I/II clinical trial in HCC patients at the end of the proposed studies. In the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810143
Entities
People
- Devanand Sarkar
Organizations
- United States Army
- Virginia Commonwealth University