The Long Noncoding RNA CRNDE in HCC-Induced Immune Suppression
Abstract
The problem to be addressed in this proposal is included in the Fiscal Year 2018 (FY18) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas of (1) Liver Cancer and (2) Immunotherapy. The goal of this proposed research is to invent an effective way to fill the gap in liver cancer treatment, which is stated as one of the FY18 PRCRP Military Relevance Focus Areas . Hepatocellular carcinoma (HCC) represents approximately 80% of cancer that start in the liver, and is diagnosed each year in more than half million people around the world. An estimated 42,220 new cases and 30,200 deaths of liver cancers are expected during 2018 in the United States (increased by 3.7% and 4.4% respectively, compared with the data of 2017); three-fourths of new liver cancer or liver cancer-related deaths are caused by HCC. Currently, several therapeutic strategies have been proposed for HCC patients with proven survival benefits in the early-stage disease. Unfortunately, the diagnosis of HCC is too often made when the disease is in an advanced state. At this stage, there is virtually no effective treatment that could improve the patient’s survival substantially. Therefore, there is a practical and urgent need to develop new effective methods for the treatment of advanced HCC. It has been known for a long time that the immune system, a collection of organs, special cells, and substances, can protect our bodies from infections and some other diseases, including cancers. However, the immune cells in cancer (called tumor infiltrating lymphocytes [TILs]) have a tougher time targeting cancer cells due to certain substances given off by cancer that keep the TILs in check. Recently, scientists have developed several immunotherapy medicines (such as Nivolumab and Ipilimumab) to counteract some of these substances specifically, and it has been found that these medicines can successfully re-boost a cancer patient’s immune cells (including TILs) and partially restore their cancer-killing functions. This strategy (called immunotherapy) has been proved to be successful in the treatment of multiple types of cancers (such as melanoma, lymphoma, and lung cancer). However, no effective method has been developed for HCC due to limited knowledge about the cancer-released inhibitory substances in the microenvironments of HCC. In our pilot studies, we have characterized a new kind of immune inhibitor released by HCC cells (called CRNDE), which has the promising potential to be a target for HCC target therapy. Consequently, our objective in this proposed study is to establish an effective approach to treat HCC through counteracting CRNDE with next generation anti-sense oligonucleotides (called gapmer ASOs). We will further evaluate the combinative therapeutic efficacy of CRNDE-specific gapmer-ASOs and other FDA-approved cancer medicines (such as Nivolumab and Ipilimumab). We anticipate that these new combination treatments could treat HCC effectively through restoring the tumor-cell-killing function of TILs in cancer. This new approach, if established successfully, will greatly benefit HCC patients with longer survivals and better life qualities. It is noteworthy that our way for cancer therapy is innovative and will bring up a new therapeutic strategy not only for HCC but also for other cancers. Liver cancer (80% of liver cancers are HCC) has long been a health problem in the aArmy. Past decades have witnessed a significant increased incidence of primary liver cancer in U.S. military personnel. A recent study has revealed a near-doubling of crude frequency of liver cancer in people received care from U.S. Department of Veterans Affairs health care system over a 6-year period (from 570 cases in the year 2001 to 1,054 cases in the year 2007). The reasons of increased liver cancer incidence in U.S. military personnel could be excessive exposures to risk factors, such as chronic hepatitis B or C virus infection, radioactive substances, tumorigenic chemicals, high c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910849
Entities
People
- Jinqiang Zhang
Organizations
- Tulane University of Louisiana
- United States Army