A Novel Therapeutic Target for Treating Aggressive and Metastatic Hepatocellular Carcinoma
Abstract
Hepatocellular carcinoma (HCC), the most common and an often lethal form of liver cancer, accounts for more than 31,000 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 the 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. The cells of a tissue or organ rely on the surface around them, called the extracellular matrix, for survival; this is referred to as “anchorage-dependent growth.” Attachment to the extracellular matrix not only provides structural anchorage for a cell, but also provides critical survival signals. When these cells lose contact with the extracellular matrix, they die in a process termed “anoikis” (from the Greek word for “homelessness”). Normal cells use anoikis to prevent proliferation at inappropriate locations. By contrast, cancer cells do not die when they lose contact with the matrix. The ability of cancer cells to evade anoikis and survive – even thrive – in a foreign tissue is essential for them to invade and metastasize – a strategy that promotes the expansion and dissemination of the cancer cell population. Anchorage-independent growth of tumor cells is a hallmark of many different types of human malignancies, including HCC, and resistance to anoikis has been shown to contribute prominently to HCC progression, metastasis, and HCC-related deaths. Therefore, a better understanding of the molecular mechanisms underlying anoikis resistance will provide new opportunities for the treatment of aggressive and metastatic HCC and improve and extend patient survival. Using a series of genomics-based experiments and by analyzing the samples obtained from HCC patients, we discovered that ALK is an important druggable protein that confers anoikis resistance in HCC cells and thus, can promote HCC progression and metastasis. Based on these results, we will test the role of ALK in promoting HCC progression and metastasis. Additionally, and most importantly, we will test a US Food and Drug Administration (FDA)-approved ALK small molecular inhibitor lorlatinib for treating HCC using pre-clinical mouse models of HCC. ALK inhibitors, such as lorlatinib, have been approved by FDA for treating ALK+ lung cancers and have immensely benefited these cancer patients. However, ALK inhibitors were never tested for treating HCC, because before our studies, it was not known that ALK is a drug target for treating HCC. Based on our results of increased ALK expression in HCC and dependency of HCC cells on ALK protein for survival and metastasis, we predict that ALK inhibitors, such as lorlatinib, will be clinically useful for treating a large majority of HCC patients (over 60%). Experiments proposed in this proposal will comprehensively establish the effectiveness of lorlatinib for treating HCC. Thereby, these studies will provide a new therapeutic opportunity for treating HCC patients. The research in this proposal addresses the Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program Topic Area of liver cancer. Additionally, our research proposal addresses both FY19 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. Second, our study will also provide a new therapy for HCC metastasis treatment
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010534
Entities
People
- Romi Gupta
Organizations
- United States Army
- University of Alabama at Birmingham