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Originally published in Forward magazine – Winter/Spring 2023
At Fox Chase Cancer Center and Temple Health, liver cancer research and treatment have long been a focus. Primary liver cancer, also called hepatocellular carcinoma (HCC), is the fifth most common cancer in the world. It is accompanied in most cases by underlying disease such as cirrhosis, which features extensive scarring of the liver. The most common causes of cirrhosis and HCC worldwide are viral hepatitis B and C.
Fox Chase has a unique history in this area. The late Baruch S. Blumberg received the 1976 Nobel Prize in medicine for identifying the hepatitis B virus as one of the major causes of liver cancer. His Fox Chase laboratory group created the first highly effective vaccine capable of preventing a human cancer, the hepatitis B vaccine, which was introduced in 1982.
The work on liver cancer treatment has not slowed since then. Researchers in both the lab and the clinic at Fox Chase and Temple Health are taking a comprehensive approach to liver cancer, making them a one-stop shop for fighting the disease as they continually work toward new and improved tools to tackle this devastating disease.
This work is particularly important, given that Temple Health’s main campus is located in North Philadelphia, where higher rates of poverty and cancer overlap. Previous studies have shown that liver cancer patients from lower-income households are not only commonly diagnosed in later stages of tumor progression, but experience significantly higher rates of mortality as well. But the state-of-the-art care being developed and offered at Temple and Fox Chase can make a difference.
“Whatever situation you find yourself in, we have either standard-of-care options or cutting-edge clinical trials to offer. We offer a thoughtful approach, which I think makes a difference in long-term outcomes,” said Jason Castellanos, a surgical oncologist at Fox Chase.
"Whatever situation you find yourself in, we have either standard-of-care options or cutting-edge clinical trials to offer."
Jason Castellanos, Fox Chase Surgical Oncologist
A Complex Disease
Liver cancer is a complex disease with multiple risk factors. In addition to cirrhosis and viral hepatitis, other factors like inherited metabolic diseases caused by genetic defects, tobacco and heavy alcohol use, obesity and type 2 diabetes play a role in its development.
Another layer of complexity is added by the fact that many patients do not experience symptoms in the early stages of liver cancer. As a result, they are often diagnosed in intermediate or late stages and miss out on the opportunity for localized treatments. Fortunately, there are still options available to them, several of which Castellanos specializes in.
“Patients with more advanced liver cancer are often candidates for surgery and we can offer them open or minimally invasive operations. The most important thing in the clinical care of these patients is multidisciplinary collaboration and treatment, whether it’s chemotherapy, radiation, interventional radiology, or complex surgery that are the methods selected for a particular patient.”
Among some of the innovative techniques that Castellanos uses are hepatic arterial infusion (HAI) and robotic surgery. HAI is a treatment option for patients with colon cancer that has spread to the liver. It is a type of chemotherapy delivered directly into the blood supply of the liver, thus sparing the rest of the body from the drug’s effects. It is a particularly useful approach for patients with advanced disease whose cancer cannot be removed with surgery alone.
“Somewhere around 50% to 80% of patients with colon cancer that has spread to the liver have disease that cannot be treated surgically, so the hepatic artery pump is one of the most effective ways to get them to a point where they can undergo surgery,” said Castellanos.
Robotic surgery is a minimally invasive approach that allows for the removal of tumors using mechanical arms with surgical instruments attached to them. It involves much smaller incisions and allows patients to recover more quickly, so it is especially helpful for patients who are older or may have difficulty recovering from an operation, said Castellanos.
Making Drugs More Effective
But if a patient’s cancer is detected early enough, treatment with drugs alone may do the trick, and it is Ling Yang’s job to make sure these drugs work as efficiently as possible. Yang, an assistant professor of medical genetics and molecular biochemistry at the Lewis Katz School of Medicine at Temple University, is investigating methods for improving current cancer drugs, which she said are not always as effective as they could be.
Currently, the standard treatment for late-stage HCC is the chemotherapy drug sorafenib. However, more than 30% of patients treated with this drug have severe reactions like increased blood pressure, bleeding, and cardiac events that can often lead to dose reduction or the drug being stopped completely.
“Combination therapies, which could be given along with the drug sorafenib to improve its effect, are urgently needed. New therapeutic strategies with better treatment outcomes are also urgently needed,” said Yang. In their search for these new therapies, she and her colleagues have been focusing specifically on non-alcoholic fatty liver disease, one of the main risk factors for developing liver cancer. They found that a gene that contributes to the progression of non-fatty liver disease can also slow its growth under certain conditions, so that is one avenue they are exploring.
Combination therapies, which could be given along with the drug sorafenib to improve its effect, are urgently needed.
Ling Yang, Lewis Katz School of Medicine at Temple University
Additionally, Yang is working on determining the role of long non-coding RNAs, a recent discovery that has been shown to act as central regulators in the development of cancer. Tumor protein 53 (TP53) is the second most frequently mutated gene in liver cancer. Her research has examined the role of a TP53-induced IncRNA called tumor protein 53 target gene 1 (TP53TG1) in liver cancer and investigated how it affects the performance of sorafenib in attacking HCC.
Their research found that by reducing the expression of TP53TG1, liver cancer cells became more responsive to treatment with sorafenib, suggesting that this method may be an improved form of therapy for HCC patients.
Understanding Liver Cancer Progression
While Yang and Castellanos are working to improve the treatment of liver cancer, Fox Chase researcher Joan Font-Burgada’s focuses on the earliest stages of the disease—how it develops and how to detect it. “We know very little about how these tumors originate and how they evolve over time. Mouse models are very important for this because we can begin to understand all these steps,” said Font-Burgada. “Having new fundamental concepts of this disease and how we need to take into account underlying disease will allow us to understand whether treatments are suitable for a patient with chronic problems in the liver.”
In order to create a more accurate model of the molecular development of HCC, Font-Burgada’s lab is combining mouse genetics with the use of transposons, which are DNA sequences that can move from one location in the genome to another.
They are using these transposons to translate mutations that are found in human patients into the mouse liver so that they can generate tumors that have a similar genetic makeup. This allows them to study how these mutations interact with each other and with the chronic underlying disease, Font-Burgada said.
His lab is also working on projects that apply findings on liver regeneration from mouse models to humans through the use of a specific kind of hepatocyte, the most common cells found in the liver. “Our recent identification of hybrid periportal hepatocytes has shown an important role in the regeneration of the damaged liver in mice. These findings form the basis for our next goal, which is to translate these results from our mouse models into human cell therapy.”
Liver Cancer Disparities
In addition to working to improve the treatment of liver cancer, researchers at Temple and Fox Chase are exploring the issue of disparities among liver cancer patients, particularly in the Asian American community.
According to the American Cancer Society, Asian Americans and Pacific Islanders have the highest rates of liver cancer, followed by Hispanics/Latinos, American Indians/Alaska Natives, African Americans, and whites.
In an attempt to remedy this, researchers like Grace Ma have begun to expand research on structural racism and discrimination (SRD) to include Asian Americans. Ma is a founding director of the Center for Asian Health and a professor in the Department of Urban Health and Population Science at the Katz School of Medicine.
The research is being funded through a five-year, $4 million grant from the National Institute on Minority Health and Health Disparities of the National Institutes of Health. The grant is the first of its kind to support research that addresses the impact of SRD on liver cancer and liver disease in general in high-risk Asian Americans.
“Our hope is that our first multilevel and longitudinal study will not only help us understand how structural racism drives disparities in hepatitis B virus infection and liver disease in Asian American populations, but will also help improve quality of care for those affected by the virus and advance hepatitis elimination initiatives,” she said.