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October is Liver Cancer Awareness Month, a time not only to spread awareness about the people it impacts, but also to highlight the research being done to make strides fighting against the disease. Devanand Sarkar, M.B.B.S., Ph.D., the associate director for research training and education, and member of the Cancer Biology research program at VCU Massey Comprehensive Cancer Center, spoke with us about how liver cancer research has evolved over the years, what improvements have been made, and what areas still need further exploration.
 

Why is there such a need for more liver cancer research?

Because the liver is such a big organ, by the time a tumor develops and symptoms are noticeable, it is quite large. Most of the time, the symptoms are quite vague—pain, nausea and weakness—which people tend to ignore. It takes time for the tumor to develop, but once it forms, it grows quickly.

In most cases, the diagnosis happens at an advanced stage. The problem with advanced stage hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is that it’s often found once it’s so big that it’s not possible to surgically resect. If the tumor is small and caught early, one relatively curative option is liver transplantation. But if the tumor is of a certain size, patients don’t have that option.

The current treatment protocol is a combination immunotherapy. There are also certain drugs like sorafenib, which are receptor tyrosine kinase inhibitors, and its analogs like lenvatinib and others. In cases of advanced disease, the immunotherapy is effective in less than 30% of patients, and the overall survival is less than two years.

So, there is definitely a huge need for understanding the disease process, how it develops and determining the key regulators to see if we can develop new treatments.

What makes liver cancer so difficult to treat?

The liver is the primary metabolic organ in the body, so all of our food and drugs are broken  down through the liver. In most cases, liver cancer develops following some kind of liver disease such as hepatitis B, hepatitis C, or obesity-associated fatty liver disease. Alcohol use is another major factor. All of these conditions injure the liver for a very long time, often decades.

The difference between liver cancer and other cancers is that you can treat them with anti-cancer drugs that can be metabolized in the liver. In liver cancer, the organ itself is damaged, so drug-induced toxicity is very high because the drug accumulates in the body and it cannot be metabolized properly. Or in some cases, the drug needs to be metabolized in the body to become an active drug, and that cannot happen properly because the liver itself is damaged.

Having a damaged liver can also cause worse side effects, and because of worse side effects, many patients just stop treatment because they have to consider the balance between their quality of life and longevity.

How has research changed the outlook for patients with liver cancer over the years?

Sorafenib was the only drug that was approved for a long time. Previously, patients were treated with cocktails of chemotherapy, which is kind of like throwing the kitchen sink at the patient. But sorafenib was the first kind of targeted therapy that works by cutting off the blood supply to liver tumors.

There have been subsequent iterations of sorafenib and combination immunotherapies which are more potent and have improved the survival of patients. It all depends on at what stage the patient is diagnosed. In early-to-mid-stage diagnoses, the outlook is much better than it was in the past, but advanced stage cases have not seen the same improvement.

We still don't know which patients respond well versus which patients do not. There are some theories, but there is no molecular signature that tells us which patient will do well and which patient won’t.

How has the $13M grant you received from the NCI helped you advance liver cancer research?

We have just started our third year of a five-year project program grant (P01) from the National Cancer Institute. Through the grant, we started four projects, all with a focus on some kind of treatment option that we can take further.

Right now, the leading cause of liver cancer is obesity-induced fatty liver disease. In cases of obesity, extra fat that is normally deposited in your fat tissue increases so much that it starts spilling over from fat tissue and starts depositing into other organs. If it starts depositing in the liver, then it causes inflammation, which can ultimately lead to cancer.

Our program project is mostly focused on this fatty liver-induced liver cancer and how we can use the molecular studies to develop new treatments. That includes immunotherapy, viral gene therapy and basic molecular work. Our goal is to understand the mechanism of the disease, how the therapy works and its efficacy. We want to renew the grant and test what we learned from this first cycle of funding and implement that in the second cycle, which could then lead to a clinical trial or more preclinical studies.

Are there any other liver cancer research projects ongoing at Massey?

Apart from my team’s program project, there are a number of investigators who are working on additional liver cancer research.

Christopher Green, Ph.D., a member of the Cancer Biology research program at Massey, is working on research related to sphingolipid metabolism and HCC.

Lauren Ashley Cowart, Ph.D., who is also part of Massey’s Cancer Biology research program, is working on a specific mitochondrial protein regulating ceramide synthesis and HCC.

Are there any clinical trials involving liver cancer at Massey?

Emily Kinsey, M.D., an oncologist and member of the Developmental Therapeutics research program at Massey, is leading clinical trials in liver cancer. Her research team is currently testing the efficacy of the drug aramchol, which is an inhibitor of a protein called SCD1 that is a key player in tumor cell growth. 

Is there anything else that people should know about liver cancer?

Liver cancer is so unlike a lot of other cancers since there is a specific etiology for it. For example, we often don't know why breast cancer or prostate cancer develops. Suddenly, there are some gene mutations and then the tumor develops.

But in the case of liver cancer, it is almost always preceded by a long-standing liver disease. So, getting vaccinated against viruses like hepatitis B is one way of protecting the liver. While hepatitis C does not have a vaccine available for prevention, we have a very good drug combination for treatment.

Another thing that is very important to be proactive about is maintaining a balanced lifestyle. Because obesity and alcoholism play a large role in the risk of developing liver cancer, be mindful of your diet, exercise and alcohol intake.

Stress also precedes a lot of different types of metabolic disorders that fit into liver cancer. While it’s impossible to live in a completely stressless world, taking care of the body and mind with strategies like mindfulness and meditation is equally important.

Written by: Tatiana Del Valle