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Liver cancer is the third-leading cause of cancer-related deaths worldwide, and the disease is often diagnosed at an advanced stage when there are significantly limited treatment options. A group of highly experienced researchers at VCU Massey Comprehensive Cancer Center was awarded more than $13 million through a team science grant from the National Cancer Institute to collectively unearth new, effective drug combinations for this largely untreatable cancer.

The five-year grant – the first P01 grant ever awarded to Massey in its five-decade history – will initiate a four-pronged approach to better understand the biology of liver tumors and advanced treatment options for hepatocellular carcinoma (HCC), the most common form of liver cancer.

“There are no other large, grant-funded projects like this in the country for obesity-associated liver cancer; it has the potential to change the way the disease is treated,” said Devanand Sarkar, M.B.B.S., Ph.D., the principal investigator on the grant, as well as associate director of cancer research training and education coordination and member of the Cancer Biology research program at Massey. “Within the umbrella of this grant, we have four separate research projects asking different molecular questions, but with the same ultimate goal of identifying how we can exploit our findings to improve the efficacy of immunotherapy in liver cancer.”

When diagnosed early, liver tumors are generally small and can be removed surgically or a liver transplant can be successfully performed. However, liver cancer is usually diagnosed when the tumor is much larger in size, the disease has spread to other organs and other associated health problems have already occurred.

Currently, there are a few available treatment options for liver cancer, including a combination of immunotherapies and a class of drugs known as tyrosine kinase inhibitors (TKIs), but their long-term effects are limited.

“Clinical trials show that immunotherapy is effective in less than one-third of liver cancer patients, and nearly 100% of patients who are treated with TKIs invariably develop resistance to the drugs within one year,” said Sarkar, who holds the Harrison Foundation Distinguished Professorship in Cancer Research at Massey and has been studying HCC throughout his entire career. “Even with the current treatments that are available for advanced disease, the patient survival rates are roughly less than two years.”

Previously, Sarkar has extensively studied MYC — a gene that operates individually to drive tumors and is amplified in about one-fifth of all HCC patients — as well as other genes that cooperate with MYC to accelerate liver cancer growth.

Through four different research projects, this grant will enable the investigators to explore the ability of a new drug, developed by collaborators at Northwestern University that inhibits the function of MYC, to effectively thwart liver cancer in combination with existing immunotherapies:

1. Arun Sanyal, M.D., and Huiping Zhou, Ph.D.: Obesity — classified as a global health epidemic by the World Health Organization — commonly leads to a form of fatty liver disease known as metabolic dysfunction-associated steatohepatitis (MASH). MASH is one of the biggest drivers of primary liver cancer. Sanyal, director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at VCU and member of the Cancer Biology research program at Massey, has studied the relationship between high-sugar, high-fat diets, the development of MASH and liver cancer growth. His recent finding has identified a role of MYC in regulating MASH-associated HCC. Zhou, member of Massey’s Cancer Biology research program whose research focuses on elucidating the role of bile acids in liver cancer, also unraveled a role of bile acids in MASH-associated HCC. Sanyal and Zhou’s project through this grant will evaluate the use of the MYC inhibitor in combination with other drugs in MASH-driven liver cancer.
2. Sarkar has identified that a gene known as TAF2 plays a critical and previously unknown role in the progression of liver cancer. He found that TAF2 partners with MYC to fuel cancer growth. Using a combination of targeted drugs and immunotherapies, Sarkar will lead an initiative attempting to block both TAF2 and MYC in liver tumors to determine if there is any clinical benefit.
3. Shawn Wang, Ph.D., co-leader of the Developmental Therapeutics research program at Massey, has previously developed an antibody against a family of molecules — scavenger receptors — in myeloid cells. Wang will use this grant funding to investigate the MYC inhibitor in combination with his antibody in liver cancer.
4. Paul B. Fisher, M.Ph., Ph.D., FNAI, member of the Cancer Biology research program and Thelma Newmeyer Corman Endowed Chair in Oncology Research at Massey, will lead an immune-focused effort to combine the MYC inhibitor with a fusion cytokine in liver cancer. A fusion cytokine is an engineered biopharmaceutical which is secreted from the cells and specifically targets and kills cancer cells, as well as elicits a targeted immune response against the tumor.

The long-term goal is to move findings from at least one, if not all, of these projects forward into a clinical trial.

“Our collective energy is a lot more synergistic than what we have all been doing individually in our own labs,” Sarkar said, adding that this group of scientists boasts more than 300 published research papers combined. “With this grant, we are asking questions that have not been asked before.”

Using a number of Massey’s shared resources, this P01 grant includes an administrative core, led by Sarkar; a mouse model and pathological analysis core, co-led by Jolene Windle, Ph.D., director of Massey’s Transgenic/Knockout Mouse Shared Resource, and Michael O. Idowu, M.D., professor in the Department of Pathology and Biostatistics; and a bioinformatics core, co-led by Nolan Wages, Ph.D., director of Massey’s Biostatistics Shared Resource, and Jinze Liu, Ph.D., director of Massey’s Bioinformatics Shared Resource.

Aliasger Salem, Ph.D., of the University of Iowa and Alexander Kilbanov, Ph.D., of UVA Cancer Center will also collaborate on this grant-funded initiative.

Written by Blake Belden