By Eliza Dysart
A collaboration that began through the UF Health Cancer Institute’s Team-based Interdisciplinary Cancer Research Training, or TICaRT, program has grown into a five-year National Cancer Institute-funded multiple-principal investigator R01 grant. The research team aims to develop a new way to treat cancers caused by Kaposi sarcoma-associated herpesvirus, or KSHV.
“This is a wonderful example of the concept of how interdisciplinary T32 training grants, developed by Dr. Dietmar Siemann at the UF Health Cancer Institute, can have a huge impact and foster novel translational cancer research,” said Rolf Renne, Ph.D., associate director for basic sciences at the UF Health Cancer Institute.
The project, titled “PROTAC-mediated Degradation of the Latency-associated nuclear antigen (LANA) to target KSHV malignancies,” brings together researchers with expertise in virology, immunology, medicinal chemistry and drug development. The work grew from a TICaRT team that paired postdoctoral trainee Sarah McMahon, Ph.D., in Renne’s lab with predoctoral trainee Alexis Smith in the laboratory of Guangrong Zheng, Ph.D.
The new R01 grant will allow the researchers to build on early findings and work toward developing a therapy that directly targets the virus itself.
KSHV can remain inside infected cells for long periods of time and disrupt normal cellular processes, contributing to cancer development. Central to the virus’s survival is a protein called latency-associated nuclear antigen, or LANA.
“LANA is essentially the Achilles’ heel of this virus because it acts as a molecular tether, physically attaching viral genomes to the cell’s chromosomes so that it can be maintained in infected cells,” McMahon said. “Without LANA, KSHV cannot maintain its genetic material in infected cells, and the viral genome is eventually lost.”
As a postdoctoral researcher in Renne’s lab, McMahon developed an approach to test whether LANA could be selectively eliminated from infected cells. She created a model system using a recombinant virus that allowed researchers to examine what happened when the protein was removed.
Those experiments helped establish the biological foundation for using a small-molecule drug technology known as PROTACs, or proteolysis-targeting chimeras, to target LANA.
“PROTACs work by grabbing a target protein, such as LANA, and bringing it into contact with the cell’s protein disposal machinery to destroy it,” McMahon said. “So instead of just disrupting the function of LANA, a PROTAC would completely remove it from cells.”
That approach differs from current treatments for KSHV-associated cancers, which generally target cancer cells or modify the immune system rather than directly targeting a viral protein.
The next challenge was developing a compound that could recognize LANA. That need created an opportunity for collaboration across scientific disciplines through TICaRT.
McMahon had already established the virology model when Smith, a medicinal chemistry doctoral student in Zheng’s lab, reached out. She was searching for a biological problem that could be addressed using PROTAC technology.
“It was a very natural fit,” McMahon said. “Our lab had the virology expertise, tools and model systems, and a validated target, while Alexis had the medicinal chemistry expertise needed to design, synthesize and optimize LANA-directed PROTACs.”
McMahon said the strength of the eventual grant proposal came not only from promising preliminary findings but also from the complementary expertise of the broader research team. Renne’s lab contributes expertise in KSHV biology and LANA and Zheng’s lab brings expertise in PROTAC development and drug discovery. In addition, the lab of Scott Tibbetts, Ph.D., another co-investigator on the grant, provides expertise in murine models of KSHV and Epstein-Barr virus lymphomagenesis to study the effects of targeting LANA.
With the new NCI funding, the researchers can expand beyond the initial work completed through TICaRT. The team plans to design and screen larger and more diverse groups of potential PROTAC compounds, identify the strongest candidates and move promising compounds into animal models to evaluate their therapeutic potential.
The long-term implications could extend beyond KSHV-associated cancers.
Other viruses that can contribute to cancers, including the Epstein-Barr virus and HPV, also rely on proteins that help maintain their genetic material inside infected cells. If targeting LANA proves successful, a similar strategy could potentially be applied to other virus-associated cancers.
“It could open an entirely new treatment strategy for patients,” McMahon said.
“It could open an entirely new treatment strategy for patients.” — Sarah McMahon, Ph.D.
