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PROTAC-mediated Degradation of the Latency-Associated Nuclear Antigen (LANA) to Target KSHV Malignancies

Award Number: R01CA302581
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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PROTAC-mediated Degradation of the Latency-Associated Nuclear Antigen (LANA) to Target KSHV Malignancies - Abstract Kaposi’s sarcoma-associated herpesvirus (KSHV), also named HHV-8, is the etiologic agent of Kaposi’s sarcoma (KS), a lymphatic-endothelial malignancy most commonly seen in human immunodeficiency virus (HIV)-infected patients. Although AIDS-KS cases have decreased in the US with the availability of combination anti-retroviral therapy (cART), recent studies suggest that KS is emerging in long-term-treated, virally suppressed HIV patients. Additionally, KS cases in sub-Saharan Africa where the virus is more prevalent and the disease more aggressive, presents in broader patient populations (e.g. pediatric) and continues to cause more than 15,000 deaths annually. Since the discovery of KSHV by Chang and Moore in 1994, the field has gained many insights into KSHV biology. Despite this knowledge, to date not a single therapeutic has been developed against KSHV viral targets that are required for viral pathogenesis and tumorigenesis. A central player that contributes to these crucial steps is the Latency-Associated Nuclear Antigen (LANA). LANA is required for both the replication and segregation of viral episomes throughout host cellular divisions. LANA has additional roles ranging from transcriptional regulation, to interacting with and modifying host chromatin remodeling proteins. Here, we propose to target LANA for degradation by a recently developed novel therapeutic approach using PROteolysis TArgeting Chimeras (PROTACs). We provide proof-of-principle data demonstrating that in Halotagged LANA containing BAC16 infected cells, PROTAC3 ligand treatment rapidly induces LANA degradation and episome loss. This highly interdisciplinary team of Rolf Renne (LANA Biology), Guangrong Zheng (PROTAC chemistry), and Scott Tibbetts (MHV68 lymphomagenesis model) proposes to generate and use LANA targeting PROTACs for testing in a KSHV xenograft model and in a g-herpesvirus lymphomagenesis model. Animal studies are required because the proposed work tests treatment modalities for complex, non-linear disease processes that occur across multiple organ systems and thus cannot be adequately replicated using in vitro or computational models. These murine models provide genetically tractable, clinically relevant systems to evaluate therapeutics in the context of virus/host interactions and gammaherpesvirusdriven disease. The combination of approaches in medicinal chemistry, virology, and in vivo tumor models has the potential to provide exciting new pre-clinical data demonstrating that LANAtargeting PROTACs represent a novel, virus protein-specific therapeutic strategy for KSHV malignancies, including lymphoproliferative diseases and KS. Moreover, these findings would provide guideposts for future studies testing a similar approach for EBV malignancies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $606,547 )
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Treatment Research	000	1	8/26/2026	NEW	$606,547
														Subtotal = $606,547

Grand Total All Awards = $606,547

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PROTAC-mediated Degradation of the Latency-Associated Nuclear Antigen (LANA) to Target KSHV Malignancies

Award Number: R01CA302581

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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