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Principal Investigator: Troy E Messick
Organization: WISTAR INSTITUTE
Fiscal Year: 2024
Award: $128,992
Funding agency: National Cancer Institute
Project Summary
EBV latent infection is responsible for ~200,000 new cancers per year. To date, there are no EBV-
specific therapeutic agents that selectively and efficaciously treat EBV-positive tumors. All known
EBV tumors consistently express one viral nuclear protein, EBNA1, that is required for maintaining
the EBV genome and promoting infected cell survival. We have developed highly selective, drug-like
small molecules that bind EBNA1 and block its ability to bind DNA, maintain EBV genomes, and
promote host-cell survival. Here we propose to better understand the mechanism through which
disruption of EBNA1 DNA binding leads to tumor growth inhibition, and use this information to identify
rational combinatorial agents to enhance chemotherapeutic efficacy. We propose to enhance the
potency of the first generation EBNA1 inhibitors by attaching proteasome targeting molecules
(PROTACS) to selectively target EBNA1 for degradation. Finally, we will take advantage of new
mechanistic data revealing that EBNA1 functions as an OriP-specific endonuclease and resolvase.
We propose to develop new structure and mechanism-based inhibitors of EBNA1 that can increase
potency necessary for highly efficacious cancer therapy. By integrating these strategies to
understand the growth arrest response of EBNA1 inhibition (aim 1) to better develop rational
approaches for combinatorial therapies (aim 2) and develop next generation molecule with
structure/mechanism based drug design principles (aim 3), we will advance EBNA1 inhibitors for the
treatment of EBV-associated malignancies and related-diseases. We will test the overarching
hypothesis that EBNA1 is an effective target for small molecule inhibitors to treat EBV
cancers. The major goal of this proposal is to understand the tumor cell response to EBNA1
inhibition and to enhance efficacy of EBNA1 inhibitors to treat EBV-associated cancers more
efficaciously. The team associated with this proposal has the unique expertise and strong
collaborative history to execute the aims of this proposal. Collectively, these investigations will
provide fundamental insights into how EBNA1 functions at the molecular level and will lay the
foundation for the development of new strategies to treat EBV cancers.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><5-FU><5-Fluracil><5FU><APF-1><ATP-Dependent Proteolysis Factor 1><Animal Model><Animal Models and Related Studies><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Apoptosis><Apoptosis Pathway><Automobile Driving><Basic Research><Basic Science><Binding><Burkitt Herpesvirus><Burkitt Lymphoma Virus><CDDP><CRISPR><CRISPR/Cas system><Cancer Drug><Cancer Induction><Cancer Treatment><Cancers><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Survival><Cell Viability><Cell model><Cellular Expansion><Cellular Growth><Cellular Immune Function><Cellular Proliferation><Cellular model><Checkpoint inhibitor><Chemicals><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Clustered Regularly Interspaced Short Palindromic Repeats><Cysplatyna><DNA Binding><DNA Binding Domain><DNA Binding Interaction><DNA bound><DNA-Binding Protein Motifs><Data><Development><Dichlorodiammineplatinum><Disease><Disorder><Drug Design><Drugs><E3 Ligase><E3 Ubiquitin Ligase><EB virus><EBV><EBV latency><EBV malignancies><EBV(+) malignancy><EBV-Related Malignancy><EBV-associated cancers><EBV-associated malignancy><EBV-positive cancer><EBV-positive malignancy><EBV-positive malignant tumor><EBV-related cancer><Elements><Epstein Barr Virus><Epstein Barr Virus Malignancy><Epstein Barr Virus associated cancers><Epstein Barr Virus positive cancer><Epstein-Barr Virus associated malignancy><Epstein-Barr Virus latency><Epstein-Barr Virus-Related Malignancy><Epstein-Barr Virus-Related Malignant Neoplasm><Fluoro Uracil><Fluorouracil><Fluoruracil><Fluouracil><Foundations><Gene Expression><Generalized Growth><Generations><Genetic><Genome><Goals><Growth><HHV-4><HHV4><HMG-20><High Mobility Protein 20><History><Human><Human Herpesvirus 4><Immune checkpoint inhibitor><In vivo analysis><Infectious Mononucleosis Virus><Investigation><Latent virus infection phase><Ligands><Macropain><Macroxyproteinase><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Medical><Medication><Medicine><Mice><Mice Mammals><Modeling><Modern Man><Modification><Molecular><Molecular Interaction><Multicatalytic Proteinase><Murine><Mus><Neoplastic Disease Chemotherapeutic Agents><Nuclear Antigens><Nuclear Protein><Oncogenesis><Oncogenic Viruses><PDX model><Pathway interactions><Patient derived xenograft><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Peyrone's Chloride><Peyrone's Salt><Pharmaceutical Preparations><Pharmacogenomics><Platinum Diamminodichloride><Programmed Cell Death><Property><Prosome><Proteasome><Proteasome Endopeptidase Complex><Proteosome><Radiation><Recording of previous events><Reporting><Resolvase><Site><Structure><Testing><Therapeutic><Therapeutic Agents><Tissue Growth><Translational Research><Translational Science><Treatment Efficacy><Tumor Cell><Tumor Viruses><Tumor-Specific Treatment Agents><Ubiquitin><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Viral><Viral Gene Products><Viral Gene Proteins><Viral Genes><Viral Genome><Viral Proteins><Virus><Work><anti-cancer drug><anti-cancer therapy><anticancer activity><cancer therapy><cancer type><cancer-directed therapy><carcinogenesis><cell growth><cell type><chemotherapeutic agent><chemotherapy><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><combinatorial><determine efficacy><developmental><driving><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><endonuclease><evaluate efficacy><examine efficacy><histories><immune check point><immune check point inhibitor><immune checkpoint><immune function><immunecheckpoint><improved><in vivo evaluation><in vivo testing><inhibitor><insight><intervention efficacy><latent infection><latent viral infection><latent virus infection><malignancy><model of animal><multicatalytic endopeptidase complex><neoplasm/cancer><neoplastic cell><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><oncogenic tumor virus><ontogeny><pathway><patient derived xenograft model><patient oriented outcomes><programs><recruit><response><shRNA><short hairpin RNA><small hairpin RNA><small molecular inhibitor><small molecule><small molecule inhibitor><small molecule therapeutics><standard of care><synergism><targeted agent><therapeutic efficacy><therapy efficacy><transcriptomics><translation research><translational investigation><tumor><tumor growth><tumorigenesis><ubiquitin-protein ligase><virus genome><virus protein>