EBV-Associated Lymphoma Consortium Annual Meeting (Abstract): Submission #8

serial: '8'
sid: '150851'
uuid: d63c82e4-4280-4105-a704-72d82c0756df
uri: /nci/ealv/venue/abstract
created: '1756935712'
completed: '1756935712'
changed: '1756935712'
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data:
  degree_s_: 'M.D., Ph.D.'
  email: sbhadurimcintosh@ufl.edu
  first_name: Sumita
  keywords_abstracts: 'DLBCL, Synthetic lethality, polymerase theta, DNA repair, PROTAC'
  last_name: Bhaduri-McIntosh
  middle_initial: ''
  organization: 'University of Florida'
  organization_address:
    address: ''
    address_2: ''
    city: Gainesville
    country: ''
    postal_code: ''
    state_province: ''
  summary: |
    With EBV+ DLBCL associated with poorer outcomes compared to EBV- DLBCL, we are focusing on EBV-associated mechanisms, in particular, repair of cellular DNA, an underexplored area. We have previously shown that EBV+ cancer cells lack the ability to repair toxic DNA double-strand breaks (DSB) by homologous recombination, the most error-free form of repair – thereby becoming susceptible to synthetic lethal (SL) therapies that target alternative mechanisms of DSB repair such as microhomology-mediated end-joining (MMEJ).  

    Our experiments demonstrate that EBV-transformed cells, EBV-cancer lines, EBV+ DLBCL xenografts, and primary EBV+ DLBCLs from AIDS patients express higher levels of polymerase theta compared to peripheral mononuclear cells and AIDS-related EBV- DLBCLs; typically, polymerase theta (POLθ) is the enzyme responsible for MMEJ-mediated repair of DSBs. We find that EBNA1 drives higher expression of POLθ in EBV+ tumors and that POLθ indeed facilitates DSB repair and contributes to cellular DNA replication and survival of EBV+ tumor cells. POLθ inhibitors (targeting the helicase or polymerase domain), alone or in combination with other agents, are in clinical trials, though in pre-clinical models, such inhibitors display biologic effects at tens of micromolar concentrations. Using PROTAC technology, we have developed small molecule degraders that degrade POLθ at nanomolar concentrations. In EBV-cancer lines, our lead compound, 23, degrades ≥90% of the intracellular POLθ at ≤10nM concentration, while the negative control compound (warhead), unable to bind E3 ligase, does not. As expected, compound 23 degrades POLθ via the ubiquitin-proteasome system. Across EBV-cancer cell lines, compound 23 consistently kills cells at concentrations that are up to 1000-fold lower than the prototypic POLθ inhibitor Novobiocin that is undergoing clinical trial testing. Following rigorous testing and lead optimization, we expect to translate the use of a POLθ PROTAC, alone or with other drugs, to cancers that demonstrate defects in DNA repair and/or reliance on POLθ. 
  title: Professor
  ttile: 'Engineering PROTACs to degrade polymerase theta'