Polymerase-Theta Inhibition for Treating Epstein-Barr Virus (EBV) Cancers and Related Diseases

Proteolysis Targeting Chimeras (PROTACs) Block Microhomology or Theta-Mediated End Joining in Cancer Cells

These polymerase theta inhibitors treat Epstein-Barr virus (EBV)-associated cancers and related diseases. EBV cancers are linked to two percent of the global cancer burden and are difficult to treat, demonstrating a strong need for effective treatment alternatives1. Cancer cell reproduction is heavily dependent on control over molecular mechanisms to repair DNA damage. While these cells usually use a variety of mechanisms to achieve this goal, if a mechanism is damaged, the cancer cells become even more dependent on alternative DNA repair mechanisms. These drug candidates treat EBV cancers by targeting the disease’s new dependence. Each year, EBV causes 200,000-300,000 new cases worldwide, and available therapeutics pose significant challenges. Such treatments are often associated with poor response, relapse, organ rejection, or long-term B-cell immunodeficiency, depending on the treatment method used.

Researchers at the University of Florida developed several PROTACs to effectively degrade polymerase theta. This treatment platform offers advantages compared to current options, providing a safer and potentially more effective approach. Because EBV-driven cancer cells lack a primary DNA repair pathway, they become reliant on compensatory repair mechanisms, specifically TMEJ (Theta-Mediated End Joining), and are more susceptible to PARP inhibition, prompting researchers to develop this therapeutic platform to target EBV-associated malignancies.

Application

Polymerase-theta inhibitors are used to block TMEJ, which, when used alone or in combination with other therapies (such as R-CHOP, PARP inhibitors, etc), effectively target EBV-cancer cells

Advantages

• The PROTAC design offers superior potency over traditional therapeutics, exposing the patient to smaller doses
• A combination of existing therapies that increase the burden of DNA damage (by causing more damage or blocking conventional DNA repair using PARP inhibitors) with polymerase theta inhibitors to block the backup repair pathway (TMEJ, Theta-Mediated End Joining), provides potential treatment for EBV-cancers
• This platform can be used to target other cancer cells with dependence on TMEJ when the HR mechanism is degraded, offering a wider range of applications (examples include solid organ cancers such as those of the breast, ovary, etc.)

Technology

When cancer cells lose one type of DNA repair mechanism, they become overly dependent on alternative types of repair mechanisms. As a result, these cells become more responsive to treatments targeting these other mechanisms. EBV cancer cells rely on theta-mediated end joining (TMEJ) when they lose the function of the repair mechanism, homologous recombination. There is now an effort to inhibit TMEJ through polymerase theta. A key characteristic of TMEJ is the upregulation of polymerase-theta. When this polymerase is degraded, TMEJ fails. The platform is to be used with PARP inhibitors (which inhibit conventional DNA repair mechanisms) and/or agents that increase DNA damage to treat EBV-cancers. Dr. Bhaduri’s lab within the UF College of Medicine, in collaboration with Dr. Zheng’s lab within the UF College of Pharmacy, has developed several candidates that are effective at degrading polymerase theta. These candidates can be used to assist in treating EBV cancers.