Adjuvants to chemotherapeutics in cancer
Cancers are often treated with chemotherapies, many of which work by causing DNA damage. DNA damage blocks the ability of DNA polymerase to act, and therefore result in cancer cell death. However, cancer cells are often able to bypass this toxicity of DNA damage by employing specialized DNA polymerases that bypass the lesion site, otherwise known as trans-lesion synthesis (TLS). Inhibiting TLS may serve as a novel strategy to increase sensitivity of cancer cells to chemotherapy.
The inventors have discovered a small molecule which inhibits TLS. The inventors used an ELISA assay to screen 10,000 small molecule inhibitors that specifically target key components of the TLS pathway Rev1 and Rev7. JH-RE-06 was identified in this initial screen, and was then shown to disrupt the Rev1-Rev7 interaction in a dose dependent manner. Structural analysis of the Rev1/JH-RE-06 interaction demonstrated that the Rev7 binding surface is the target site of the drug, as well as that JE-RE-06 induces dimerization of Rev1. In vitro studies on a variety of human and mouse cancer cell lines demonstrated that the addition of JH-RE-06 decreased the ability of the cancer cell lines to form colonies, while the actions of JH-RE-06 were dependent of Rev1, as the effect was lost in Rev1-/- cells. In a murine xenograft model of human melanoma, the inventors show that the combination of JH-RE-06 and cisplatin resulted in virtually complete inhibition of tumor growth compared to saline, JH-RE-06, or cisplatin alone treatments.
Inhibition of the TLS pathway may be useful as an adjuvant in other DNA-damage inducing chemotherapeutics in addition to the platinum family, including:
- Alyklating agents (cyclophosphamide, chlorambucil, melphalan)
- Alykating and crosslinking agents eg. nitrosureas (carmustine, lomustine) and triazenes (dacarbazine and temozolomide).
- Topoisomerase inhibitors (doxorubicin and daunorubicine)
- DNA synthesis inhibitors (methotrexate)
- Small molecules are facile to manufacture and administer to a broad range of patients.
- Platinum-based chemotherapeutics already have large market distribution and are broadly used.
- Improving the efficacy of those chemotherapeutics may improve patient outcomes.