Modulation of DNA Repair-related Drug Resistance
DNA repair mechanisms within cancer cells may antagonize the effects of DNA-damaging chemotherapeutics. The central hypothesis being addressed by this group is that inhibition of DNA repair mechanisms in CNS tumors in can overcome resistance to chemotherapy, particularly alkylating agents.
- The combination of base excision repair and NAD(+) inhibition significantly sensitized glioma cells to temozolomide. Dual targeting of these two interacting pathways biosynthesis) may prove to be an effective treatment combination for patients with resistant and recurrent GBM (Goellner et.al., Cancer Res. 2011, 71:2308-17).
- Temozolomide (TMZ) is the preferred chemotherapeutic agent in the treatment of glioma following surgical resection and/or radiation. Resistance to TMZ is attributed to efficient repair and/or tolerance of TMZ-induced DNA lesions. Majority of the TMZ-induced DNA base adducts are repaired by the base excision repair (BER) pathway, which is initiated by N-methylpurine DNA glycosylase (MPG). MPG overexpression, together with inhibition of BER, sensitizes glioma cells to the alkylating agent temozolomide in a Polβ-dependent manner (Tang et.al., Neuro Oncol. 2011, 13:471-86).
|Hamilton, Ronald, MD
|Pollack, Ian, MD
|Jakacki, Regina, MD
|Sobol, Robert, PhD
Pharmacology & Chemical Biology