Research Projects

Cancer cells develop resistance to genotoxic drugs used for treatment, which makes treatment protocols difficult, and this is the main cause for recurrence of the disease. Enzymes involved in DNA repair are in the top list of proteins that are being linked to refractory behavior of tumor cells for genotoxic drugs. Among the DNA repair enzymes, Apurinic/apyrimidinic endonuclease 1 (APE1) is one of the targeted proteins worldwide for developing drugs to sensitize drug resistant tumor cells including our lab. It has been demonstrated by several labs that a drug resistant tumor cells can be sensitized to genotoxic drugs by either inhibiting APE1 or knocking down the enzyme expression. In a study involving screening of novel APE1 mutants in Indian head and neck cancer patients, we have identified a mutant APE1 which is readily poly-ubiquitinated in vitro, and the protein has less half – life compared to the wild type protein. Preliminary studies carried out with WT and mutant APE1 protein suggest that a kinase is positively regulating APE1 at protein level by phosphorylation. In this study we propose to identify the kinase responsible for upregulating APE1 and develop a competitive peptide that would interfere in the kinase - APE1 interaction and test ability of the peptide to decrease the half-life of APE1 thereby increasing the sensitivity of tumor cells to genotoxic therapeutic drugs in vitro. The long-time goal of this work is to develop a peptide would sensitize drug resistant tumor cells to genotoxic drugs in cancer patients which would also decrease the dosage of the drugs administered to cancer patients.

Cancer, Drug resistance, Ape1, Therapeutic peptide, Apoptosis