HMGA-1 Inhibitors
Dr. Kennedy has developed a novel class of HMGA-1 inhibitors that can be used potentially in combination with existing chemotherapy agents for certain types of cancer.
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Background
Overexpression of high mobility group 1A (HMGA-1) protein is a well-characterized aberrancy in certain human cancers. HMGA-1 overexpression is a malignant adaptation that contributes to decreased sensitivity to chemotherapy agents used to treat pancreatic cancer, and many studies have focused on inhibiting HMGA-1 activity as a means to improve chemotherapy efficacy.
Project Details
Dr. Kennedy has developed a novel class of HMGA-1 inhibitors that can be used potentially in combination with existing chemotherapy agents for certain types of cancer. The sulfur-substituted DNA analogues demonstrate a higher affinity to HMGA-1 and compete for HMGA-1 binding to native DNA. HMGA-1, an architectural transcription factor, is involved in both positive and negative regulation of genes responsible for apoptosis, cellular proliferation, immune response and DNA repair. While previous studies have focused on HMGA inactivation using small molecules that bind to HMGA-1 binding sites, or reduction of HMGA-1expression levels using RNA interference, Dr. Kennedy’s group sought to reduce HMGA-1 activity using a novel group of AT-rich phosphothioate DNA aptamers to compete with HMGA-1 binding to genomic DNA and other proteins. In a cell line model of pancreatic cancer, HMGA-1 targeted AT-sDNA combined with gemcitabine treatment decreased pancreatic cancer cell proliferation. These results suggest the potential use of HMGA-1 targeted DNA analog competitors to enhance chemotherapy efficacy in cancer treatment.