HMGA1-Targeted Nanoparticles as Novel Therapy for Pediatric Leukemias

Background:

The high mobility group A1 (HMGA1) protein plays an important in role during embryonic development, but in cancer the HMGA1 gene becomes re-expressed, stimulating stem cell pathways which enables tumors to rapidly proliferate and evade many conventional treatments. HMGA1 is present in high levels in virtually all aggressive cancers studied to date, including pediatric ALL and AML. Together, ALL and AML are two of the leading causes of death for children with cancer.

Project Goal:

Modified DNA or RNA sequences that disrupt HMGA1 function are promising strategies with tremendous promise as therapeutics. I have been using this approach to deliver short hairpin RNAs that inhibit expression of the HMGA1 gene.  Short hairpin RNAs are small RNA molecules that, when expressed in cells, form complexes that seek out and disrupt HMGA1 gene transcripts before they are translated into HMGA1 protein.

We also propose to test L-enantiomer RNA aptamers. Our aptamers are RNA sequences that are formulated with binding sites specific for HMGA1. These molecules act as decoys that bind HMGA1 proteins before they have a chance to activate the stem cell pathways in tumor cells. We have established two collaborations in order to create each of these "nanoparticles.” We hypothesize:

1) HMGA1 is an important factor required by ALL and AML cells to survive and grow, and,

2) Anti-HMGA1 nanoparticles will kill pediatric leukemia cells.

For my POST award project, I will develop these promising novel approaches in pediatric leukemia cells, using both in vitro (tissue culture) and in vivo (mouse) models.