Development of RADARS-based Therapy to Treat Fusion Molecule Driven Pediatric Malignancies
Although there have been significant strides made in treating pediatric cancer, a large number of children still succumb to their disease. Moreover, survivors can have detrimental late effects from their chemotherapy and radiation including abnormal growth and development and acquisition of secondary cancers. Therefore, improved and less toxic treatments are urgently needed. A common event leading to pediatric cancer is the breakage of two chromosome and swapping of genetic material between ends. These are called “balanced translocations” and lead to the generation of “fusion molecules” within the cancer cells. Characteristic fusion molecules occur in a wide array of pediatric cancers including leukemias (for example. MLL-AF9, RUNX1-ETV6, RUNX1-ETO) and solid tumors such as Ewing’s sarcoma (EWS-FLI1), rhabdomyosarcoma, and brain tumors. Importantly, the fusion molecules represent a unique “tag” that can be used to distinguish a cancerous (or pre-cancerous) cells from healthy cells. They also mark the most primitive cancer cells, which can sometimes fuel the relapse of a cancer following treatment. CRISPR/Cas9 is a recently discovered system that enables the recognition and modification of specific stretches of DNA sequence. It has received a lot of publicity (as well as a 2020 Nobel Prize) for its potential to treat human genetic diseases. More recently, it has been adapted as a means to “sense” when there is an abnormal stretch of DNA or RNA in the cell. In 2022, this was adapted into a system that can activate a “suicide gene” when an abnormal RNA sequence is detected.
Project Goal:
This proposal seeks to develop this new system to “sense” the presence of an abnormal pediatric cancer fusion molecule, and once engaged, to activate the “suicide gene” to kill the cells. It will optimize and test different “sensor” molecules using cell systems representative of an aggressive childhood leukemia (MLL-AF9 fusion) and Ewing’s sarcoma solid tumor (EWS-FLI fusion). This will first be developed using cells grown in the petri dish initially and then applied to a mouse model of these cancers. Positive results will provide key “proof-of-principle” for this novel approach. If successful, future studies will move towards translating this approach into a new treatment for patients. The ability to readily adapt this system to the new “mRNA” technology employed in the COVID-19 mRNA vaccines should greatly facilitate the translation, delivery and commercialization of this approach.
