Targeting LIN28 in Pediatric Brain Tumors Using Circular RNA Decoys
Abstract
More than half of active-duty military service members are less than 25 years of age, and one of three active duty military members has children. The preponderance of young people and parents in the active duty military means that pediatric and young adult brain tumors have a disproportionate impact on the health and well-being of military service members and their dependents. We have identified a protein called LIN28 as a key driver of pediatric and young adult brain tumor growth. LIN28 is important for atypical teratoid/rhabdoid tumor (AT/RT), diffuse intrinsic pontine glioma (DIPG), and glioblastoma (GBM). This proposal will develop a new therapy for tumors that make large amounts of LIN28 protein. Normal cells communicate by sharing proteins, fats, and even RNA (which is related to DNA) through small fat droplets known as extracellular vesicles. Cancer cells take up and send out extracellular vesicles in abundance. We propose to use this system against the cancer cells, to make a Trojan horse that will deliver an RNA molecule that will kill the cancer cell by reducing the amount of LIN28. LIN28 is only found at high levels in cancer cells. Normal cells – even those in children – do not express LIN28. Our new therapy should therefore not have any negative effect on normal cells, even those found in growing children. The dependency of AT/RT tumor cells on LIN28 suggests that if we can use our therapy to take away LIN28, the cancer cells will die. Because LIN28 likes to attach to a particular type of RNA, which is called let-7, we propose to make a synthetic RNA molecule containing many loops of let-7. We will package this artificial molecule into the EV fat droplets, and then we will test if we can kill AT/RT tumor cells in a dish and in brain tumors grown in mice. Once we demonstrate that our new therapy works in AT/RT, we can propose to test it in other tumor types, with the goal of advancing this therapy to human clinical trials within 5 years of the start date of this proposal (2 years to complete the studies in this proposal, 2 years to conduct safety studies in higher animals such as pigs and then 1 year to obtain US Food and Drug Administration approval for initial human testing). With support from the DoD Idea Award, we anticipate that our innovative approach will lead to new, more effective therapies for AT/RT, thereby improving outcomes for the militarily relevant populations of young adults and their dependent children.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910366
Entities
People
- Eric Raabe
Organizations
- Johns Hopkins University
- United States Army