Childhood Cancer

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Using Splice Switching Oligonucleotides (SSOs) to target MDM2 for rhabdomyosarcoma therapy

Research Institute at Nationwide Children's Hospital
Dawn Chandler, PhD
Grant Type: 
Innovation Grants
Year Awarded: 
Type of Childhood Cancer: 
Project Description: 

We are so thankful to the Flashes of Hope and the Dale and Marsh Earnhardt Fund for co-funding our project to identify new treatments for rhabdomyosarcoma (RMS), which is the most common soft-tissue sarcoma of childhood. Even in times of the pandemic, we have been steadfast in our commitment to cancer research to help protect and ensure a future for pediatric cancer patients. As these patients are especially vulnerable to infections, we are reminded of the urgency of our mission and that of Flashes of Hope, the Dale and Marsh Earnhardt Fund, and their partner Alex’s Lemonade Stand Foundation. In the past two years, we have been able to take great strides to target genes that will reactivate tumor suppressor pathways that have been turned off in cancers. Tumor suppressor pathways suppress cell growth and prevent cancer and can be targeted for therapy both directly and indirectly. We have been working to activate a key tumor suppressor gene, p53, which is regulated by another gene called MDM2. In our earlier work, we have shown that MDM2 is altered by a process called alternative splicing by which sections of the gene are differentially excluded to make MDM2-ALT1. MDM2-ALT1 is able to turn off p53 and thus promote the formation of RMS tumors. In the first year of the grant we were able to interfere with alternative splicing of the MDM2 gene so that the important region is once again included to generate the native MDM2 isoform to increase the tumor suppressor activity of p53. The ability p53 activation to slow cell growth in cancer cells was achieved by the splicing changes. In the second year we tested the ability for the SSOs to be delivered to the tumors to activate p53 and apoptosis for therapeutic benefits. We were unable to see any effects through systemic delivery of the SSOs and are now pursuing alternative methodologies to introduce the SSO sequences to the cancer cells in vivo. Importantly, we were able to make great strides and gather the preliminary data to be able to continue these studies with the support of an NIH-R01 award.

Project Goal

Our proposed work will test the hypotheses that preventing alternative splicing of the MDM2 will likewise prevent cancer growth and progression to provide a therapy for RMS.

Co-funded by: 
Flashes of Hope
Tap Cancer Out