Modulating Insulin Receptor Alternative Splicing to Treat Pediatric Rhabdomyosarcoma
Soft tissue sarcomas, of which rhabdomyosarcoma (RMS) is the most common type, account for 7% of childhood cancer. Important in the physiology of RMS is that these tumors show altered insulin-like growth factor (IGF) signaling. Treatments designed to inhibit IGF signaling with insulin like growth factor 1 receptor (IGF-1R) antibody-based therapies were initially promising as treatments. However, they have largely failed in clinical trials. Treatment resistance is thought to be due to circumvention of the antibody blockade through an alternate/shortened form of the insulin receptor, IR-A, which results from RNA alternative splicing. RMS cells predominately express this shortened isoform, which we hypothesize is generated in response to the hypoxic tumor microenvironment. Additionally, we hypothesize that
IR-A production can be diminished utilizing antisense oligonucleotide (ASO) technology as a therapeutic against RMS.
In support of our hypotheses, we have found that IR-A is indeed upregulated in response to hypoxia. We have also discovered ASOs that modulate alternative splicing to decrease IR-A production. Importantly, these ASOs inhibit migration in RMS cells. Based on these promising discoveries, we are moving forward with this project to further test the efficacy of our ASO treatment in other cancer cell lines and mice, as well as to explore the underlying molecular mechanism by which hypoxia induces IR-A production. In addition to the treatment of RMS, our paradigm is potentially effective against any cancer that exhibits alternative insulin receptor splicing. These include other pediatric sarcomas as well as breast, lung, colon, thyroid and liver cancer. Besides the potential of our treatment to work alone, it is also specifically designed to work in conjunction with IGF-1R antibody therapeutics. While facing the potential abandonment of the development of these therapeutics, our approach has the potential to revive IGF-1R antibodies as treatments for rhabdomyosarcoma by combination therapy with our splicemodulating drug.
As a student in our lab, you will have the opportunity for in-depth involvement in a cutting edge drug discovery project. You will be expected to contribute to the execution of this project both intellectually and experimentally. This will provide you with experience in scientific inquiry in general, and drug development and mechanistic determination specifically. During this time you will learn an array of modern molecular and cellular biology techniques including tissue culture, nucleic acid isolation and detection, proteome profiling and cancer cell-based behavioral screens for differentiation, proliferation, and migration.
Contact Information
Dawn Chandler
Phone: 614-722-5598
E-mail: dawn.chandler@nationwidechildrens.org