Pax3-FKHR targets that enable bypass of cellular senescence in rhabdomyosarcoma.
Photo, left: Dr. Linardic's lab. She is standing at the back, on the left.
Rhabdomyosarcoma (RMS) is a malignant tumor resembling skeletal muscle that occurs most frequently in children and adolescents. Although great progress has been made in treating patients with this cancer, those individuals with a particular subtype of RMS, called aRMS, are more difficult to cure. One of the most common genetic errors in aRMS tumors is the inappropriate swapping of DNA between chromosomes 2 and 13, resulting in a mutant gene called PAX3-FKHR. Discovered in 1993, PAX3-FKHR is known to predict a very poor outcome, as patients with metastatic aRMS have a 4-year survival of less than 8%. New approaches are needed in order to understand RMS at the molecular level and design new treatments.
We have developed a novel model of RMS in which we convert normal human skeletal muscle cells to their tumorigenic counterpart by the step-wise introduction of a defined set of mutant genes, essentially creating RMS in the laboratory. We have begun using this model to understand RMS formation from its beginnings, and to evaluate genes such as PAX3-FKHR. Surprisingly, we found that when we introduced PAX3-FKHR into human skeletal muscle cells in cell culture, it enabled them to continue dividing past the “senescence checkpoint,” the predetermined time when normal cells are hardwired to become permanently dormant. Accompanying this bypass of the senescence checkpoint, we found that an important gatekeeper of senescence, called p16, was no longer being expressed.
Our recent work suggests that PAX3-FKHR works in collusion with the loss of p16 to coax skeletal muscle cells past the senescence checkpoint, and we hope that by interfering with PAX3-FKHR-p16 network, we can block early steps of RMS formation. However, because of the complex nature ofPAX3-FKHR, there are no chemotherapy agents that directly shut it down. Thus our goal is to identify proteins that are downstream of PAX3-FKHR, known as PAX3-FKHR targets, which enable bypass of the senescence checkpoint. We have three aims:
- to identify these targets that carry out this bypass of senescence
- to determine whether the targets work in collusion with p16 loss, and after having identified these targets, to
- examine their expression in actual human RMS tumors
The accomplishment of our aims will provide insight into designing new therapeutic strategies for RMS.
We intend to continue studying the role of FGFR4 in RMS. Although we are most interested in developing new therapies for aRMS, because of the high mortality rate associated with this disease, we will continue to include eRMS in our analyses, since there are subpopulations of pediatric patients who also die from this disease, and if we can develop a therapy useful to both groups, then all the better.