Childhood Cancer

You are here

Modeling and Therapeutic Targeting of p21-Activated Kinase Members in High-Risk Rhabdomyosarcoma

Baylor College of Medicine
Jason Yustein, MD/PhD
Grant Type: 
Innovation Grants
Year Awarded: 
Type of Childhood Cancer: 
Project Description: 

Rhabdomyosarcoma (RMS) is the most common tumor of the muscles affecting the pediatric population. RMS is highly aggressive and is classified by two subtypes, embryonal (ERMS) and alveolar (ARMS). Unfortunately, RMS has a high tendency to metastasize or to spread to different locations in the body. Despite aggressive treatments, patients with high-risk RMS still have a 5-year overall survival rate of only 20-30% highlighting the need for the new treatment options. Our lack of knowledge about the biology that contributes to metastasis limits the development of new treatment options for RMS. High-dose cytotoxic (cell-killing) chemotherapy and radiation are the current treatments for RMS and can have tremendous side effects in children such as damaging the heart and kidneys. 

Project Goal
Therefore, we must gain insights into the critical changes occurring in the RMS cells that are contributing to tumor formation and aggressive metastatic disease in order to develop less toxic, targeted therapies. Targeted therapy exploits a feature unique to the tumor to kill it while traditional chemotherapy kills any rapidly dividing cell. To date, few actionable alterations have been identified for the development of targeted therapies in RMS. In our studies of pediatric sarcomas, we have identified p21-activated kinases (PAKs) as key contributors to RMS cell survival and tumor cell spreading. PAKs are altered in many cancers and are attractive therapeutic targets for drug development. No prior studies have demonstrated the role of PAKs in RMS but our ongoing studies demonstrate PAKs are a key mediator of RMS tumor progression.

Project Update - June 2, 2020
Rhabdomyosarcoma is the most common skeletal muscle tumor in children. Unfortunately for children with disease that behaves more aggressively or metastasizes, it is often difficult to treat. Our laboratory has identified a pathway in rhabdomyosarcoma cells that appears to be vital for their survival and spread to other parts of the body. Specifically, we have found that p21-activated kinases, or PAKs, are active in these more aggressive conditions. We have been assessing inhibitors of this pathway and noted significant anti-tumor activity using these inhibitors. We are now actively working on identifying additional therapies that we can combine with PAK inhibitors to combat and eradicate rhabdomyosarcoma. We are using our experience in using human tumor models and testing novel therapies to determine optimal therapies.