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Therapeutic Potential of the MST1/Hippo Tumor Suppressor Pathway in Alveolar Rhabdomyosarcoma

Duke University
Corinne Mary Linardic, MD, PhD
Grant Type: 
Innovation Grants
Year Awarded: 
Type of Childhood Cancer: 
Project Description: 

Alveolar rhabdomyosarcoma (aRMS) is an aggressive cancer of skeletal muscle. Survival for children in high-risk groups is less than 30%, and this has not improved appreciably in over 30 years. aRMS is characterized by the DNA mutation PAX3-FOXO1, which acts in part by tricking cells into thinking they are building muscle. Although PAX3-FOXO1 is found only in aRMS and should be an ideal drug target, it is not druggable.

Project Goal
Our long-term goal is to identify proteins and pathways downstream of PAX3-FOXO1 amenable to pharmacologic blockade.

Several years ago, we created a model of aRMS by defining a cocktail of genes needed to change normal muscle cells to cells that mimic aRMS. Using this model, we figured out that PAX3-FOXO1 switches on a protein called RASSF4, which in turn silences a pathway that ordinarily limits cell growth. This pathway is called 'Hippo,' because organisms (for example laboratory flies and mice) with defective Hippo signaling have too many cells and organs that are too large. The main protein in the Hippo pathway is called MST1.  We suspect that in aRMS, PAX3-FOXO1 switches on RASSF4 to shut down MST1, resulting in too much cell growth and ultimately cancer.

In this project we propose to determine using human cell-based and mouse models whether MST1 loss is critical for aRMS formation and also determine whether proteins downstream of MST1 might be useful drug targets. This work will provide a new roadmap for Hippo/MST1 in aRMS, and support development of novel therapies for this childhood cancer.

Project Update

Final Report - 8/2016

This work pioneers the investigation of the Hippo signaling pathway in rhabdomyosarcoma (RMS). Originally intended to focus on PAX3-FOXO1-positive alveolar RMS, we have also gained insight into embryonal RMS. Some of these results have been presented and published, and some have already provided the preliminary data for new grant applications to continue our work. Importantly, these projects have been executed by dedicated undergraduates, technicians, graduate students, and post-doctoral associates who through this Innovation Award have realized their passion to incorporate pediatric oncology research and advocacy as life-long professional goals. For translational purposes, we have demonstrated in pre-clinical studies that reactivation of Hippo signaling in RMS synergizes with standard chemotherapy to block RMS tumorigenesis. We have also generated a novel genetically-engineered mouse model of PAX3-FOXO1-positive alveolar RMS, showing that Hippo pathway inactivation hastens RMS tumor initiation. This new model is a powerful tool to examine the biology underlying RMS tumor aggression, to identify critical pathways common between this model and actual human RMS tumor samples, and to identify new therapeutic opportunities for RMS. We are so grateful to ALSF for supporting this work.

September 2014 Dr. Linardic answered questions about her research

What were you initially studying with your grant funded by ALSF?
When we submitted our ALSF letter of intent, we had just begun to understand the role of the Hippo signaling pathway in alveolar rhabdomyosarcoma (RMS). We suspected that the Hippo pathway was inappropriately silenced in this cancer, suggesting that reactivating it could be a new therapeutic strategy. The premise was very exciting, because there was a lot of new information coming out at the same time on the role of the Hippo pathway in adult cancers. When we received news that our grant was funded, we were ecstatic, because it meant we could keep pursuing this brand-new research direction.

What have you found?
We have found that the Hippo pathway is inappropriately silenced not only in alveolar RMS, but in embryonal RMS as well. Using combinations of genes found mutated in RMS, we have been able to generate new models of both types of RMS and figure out how silencing of specific members of the Hippo pathway is contributing to RMS. We have also examined the effect of pharmacologic agents that re-activate the Hippo pathway on RMS growth both in tissue culture and in animal studies. Although it’s preliminary, it looks like RMS growth is indeed slowed. Last, we are working hard on generating genetically engineered mouse models of RMS and understanding how deficient Hippo signaling contributes to tumor formation in a whole organism.

What does this mean for children with cancer and their families?
This means that there is now a whole new field of study in RMS, and that there will be a new effort to find medicines that re-activate the Hippo pathway, which we hope will eventually get to pediatric cancer clinical trials.

What are your next steps?
We have more biochemistry, molecular biology, and mouse work to do. The mouse work is particularly slow, but it is steady. We also would like to figure out (reliably) how the reactivation of Hippo signaling through pharmacologic means might work with existing chemotherapy regimens.

Has this research been published?
We published our first paper on Hippo signaling in alveolar RMS this past winter in the Journal of Clinical Investigation, and are working on two additional papers that stem directly from the work supported by this grant.

What has this grant from ALSF allowed you to do that you wouldn’t have been able to do otherwise?
Our research team has traditionally used cell lines to study RMS. This grant has supported our move to use genetically engineered mouse models of cancer to see how the Hippo pathway works in a whole organism. This grant has also resulted in new models of RMS that we otherwise could not have afforded to generate. With the decline in NIH funding, there is really no other way we could have sustained this line of research except through ALSF.

Why did you choose to work in this field/on this topic?
When I was a pre-teen, I had several experiences with friends and family that made childhood cancer very real. Being 12 years old, I was just beginning to understand my own mortality, and I was incensed that cancer could take away a child’s life. I couldn’t really fathom how it was even possible. I made a plan to learn about childhood cancer and figure out how I could directly make a difference when I became an adult. At the time, I certainly did not know I would focus on RMS. My later experiences during fellowship training made it very clear that there are sub-groups of children that have particularly high-risk cancers, and so I was drawn to that challenge. I have been fortunate to have a super-dedicated team of researchers that understand the need to bridge the bench and the clinic. And so far we haven’t given up!