The Kristian Project: Taming the Hulk by altering rhabdo metabolism

Tina and Colin Hoogenkamp / Honor Pages

This research project is in Kristian’s Honor and Memory and addresses rhabdomyosarcoma metabolism as an Achilles’ heel of this cancer and the starting point for an innovative new treatment.

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About The Kristian Project: Taming the Hulk by altering rhabdo metabolism

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood, adolescent and young adults. Clinically, survival amongst metastatic RMS patients has remained unacceptably low and unimproved for years, if not several decades. The most aggressive (alveolar) subtype of rhabdomyosarcoma (ARMS) when metastatic is a substantial unmet need at the clinical, scientific and patient level. The challenges for rhabdomyosarcoma treatment are that: 
  
- No new agents have emerged to be tested in clinical trials for high-risk or relapsed rhabdomyosarcoma in the last 6 years.   
- The disease-free survival for metastatic embryonal and alveolar rhabdomyosarcoma (43% and 8%, respectively) have remained unchanged for 47 years. 
- No primary drug approvals for rhabdomyosarcoma have occurred in history ever, and only 8 drugs developed for childhood cancer have been FDA approved since 1978. By comparison, 12 or more adult cancer drugs on average are FDA approved annually. 
  
So what's a possible solution? 
  
A holy grail of cancer is to change cancer cells to normal cells. Remarkably, a few childhood cancer do this with or without treatment (acute promyelocytic leukemia and neuroblastoma are examples). Embryonal rhabdomyosarcoma does so also partially following the stress of chemotherapy and radiation treatment. Alveolar rhabdomyosarcoma is much more difficult to tame (for a summary, see our publication here and here). 
  
To convert alveolar rhabdomyosarcoma to maturing muscle rhabdomyoblasts that no longer divide and no longer act as a cancer, we will need to alter the ARMS cells’ metabolism to move cells from a muscle stem cell-like fate to a maturing muscle fiber state of differentiation, as is seem in embryonal rhabdomyosarcoma. 
  
In this research project, we propose to screen a set of 60 novel drugs for the ability to convert ARMS tumor cells to non-dividing rhabdomyoblasts. We will compare these drugs’ effects on ARMS to effects on normal myoblasts (muscle progenitor cells, also called C2C12 cells). 
  
We will test these drugs ability to induce muscle differentiation in many ways: 
• assessment of cell growth inhibition (desired for cell killing or differentiation) 
• high content analysis for differentiation marker myosin heavy chain (either by staining, or by using a genetically-encoded MyHC-2A glowing reporter 
• high content analysis measuring the induction of muscle fiber mitochondria (by a Cdy2 dye from our collaborators in Singapore) 
  
All cell cultures will be grown in realistic conditions of the body with respect to glucose and amino acid (glutamine, glutamate) levels. Metabolism-altering drugs in the mTOR pathway (TORC1 and TORC2) as well as muscle fiber energy metabolism (2-deoxyglucose and 3-guanidinopropionic acid) will be included in our study. If ARMS tumor cells do not respond to these drugs alone, we will combine them with radiation. 
  
When the studies above combined with validation studies then we will validate the best 3 drug/drug combinations in animal models as a stepping stone to a clinical trial concept.  
  
This project will be maintained as an Open Science Forum, with a blog updated every month.  

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