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Identification and Validation of Differentiation Therapy for Osteosarcoma

Institution: 
Dana-Farber Cancer Institute
Researcher(s): 
Katherine Janeway, MD
Grant Type: 
Young Investigator Grants
Year Awarded: 
2008
Type of Childhood Cancer: 
Osteosarcoma
Project Description: 

Background

Between the 1970s and the 1990s there were dramatic improvements in outcomes in most pediatric sarcomas. However, in the past 2 decades there have been few treatment advances and there are still significant gains to be made. Overall survival following diagnosis remains at 50-60% for most pediatric sarcoma types. In addition, successful treatment often involves surgeries that can be disfiguring, disabling and potentially life-threatening. In most sarcoma tumor types, recent attempts to add additional cytotoxic chemotherapy agents to established regimens, adjust administration schedules or change surgical techniques have not lead to substantial survival gains or significant reductions in side effects. Thus, the maximal benefit of available cytotoxic chemotherapy agents and surgical techniques has largely been realized. While still important, descriptive studies and multi-institutional trials comparing combinations of traditional chemotherapeutic agents are less likely to lead to significant gains in pediatric sarcoma treatment than in the past.

Instead, significant advances in pediatric sarcoma therapy will likely result from translation of laboratory findings to the clinic. For pediatric sarcomas, clinically relevant laboratory findings are quite likely during the next decade. Recent technological advances such as conditional genetically engineered mouse models, sophisticated imaging systems, laboratory techniques that require very small amounts of tumor material and the existence of tumor banks have increased our ability to study solid tumors.

Goals

The goal of my research is to bridge the gap between the laboratory and the clinic by conducting clinically relevant laboratory work and by using knowledge gained in the laboratory to design rational clinical studies. The Alex's Lemonade Stand Foundation for Childhood Cancer Young Investigator Award supports my laboratory research on osteosarcoma:

Osteosarcoma is the most common primary bone tumor in children, yet 35% to 40% of patients will not be cured. No advances have been made in the treatment of osteosarcoma for two decades. Achieving the goal of curing more pediatric osteosarcoma patients requires novel approaches to identifying effective drugs and to finding new drug targets. In addition, new models of the disease in which to test potential therapies prior to testing in patients are sorely needed. My project in the laboratory uses a new mouse model created at Dana-Farber Cancer Institute that closely mimics human osteosarcoma.

The goal of this project is to identify and validate drugs that cause osteosarcoma to act more like normal bone than like cancer. This treatment approach is called differentiation induction. Differentiation induction has led to improved survival in two different pediatric cancers, neuroblastoma and acute promyelocytic leukemia. This type of therapy has the potential to have fewer side effects than traditional cancer chemotherapy. Differentiation induction has not been adequately studied in osteosarcoma. I will use two novel techniques - gene expression based high throughput screening (GE-HTS) and the Connectivity map - to identify osteosarcoma specific differentiating agents in a high-throughput manner. Each promising new therapy will be further tested for activity in the mice that get osteosarcoma in order to determine which of the therapies might be most useful in patients. This approach will greatly accelerate the ability to determine which research findings will be useful in patients and will speed the rate at which these research findings reach the clinic, where cure rates for metastatic osteosarcoma can ultimately be increased.