Update on Timothy O’Brien Fund Project "Drug and drug target discovery in metastatic osteosarcoma"

Osteosarcoma is the most common primary bone tumor in children, yet 80% of metastatic cases remain incurable. This is a critical problem since almost all osteosarcoma deaths result from metastatic disease. There has been no improvement in osteosarcoma cure rates in two decades. Achieving the goal of curing more pediatric osteosarcoma patients requires novel approaches to finding new, effective drugs. In addition, new models of metastatic disease in which to test potential therapies in the living organism are sorely needed. Using a new mouse model created at Dana-Farber that closely mimics human osteosarcoma, the project funded by the Timothy O’Brien Fund has the goals of: 1) identifying and validating drugs that cause osteosarcoma to act more like normal bone than like cancer (called differentiating agents); 2) uncovering the pathways that, if altered, could halt the progression to metastatic osteosarcoma; and 3) developing our mouse model so that it serves as a useful testing ground for drugs to treat metastatic osteosarcoma. Accomplishing these three aims 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 osteosarcoma can ultimately be increased. The support of this project by the Timothy O’Brien Fund has allowed us to make significant progress on these three goals. Below is a brief synopsis of the accomplishments.

Goal 1: Identify and validate drugs that cause osteosarcoma to act more like normal bone than like cancer. In order to identify drugs that might cause osteosarcoma to act like normal bone, we are using two novel techniques – gene expression based high throughput screening (GE-HTS) and the Connectivity Map (CMAP). During the past year of funding we added the CMAP technique to the project with the goals of identifying a larger number of potential differentiating agents and finding a control drug to be used to improve the performance of GE-HTS. In the past year, with the CMAP technique, we identified 7 potential differentiating agents. We have further tested 6 of these drugs and 2 look, on initial experiments, as though they may act as differentiating agents and be good positive controls for GE-HTS. Over the next year these two drugs and additional drugs with similar function will be further studied in the lab and in the living mouse for their ability to convert osteosarcoma into normal bone cells and to halt the growth of osteosarcoma cells. In addition, we are poised to conduct GE-HTS to identify additional drugs that will be able to convert OS cells into normal bone cells.

Goal 2: Uncover the pathways that, if altered, could halt the progression to metastatic osteosarcoma. We have identified 2 pathways that seem to be abnormally active in metastatic osteosarcoma tumors. For both pathways, there are drugs already in development that could shut them down. For one of these pathways, we have demonstrated that in the lab shutting the pathway down decreases the ability of osteosarcoma cells to invade, a process necessary for metastasis. During the past year, we have designed a new and more precise method for studying the impact of these pathways on the development of metastatic osteosarcoma in the living mouse and in the next year we plan to use this method to determine the impact of these pathways on the development of metastasis.

Goal 3: Develop our mouse model so that it serves as a useful testing ground for drugs to treat metastatic osteosarcoma. When the mouse model was initially developed, only 10% of the mice developed metastases. By altering the timing of the gene mutations that cause our mice to develop osteosarcoma, we have modified the model so that almost 100% of the mice develop metastases. In addition, we have determined that by injecting osteosarcoma cells into mice, we can reliably cause lung metastases within 2 months. These models will allow us to more rapidly study the impact of drugs on the development of metastases in live animals.

The Principal Investigator of this project was invited to present these studies at the American Association of Cancer Research annual meeting in April, 2009 and at a sarcoma biology meeting in November, 2009. She is planning a clinical study on relapsed or recurrent osteosarcoma sponsored by the Children’s Oncology Group. She has recently conducted a study on survival after osteosarcoma. This study was presented at an international sarcoma meeting in November, 2010 and will soon be submitted for publication. Timothy O’Brien Fund support was acknowledged in the November, 2010 presentation and will be acknowledged in the manuscript when published.