Scientists at the British Columbia (BC) Cancer Agency, an agency of the Provincial Health Services Authority, have proven that a new strategy in devising drug combinations can quickly improve the results of existing therapies. Motivated by a pressing need to find new treatments for high-risk childhood sarcomas, Dr. Poul Sorensen (pictured), senior scientist, BC Cancer Agency Childhood Cancer Research Program and Johal Endowed chair in Childhood Cancer Research at BC Children's Hospital and BC Women's Hospital & Health Centre, and colleagues, used cutting-edge gene silencing technology to identify a specific protein involved in resistance to therapies against a target called IGF1R in childhood sarcomas.
While IGF1R therapy has shown great success in the treatment of childhood sarcoma patients, approximately 50-60 per cent of patients’ tumors develops resistance to or do not respond to the drugs. “Basically, we know that drugs inhibiting IGF1R can be highly effective in treating some, but not all, patients with these diseases. The question is, how can we make IGF1R drug therapies work even better especially for resistant patients,” says Dr. Sorensen. “First, we had to solve the mystery behind the resistance to these drugs.” He explains, “By using a technique called RNA interference gene silencing, we discovered the problematic protein that drives resistance to IGF1R inhibitors.”
Dr. Sorensen’s paper shows that resistant and non-responsive tumors have a second protein, MST1R, which steps in to take over the role of IGF1R once the latter has been incapacitated by initial drug treatment. This research is particularly relevant as several drugs against MST1R and related proteins are actually already on the market, with the potential to dramatically improve the effectiveness of IGF1R drug therapy in resistant cancers. “By introducing a second drug already on the market, we can rapidly implement these ‘drug teams’ into clinical trials and incapacitate the patients’ cancer causing proteins,” says Dr. Sorensen. He added, “This accelerated process wouldn’t be possible without the RNA interference technology and expertise available at the BC Cancer Agency’s Department of Molecular Oncology.”
“Targeted therapies against cancers are becoming increasingly available and may have advantages over the agents we have had available in the past,” says Dr. Mason Bond, principal investigator for the Children's Oncology Group, BC Children's Hospital. “Using combined drug therapies, as Dr. Sorensen has shown, will hopefully increase the effectiveness of the new targeted agents and increase our patients’ survival.”
BC Cancer Agency scientists analyzed hundreds of proteins until finding the one responsible for mimicking IGF1R’s functionality, causing resistance to treatment and allowing the cancers to grow even under therapy.
IGF1R is a growth factor receptor that has been implicated in the development and progression of many cancers, including other childhood cancers and adult cancers such as breast carcinoma. Therefore, Dr. Sorensen’s findings may have broad applicability to cancer therapeutics. Sarcomas are specific types of cancer that develop in the supporting connective tissues of the body. These malignancies have a relatively higher incidence in children compared to adults. “Finding ways to improve existing therapies is extremely important in pediatric oncology as it is very difficult logistically to introduce new drugs into the management schemes for these diseases,” says Dr. Sorenson.
Illustration: BC Cancer Agency.
BC Cancer Agency (10/19/10)
Life Sciences British Columbia (10/19/10)
Abstract (Cancer Research; 2010 Nov 1;70(21):8770-81)