Monday, April 22, 2013
Two clinical trials of targeted therapies led by Memorial Sloan Kettering investigators show promising results against different types of sarcoma.
Sarcoma, a type of cancer that can affect the bones or the body’s soft tissues — such as muscle, fat, and tendons — is often curable with surgery. But for those tumors that cannot be surgically removed or that come back after surgery, there have been few treatment options. This is in large part because sarcomas usually do not respond to traditional chemotherapy.
Targeted therapies, which work by taking advantage of genetic alterations in tumor cells, hold promise for bringing sarcomas under control. Now two trials of experimental drugs are showing encouraging results in treating certain subtypes of sarcoma.
A Diverse Group of Tumors
“Historically, the challenge of treating sarcoma has been that it’s a very complex group of different diseases,” says Memorial Sloan Kettering medical oncologist and sarcoma expert Mark A. Dickson. “Sarcoma is not one cancer, but more than 50 different subtypes. Trials that have tried to give the same drug for all sarcomas have not been successful.”
To develop targeted therapies, investigators need to determine the molecular changes that cause the disease in each of the different subtypes. Memorial Sloan Kettering is a leader in that effort, with a database that combines our collection of tumor samples from patients with information about those patients, such as age at diagnosis and details about their tumors and treatments.
“Our research is focused on looking for genes that are either mutated or amplified,” says Gary K. Schwartz, Chief of Memorial Sloan Kettering’s Melanoma and Sarcoma Service. “If a gene is amplified and makes many more copies than it should, it can often be a driver for cancer.”Back to top
A recent phase II trial led by Dr. Dickson focused on one of the most common types of sarcoma, called well-differentiated or de-differentiated liposarcoma, a more common type of sarcoma that originates in fat cells. The study was published online April 8 in the Journal of Clinical Oncology.
The trial was of a drug called PD0332991 (palbociclib), which targets a protein called CDK-4. That protein is overexpressed in this type of sarcoma because of a gene amplification and leads to the growth of cancerous cells. All patients in the trial had this particular molecular abnormality.
In the study, 30 patients received PD0332991 for 12 weeks. The investigators found that 70 percent of the patients did not have their disease progress during that time, which greatly exceeded the researchers’ expectations. In addition, some patients had significant shrinking of their tumors.
“As far as we know, this is the first time anyone has done a phase II trial for this subtype of sarcoma, and in that way it’s a pioneering study,” Dr. Dickson says. “Based on our results there has been a lot of interest from doctors around the country who want to get their patients on this drug, and we are expanding the trial so that we can treat more patients.”Back to top
Testing Combination Therapies
Another trial, published in the April issue of Lancet Oncology, was led by Dr. Schwartz. In that study, also a phase II trial, investigators combined an experimental drug called cixutumumab with temsirolimus (Torisel®), a drug already approved for some forms of kidney cancer, to treat several subtypes of bone and soft tissue sarcoma.
Cixutumumab is an antibody that targets a receptor on cancer calls known as IGF-1R. Temsirolimus blocks a cancer-related pathway called mTOR. Both IGF-1R and mTOR are critical for the growth of many sarcoma types.
“You can think of mTOR as the engine of the cancer cell that’s responsible for its survival, and IGF-1R as the ignition,” Dr. Schwartz explains. “The idea is that you use cixutumumab to cap the ignition, so that the key can’t go in the lock. But you are also adding the extra benefit of inactivating the engine itself by using temsirolimus to block mTOR.”
“This is the first multicenter clinical study ever conducted to evaluate this combination,” Dr. Schwartz adds.
The multicenter trial, which included 388 patients, found that the number of patients whose disease did not progress after 12 weeks of treatment was improved compared with other treatments. In addition, some patients with a type of sarcoma called solitary fibrous tumor had stable disease for more than a year. Patients with the subtypes Ewing sarcoma, osteosarcoma, and chondrosarcoma had partial shrinkage of their tumors.Back to top
Moving Forward with New Trials
Dr. Dickson and Dr. Schwartz plan to move their research forward with larger, phase III trials, but challenges remain. Dr. Schwartz notes that it is difficult to find funding from pharmaceutical companies to treat sarcomas, which are considered rare diseases. Recruiting enough patients to participate in a larger trial can also be a roadblock.
“For research on these rare cancers like sarcoma, which affects about 13,000 people per year, funding from organizations like Cycle for Survival is becoming increasingly important,” Dr. Schwartz says. “Money from Cycle for Survival funded much of this research, from the basic research in the laboratory up to and including this phase II trial.”
Both physicians have trials under way for other experimental sarcoma drugs and continue to focus on research looking for new targets.Back to top