Tuesday, April 28, 2015

Clinical trial will use mice to guide treatment choices in soft-tissue sarcoma

Mice in Champions lab.
By Suzie Siegel

Cancer treatments have been tested on mice for years. Now a new technology uses mice to determine which treatments may best fight an individual patient’s sarcoma.

The TumorGraft technology “provides options for patients in difficult situations when, often as doctors, we are not sure how to treat people,” said medical oncologist Justin Stebbing, a professor of cancer medicine and oncology at London’s Imperial College. “In doing so, it advances the frontiers of science and medicine, but in a practical way, giving clinicians information on treatment choices – what is likely to work, and as importantly, what is likely to not work.”

Champions Oncology soon hopes to open a phase II clinical trial of its TumorGrafts for patients with soft-tissue sarcoma, Chief Medical Officer Angela Davies said. About 200 people whose sarcoma has recurred or metastasized will be enrolled at sarcoma centers across the United States and Canada.

“We have plans for clinical trials in many different tumor types,” she said. “We currently are partnering with academic centers conducting a clinical trial in breast cancer and advanced non-small-cell lung cancer, with plans for a trial in head-and-neck cancer and colorectal cancer to start within the next 12 months.”

In the sarcoma trial, she said, patients will start standard treatments while waiting for results from the TumorGraft process, which can take 4-6 months. The trial will accept only patients who are expected to survive at least six months and who are healthy enough to undergo systemic therapy, such as chemo. If the initial treatment fails, the TumorGrafts may help a doctor choose which treatments to try next.

Until a clinical trial validates the process, a U.S. doctor can’t use it to justify delaying or changing treatment in a patient with advanced sarcoma, said Sujana Movva, a sarcoma medical oncologist at Fox Chase Cancer Center in Philadelphia.

Dr. Sujana Movva

Dr. Movva helped design the trial, which was discussed last fall at the annual meeting of the Connective Tissue Oncology Society in Berlin. Other physicians involved in the research were from Massachusetts General Hospital in Boston; University of Michigan, Ann Arbor; Oregon Health & Science University, Portland; Mount Sinai Hospital, New York; Rutgers Cancer Institute of New Jersey, New Brunswick; Johns Hopkins University, Baltimore; M.D. Anderson Cancer Center, Houston; Sarcoma Oncology Center, Santa Monica, Calif.; University of California, Los Angeles; and University of Pennsylvania, Philadelphia.  

Dr. Stebbing serves on Champions’ Scientific Advisory Committee, as does medical oncologist George Demetri, director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute in Boston.

Before surgery, patients can ask for a piece of their tumor and its surroundings to be saved for Champions. The fresh tissue will be implanted into one or more immunodeficient mice. If the graft grows, it will be divided again and implanted in more mice. Grafts also will be preserved for future testing.

These grafts are called patient-derived xenografts (PDX) or patient-derived tumor xenografts (PDTX).

“Champions can test chemotherapy, targeted agents, monoclonal antibodies and antiangiogenics as single agents or in combination,” said Dr. Davies, a medical oncologist. Immunotherapies cannot be tested now, but scientists are working on a mouse model with a humanized immune system engrafted.

“No model system is perfect,” Dr. Movva said, “but it is the best ‘in-vivo’ testing available so far.”

The Hackensack, N.J., company began testing different cancers in 2007, with the greatest number of tests in sarcoma, Dr. Davies said. “The rare and heterogeneous nature of sarcomas and the lack of well-defined treatment strategies make sarcoma well-suited to a personalized approach.”

More than 150 sarcoma patients have tried TumorGrafts, she said. “We managed to grow approximately 100 tumors. Currently, we have 60 successful mice models for sarcoma patients.” That translates into a 65-percent success rate for growing sarcomas in mice, she said, “and 67 percent of patients for whom a model was successfully developed decided to proceed with drug sensitivity testing in the model.”

Implantation costs about $2,000, she said. Testing one therapy costs an additional $2,500-$3,000, and the cost mounts as more therapies are tested. The upcoming clinical trial would be free to patients, however. A successful phase III trial could lead to insurance coverage for TumorGrafts.

Some sarcoma patients choose to do chemosensitivity or chemoresistance tests in which their cancer cells are grown in a Petri dish. TumorGrafts have an advantage because they preserve the biological characteristics of the original human tumor, Dr. Davies said.

“Previous work has shown that implanted tumors are able to spontaneously metastasize,” Dr. Movva said. “This suggests that there is interaction between the tumor and its microenvironment, which may therefore mimic the patient response better.”

Genetic testing can help people with certain cancers, but researchers have found few targeted therapies for people with sarcoma, she said. There are more than 70 subtypes of sarcoma, and chemo is less effective in many of them than in more common cancers.

“A recent paper by Stebbing et al. summarizes the clinical experience of 29 patients,” she said. “A few of these patients did have DNA sequencing of their tumors, which guided the physician in selection of drugs for the sensitivity testing.”

In 13 cases, treatments that worked in the mice also helped the patients. “A few patients derived benefit from drugs not normally prescribed for patients with soft-tissue sarcoma,” Dr. Movva said. Grafts failed for seven patients. Six died before data from the mice became available. In three cases, there was no correlation between the mice and the patients.

“It is unclear, therefore, if this approach (using a PDX model to direct care) is better than participating in a phase I trial, for example,” Dr. Movva said. Nevertheless, “patients should definitely consider participating in the TumorGraft clinical trial when it becomes available. This will help determine how well the PDX model predicts patient response and also help sort out some of the issues related to engraftment rates and feasibility.”

Other companies have developed PDX models for research. But Champions is the only one that sells them to individual patients, Dr. Davies said.

1 comment:

Creative Animodel said...

That's true, mice have been used as the experimental tools for many years because they have the similar characteristics and genetic relationship with human beings. So there appears knock-in mouse models, knockdown mouse model, crispr mouse models, etc..