Connections: National research team tries new approach to speed treatments
About a dozen university cancer centers also are participating in the project, but UC Davis Cancer Center is the consortium’s principal university partner.
Chemotherapy temporarily wipes out the immune system and kills millions of cells needed for health. Other treatments can provoke severe autoimmune attack, and cancer often develops resistance to even the most effective medicines.
So, it’s a big added burden when mice used to model different types of human cancers become progressively poorer mirrors of the disease the longer they are bred. Experimental animals that at first provide vital insights about cancers and how to treat them may start to confound researchers after being bred for a few generations.
Take mice models of prostate cancer, for example. When scientists examine tumors from fourth or fifth generations of the mice, they often see ramped-up activity in key receptors, or molecular docking stations that can speed tumor progression. Mutations crop up in genes that normally suppress tumors, disrupting normal defense. The errant behavior does not necessarily model the traits and progress of human cancer, and so the original research intent is compromised.
Even more distressing is the fact that more than 90 percent of treatments that are effective in mice never save a human life. This gives false hope and adds billions to the cost of health care.
Vast room for improvement exists, and this is the core mission of a potent new collaboration between the UC Davis Cancer Center, Jackson Laboratory-West and the National Cancer Institute (NCI) Center for Advanced Preclinical Research (CAPR).
Of the dozen university cancer centers participating in the project, UC Davis Cancer Center is the consortium’s principal university partner. Research support comes from the National Institutes of Health (NIH).
The Primary Human Tumors Consortium integrates complementary cancer research and clinical capabilities of the three institutions. The aim is to strengthen the ability to diagnose cancers quickly and more precisely, and to develop targeted treatments. The consortium has started "growing" a public library of living primary human tumors to aid cancer research worldwide.
"Our animal models have provided great insights, but their inherent limitations have been a hurdle to faster progress," says Ralph deVere White, director of the UC Davis Cancer Center.
"We need to find, say, the five or six characteristics that are shared by all the cancers – the most common mechanisms. That’s where we should focus treatment."
The Jackson Laboratory (JAX)-West is the Sacramento-based arm of the preeminent East Coast mammalian genetics institute, while NCI-CAPR has long supported top cancer research nationally. JAX-West has developed and maintained a new mouse line called NSG that lacks immune defenses, and so has a very high "take" rate of engrafted human tumors.
The proximity of the lab to UC Davis Cancer Center means that tumor tissue surgically removed from patients can be rushed to JAX and engrafted intact onto mice within hours. The tumor’s growth at the cellular and tissue level closely resembles that seen in the patient, making it more likely that the tumor will behave similarly.
The lab’s procedures quickly and efficiently establish viable new lines of mice carrying specific cancers, and provide prime conditions for scientists to apply molecular and genetic tools to understand the tumors’ pernicious strategies, as well as their vulnerabilities. The setting is designed to test different drug regimens against specific types of tumors from different patients.
"There are at least 150 different types of lung cancer, so every patient a physician sees is going to be a little different," says David Gandara, an oncologist and special advisor for experimental therapeutics at the cancer center. "We need to find, say, the five or six characteristics that are shared by all the cancers – the most common mechanisms. That’s where we should focus treatment."
In collaboration with JAX and CAPR, Gandara uses a genetically engineered mouse model, or GEMM, to study cancer’s growth strategy. Gandara and other researchers can seek a target in the tumor cells that a new drug or combinations of drugs can exploit.
The Jackson Laboratory has thousands of NSG mice ready to receive tumor tissue. JAX staff take a tumor sample no larger than the tip of a ballpoint pen and engraft it onto a mouse. The tumor fragment, now a "patient-derived xenotransplant," or PDX, grows to 30 times its original mass, allowing for grafts in 30 more mice from this first generation. Within weeks, the lab can generate thousands of NSG mice engrafted with one type of tumor. Each mouse is a ready subject for testing different drugs against the patient’s potentially unique cancer.
JAX-West already has engrafted 200 NSG PDX tumors, representing 200 cancer patient specimens. The consortium’s goal is for half of the specimens to be from drug-resistant tumors to accelerate research on the most resilient cancers, says Neal Goodwin, program director of the JAX-West Cancer Services.
Some cancers lie dormant for 15 years before their unexpected and unwelcome return, deVere White says. Many researchers now suspect that such recurrences often result from stem cells that have lurked in tissue undetected or have evolved a resistance to the cancer treatment.
"We want to be able to expand these stem cells in the mice," he explains. "We hope the mice will preferentially grow a greater number of stem cells than we can find in patients. We can search these cells for molecular differences between them and the rest of the tumor, and then develop therapies against both the stem cells and the rest of the tumor.
"We have developed a powerful research and clinical alliance here," he continues. "This focus on patient-derived tumors and our growing library of live patient tumors should speed discovery of drugs and drug combinations.That’s where progress will come to improve our patients’ lives."