Can Mouse Avatars Guide Cancer Treatment?

Ralph de Vere White, MB, BCh, BAO

A focus on prevention, early detection, and treatment has lowered cancer death rates, but long-term survival for patients with advanced disease has been far less dramatic. Researchers expect that routine tumor sequencing will improve this picture.

UC Davis Comprehensive Cancer Center has embarked on an exciting collaboration with Jackson Laboratory (JAX West), a National Cancer Institute— designated cancer research facility headquartered in Maine with a campus in Sacramento, California. Our patients’ tumors are rushed from operating rooms to JAX West in Sacramento and then grafted, without manipulation, into NSG mice. Since these mice have no natural killer cells, the tumors have a high take rate, look like the tumors taken from the patients, and, at this stage of research, appear to have comparable molecular markers.

While studies of a tumor’s molecular characteristics can be carried out in the patient, only one such study can be done at a single point in time. By growing the tumors in many mice, this problem is overcome. Sequencing determines whether the molecular drivers of tumor growth and drug resistance are comparable between the human and mouse tumors. For patients battling a disease recurrence, results of these tests in mice can translate to novel treatment approaches for individual cancer patients. This work, led by renowned lung cancer expert David Gandara, MD, of UC Davis, is designed to improve outcomes for lung cancer patients.

UC Davis researchers now plan to utilize the mice to predict response to chemotherapy in patients with muscle-invasive bladder cancer. Twenty percent of bladder cancer patients have muscle-invasive transitional cell carcinoma, the type responsible for 80% of bladder cancer mortality. Fortunately, the 40% of these patients who receive neoadjuvant cisplatin-based chemotherapy will have no detectable cancer at the time of surgery, and 80% to 85% percent will survive 5 years or more. Unfortunately, only about 9% of these patients ever get neoadjuvant chemotherapy because bladder cancer lacks definable mutations to predict which patients will benefit from a given drug. Physicians and patients must weigh the uncertain benefits against the drug’s toxicity, delays in surgery, and cost. Consequently, the death rate for muscleinvasive bladder cancer has not improved in 30 years.

The challenge for UC Davis researchers, working with Jackson Laboratory, is to find a way to predict chemotherapy responders with the hope of improving survival and ultimately reducing the nonbeneficial toxicity associated with chemotherapy.

Neal Goodwin, PhD

“We have an opportunity to create mouse avatars of actual patients and to use those to research what therapies actually do to these tumors, which tumors are resistant to therapies, and how patients can overcome resistance and extend their lives,” said Neal Goodwin, PhD, director of Research and Development for In Vivo Pharmacology Services at Jackson Laboratory. “It is a very rewarding collaboration.”

Bladder cancer researchers at UC Davis have an ambitious goal: within 5 years, all patients will get their primary treatment based on a molecular analysis of their bladder tumor. To get there, they are starting with eight different groups of NSG mice, each with stable growth of muscle-invasive transitional cell carcinoma taken from eight individual patients. Seven additional tumors will similarly be analyzed. The study involves testing the mice for their response to microdoses of cisplatin. The tumors in the mice are simultaneously sequenced for any druggable targets, and then treated with drugs for which targets are identified. If the mice respond and the tumors shrink, researchers will next sequence the original patient’s tumor for the same targets. If the targets match, clinical trials will be conducted to confirm the benefit in patients.

If successful, patients in the clinical trial will be treated based on the molecular analysis of their tumor. The corresponding mice will be treated simultaneously with the same agents and monitored. Since mice grow tumors, respond to treatment, or relapse much more quickly than humans do, their response can serve as a model for what the patient likely will experience. In the event of a relapse of the cancer, the mice can be used to test different therapies. By the time the patient relapses, a new treatment or combination of drugs will be identified for the patient and confirmed with tumor sequencing.

UC Davis cancer researchers say the research and clinical trial represent a new era in the battle against muscle-invasive bladder cancer, one in which individual patients receive therapies based on their specific tumor’s molecular characteristics. If all goes as planned, mortality from this disease could be cut in half in the next decade.