Murine Clinical Trials
If there is one thing we're learning from decades of studying tumors, it's that they are highly diverse, not just from cancer type to cancer type, but also from patient to patient.
A Pharmaceutical Research and Manufacturers of America (PhRMA) report released last year estimates that cancer is not one disease but actually more than 200 unique diseases; this number is likely even higher. Genomic and molecular tools are revealing all kinds of subtle differences between tumors that impact how a patient responds to treatment. Therapies need to be optimized in order to treat patients efficiently, and figuring out which treatments work for which patients can be expensive and time-consuming.
A potentially quicker way to personalize cancer treatment is by enrolling in "mouse hospitals," tiny "clinical" trials that that run parallel to the early human trials. The "patients" are primarily genetically engineered mouse models (GEM models) representative of the diversity of human cancer, but are also patient-derived xenograft (PDX) mouse models.
Using mice—primarily transgenic mice—to evaluate drugs is not new, of course. They have probably informed every drug on the market since the dawn of chemotherapy. In addition to GEM models, humanized mice and syngeneic mice also provide platforms to interrogate how tumors grow and respond to therapy.
But the mouse hospital is different. It builds on what has been more of a "miss" system than a "hit" system in drug development by identifying increased or decreased sensitivities to a given therapeutic regimen being tested in subgroups of patients. Knowing this allows clinical investigators to adjust—almost in real-time—the parameters of a trial and improve outcomes.
In order to measure tumor responses without having to sacrifice the mice, researchers use miniature CT scanners, PET scanners and MRIs to watch tumor growth. The mouse hospitals also have on-site pharmacies that ensure appropriate formulation, dosage and administration of drugs for an animal of this size, and carefully-monitored housing to ensure that the mice are living in areas free of pathogens and parasites that can bias the findings.
Early evidence of the value of mouse hospitals came about a decade ago, when a research team at Memorial-Sloan Kettering Cancer Center led by Pier Paolo Pandolfi used transgenic models of acute promyelocytic leukemia (APL) to optimize treatment and ultimately cure what was once a usually fatal disease.
Pandolfi, who now serves as Director of the Cancer Center at Beth Israel Deaconess Medical Center and the Cancer Research Institute, has continued to explore the use of mouse hospitals. One of his more recent projects looked at androgen deprivation therapy (ADT), otherwise known as hormone therapy, in the treatment of advanced prostate cancer. ADT is considered the standard of care for metastatic disease because prostate tumors usually respond initially. However, many men eventually relapse, which led Dr. Pandolfi and his laboratory team to evaluate how prostate tumors harboring a mutation of the Pten gene, either alone or in combination with other genes, appeared to impact tumor response to ADT. By categorizing men with similar genetic lesions, they were able to demonstrate that the responses to therapy correlated well with those of the GEM models with the same lesions who were "co-enrolled" in their study.
As another example, co-clinical studies are also informing how we treat lung cancer patients whose tumors harbor mutations in the KRAS gene, and two other genetic mutations in NSCLC that seem to work in tandem. The drug combination of docetaxel and the MEK inhibitor selumetinib uncovered important distinctions in tumor responses depending upon the genetic makeup of the disease.
Pandolfi, who presented an update on mouse hospitals at a May 10 cancer symposium at Charles River Laboratories' Shrewsbury campus, is now using the co-clinical trial platform to study the immune landscape.
When we think of the immune system, we automatically think of different squadrons of cells—from antibodies and natural killer cells to macrophages and T cell populations—that work in concert to respond to pathogens and keep us safe from infection.
But it turns out that some groups of immune cells recruited to tumor sites actually help maintain tumors rather than kill them.
Pandolfi's group has been studying the immune landscape of different genetically engineered mouse models that, due to the loss of one or more tumor suppressor genes, develop tremendously aggressive and lethal forms of prostate cancer.
While some categories of immune cells appeared to have been pushed out by the cancer, in some but not all mouse models, certain types of granulocytic cells were abundant. When the granulocytes were blocked or killed, the tumor melted away.
Understanding the precise mechanisms driving granulocytic activity—and identifying the specific subgroups of patients that demonstrate these responses could hopefully improve outcomes, and in fact work is now underway to try and rescue an experimental immunotherapy drug that initially failed in efficacy studies because its study population was too broad.
Mouse hospitals are mostly found in academic research settings, but Pandolfi would like to see more pharmaceutical companies supporting such systems. Mouse hospitals won't solve all the problems that have led to poor translation, but it does represent one way to impact some of the late-state cancers that contribute to those 600,000 deaths by making treatments more precise.
How to cite:
McEnery, Regina. Murine Clinical Trials. Eureka blog. June 2, 2016. Available: https://eureka.criver.com/murine-clinical-trials/