Researchers from the Jacks Laboratory at MIT's Koch Institute for Integrative Cancer Research (KI) have developed and characterized a genetically engineered mouse that successfully models progression from papillary thyroid cancer, which has an excellent prognosis, to anaplastic thyroid cancer (ATC), a highly lethal disease. The model, described in the Proceedings of the National Academy of Sciences, recapitulates the cardinal features of the human disease and expands the limited repertoire of preclinical models of aggressive thyroid cancers. The study also shows that, in this model, combination treatment with MEK and BRAF inhibitors results in enhanced anti-tumor activity as compared to treatment with a BRAF inhibitor alone, suggesting that this combination could be useful as a component of treatment regimens in human ATC.
From bedside to bench
Most patients diagnosed with thyroid cancer do very well, but in a small fraction of patients it evolves into aggressive forms of thyroid cancer. Among these, the extremely aggressive human ATC is associated with one of the worst prognoses of any kind of human cancer. To complicate matters more, ATC is extremely rare. The combination of aggressiveness and low incidence has hindered research efforts to learn more about this cancer and systematic clinical trials, and there has been little progress in developing effective therapies for ATC. "There have been very few successful clinical trials in ATC in part because it is hard to get patients recruited, and, when these patients present with ATC, the disease may be so aggressive that they are too sick to participate in the trial," says Koch Institute postdoctoral research David McFadden, lead author of this work. McFadden has witnessed these roadblocks first hand: he is also a thyroid cancer endocrinologist at the MGH Center for Endocrine Tumors. "My clinical training has allowed me to identify the real areas of need in thyroid cancer," he explains. It is McFadden's clinical practice that drove him to join the laboratory of KI Director and David H. Koch Professor of Biology, Tyler Jacks, with one goal of engineering a mouse model of ATC to better understand what causes these tumors to form and resist treatments, otherwise so hard to study in human trials.
Modeling ATC progression
Mutations affecting the tumor suppressor p53 are the most common genetic mutation in human ATC. BRAF mutations occur in a subset of these tumors as well. McFadden hypothesized that if they could build a mouse with these mutations in the thyroid gland maybe they would observe development of ATC. Taking advantage of genetically engineered mice generated by the Jacks Laboratory as well as models shared by other investigators in the scientific community, the group engineered a mouse where BRAF and p53 can be conditionally mutated specifically in the thyroid gland.
In this model, expression of mutant BRAF V600E was sufficient to initiate tumor formation in adult animals, but only its combination with p53 loss enabled progression from papillary thyroid cancer to ATC. This study demonstrates that combined BRAF mutation and loss of p53 cooperate in vivo to facilitate progression to ATC.
In the model, thyroid tumors develop and progress in the natural tissue environment, including an intact immune system, and the tumors recapitulate the hallmarks of human ATC, including rapid progression once disease presents, gene expression programs, and intrinsic resistance to BRAF inhibitors. Of note, it takes months between the initiation of BRAF and p53 mutation in the mouse's thyroid gland and the actual development of ATC. What causes these tumors to convert from a low-grade papillary cancer to the very aggressive ATC? The team hypothesizes that other genetic or epigenetic changes may occur in these tumors and that these may facilitate the progression from papillary to anaplastic cancer. They now plan to use this mouse model to identify and study the molecular events that may be driving this transition.
Modeling ATC treatment and drug resistance
Small molecule inhibitors of BRAF have been developed to target BRAF mutations that are common in a variety of human tumors, including melanomas, colon cancers, and thyroid cancers. However, BRAF-mutant tumors in the ATC mice did not respond to BRAF inhibitors. Based on promising clinical results in BRAF-mutant melanoma and mechanistic models of BRAF-resistance in several cancer types, the team predicted that addition of another drug, called a MEK inhibitor, that targets the same pathway activated by BRAF mutation, could improve the response to treatment. Indeed, in this preclinical model, the combination of these inhibitors shrunk ATC tumors dramatically. The combination was also effective slowing down cell proliferation and inhibiting BRAF signaling in a human ATC cell line that carries both BRAF mutation and loss of p53. "In spite of the aggressiveness of the tumors, blocking this pathway very effectively may allow us to improve the initial responses of patients with ATC and provide an entry point to improve ATC treatments," McFadden points out.
"Despite our efforts to maximize ATC treatment approaches by integrating surgery, radiation, and chemotherapy, we have made little to no headway with these standard therapeutic tools. A more sophisticated targeted approach will likely be required to improve ATC treatment options and offer some hope for improving survival," says Dr. Lori Wirth, the Medical Director of MGH's Center for Head and Neck Cancers and a leading expert in new treatments for advanced thyroid cancers. "The greatest promise for this new ATC mouse model is, perhaps, its utility in studying new treatment approaches for this rare and devastating disease. McFadden and colleagues' data are readily applicable to ATCs in humans that harbor mutant BRAF V600E, and will hopefully be translated directly to clinical trial development soon," Wirth adds.
Regardless of the initial responses to the MEK-BRAF combination treatment, however, tumors in these animals do come back after a few months on this regimen. The group plans to look at these resistant tumors to dissect the molecular drivers of the acquired resistance to this drug combination. They also intend to use this new preclinical model to study whether the MEK and BRAF inhibitors work in combination with standard chemotherapy used to treat human ATC. "The goal is to stay one step ahead of the human clinical trials and be able to inform the design of these human trials with the mechanistic details learned from the mouse," says McFadden.