Anaplastic thyroid cancer is an extremely aggressive form of cancer that cannot be cured by surgery and has a median survival of about 6 months. The malignancy normally occurs in patients over the age of 60, and there is not a standard of care, according to John A. Copland III, PhD, professor, Cancer Biology, Mayo Clinic.
Copland and his team of researchers have designed, and currently utilize, a patient-derived xenograft model to test new therapies for anaplastic thyroid cancer. The models are created in mice, using bits of tissue taken from patients who have undergone surgery and have been diagnosed by a pathologist.
In an exclusive interview withTargeted Oncology, Copland discussed these models, as well as potentially effective treatments in the realm of personalized medicine for anaplastic thyroid cancer.
What are the goals of your research into anaplastic thyroid cancer?
We are trying to better understand the cancer biology of anaplastic thyroid cancer, which is probably the most deadly cancer known to humans. It's 99% lethal and there is about a 4- to 6-month median survival in patients who have it. It's a fairly rare cancer, so there is no standard of care for anaplastic thyroid cancer. This makes it hard to do clinical trials.
My laboratory has developed these patient-derived xenograft models, or PDX for short. These are models where we take surgical tissue when patients are operated on and implant these samples in immune-incompetent mice. So these tumors now grow and we can actually test these tumors with different therapies.
These models are highly predictive of a patient's response to therapy. You can envision this idea of individualized medicine where we're taking your tumor, and we're testing a lot of FDA-approved drugs on it. We're also testing these drugs in combination, this way we can give the best increase in survival benefit.
You can see where, in this rare tumor where we can't do clinical trials, this helps to come up with a novel therapy that is specifically geared toward your situation. As we build these PDX models and develop these oncogene panels, it will benefit patients in the future as well because you can say "we screened your tumor for these specific oncogene mutations and it matches a previous PDX model, so we think this therapy might be helpful for your particular cancer." This is one way that we can help patients now, and in the future, with this very rare and deadly cancer.
Can you talk about how you and your lab built these PDX models?
We first put together institutional board review (IRB) protocols and got patient consent for their tumor tissue when they go into surgery. As soon as the tumor tissue comes out of surgery, they go to pathology. The pathologist then makes the diagnosis and we get the leftover tissue from that wasn't part of the diagnosis. That tissue then comes to our laboratory, and we immediately implant these small pieces of 5 cubic millimeter tissues underneath the skin of these immune-incompetent mice.
These tumors will then grow in the mice and we can then take these large tumors out and cut them again into small, 5 cubic millimeter pieces, and implant them into a number of mice. With these mice, we can divide them up into different groups and test potential therapies that we think may work based on a gene mutation panel that we would have done on the patient's tumor tissue.
Are there additional steps planned in this research?
Importantly, we continue to collect anaplastic thyroid cancer tumors. Again, there are numerous mutations in anaplastic thyroid cancer that we have discovered and there will be different combinations of mutations. There are going to be very different therapies for each patient based on their specific mutations and their tumors, so it is very important to us to continue to collect these live tissues and implant them and develop these PDX models. This way we can test new therapies that are continually being developed.
These PDX models allow us to test therapies in combination, which could potentially lead to beneficial therapies that could save a patient's life. We have numerous collaborations across the country with oncologists and surgeons who will ship us tissues overnight so we can get them and implant them.
Has there been any research like this done over the years?
There has been a lot of research done using these PDX models on a number of different cancers. Importantly, these data and experiments have shown a high correlation between using a PDX model and matching patients to specific therapies they respond to. There hasn't been a lot of good preclinical models that will predict response, and this is one of the best predictive models we have right now.
The tough part of this is potentially the timeline of these models and testing the therapies related to the patient's progression. That is potentially very critical to a patient who is diagnosed with anaplastic thyroid cancer, where their median survival is potentially 4- to 6-months. If we can potentially prolong that, we might be able to come up with novel therapies that are helpful to them, as opposed to coming up with them later and helping another patient who might have a similar profile.
Are there any surprises you saw from these models?
We have certainly gotten surprises. Some recent data showed that we profiled a patient and they had anHRASmutation and aTERTmutation. So we used tipifarnib, which can target HRAS, and we saw a very nice response in combination with other therapies.
Some other combinations we have used have been sunitinib and paclitaxel, which had shown some survival benefit in patients with anaplastic thyroid cancer. We saw enhanced antitumor activities with the combination therapies using those drugs.
One of the surprises was, when using sunitinib in combination with paclitaxel, we got a durable and prolonged response. In 6 of the 8 animals we tested it on, there was no evidence of a tumor. So it was a surprise for us that we have thisHRAS-mutated andTERT-mutated tumor that grows to endpoint within 12 days, and we could carry these animals out to almost 80 days without any evidence of disease.