Originally published June 3.
CHICAGO (GenomeWeb) -- Patient-derived xenografts (PDX), also called mouse avatars, have proven themselves to be accurate proxies for ovarian tumors in human patients and are aiding in the development of response predictors for therapies, according to presentations at the annual meeting of the American Society of Clinical Oncology this week.
Avatars are also poised to guide treatment selection for patients directly in a newly funded Mayo clinic trial, said Paul Haluska, who chaired the educational session highlighting the potential of PDX mice in advancing personalized treatments for ovarian and other gynecologic cancers.
Haluska told PGx Reporter in an email that the trial will be the first of its kind in ovarian cancer and will establish the feasibility of using avatar mice as proxies to predict patient response to therapies after becoming resistant to platinum-based chemotherapy.
The Mayo Clinic has collected strong data, he said, that ovarian tumors implanted into mice remain a close match to patients' cancers in terms of tumor biology, histology, and genetics.
With this background established, the NIH has provided the team with $2.7 million in funding over four years to support a trial using the mice to guide treatment in humans, Haluska said.
The group plans to produce avatars for approximately 290 patients and hopes to be able to direct therapy in at least 70 of them based on the response of these mice to a handful of drugs that have been shown to be effective in small subsets of platinum-resistant ovarian cancer. This will be enough to power the study to demonstrate whether avatar-directed therapy will be better than random assignment, Haluska said.
Though Mayo is also using mouse avatar populations screened for particular genomic alterations to aid drug development and further understanding of the biology of ovarian cancer, Haluska explained that the mice can also serve a much more basic role in personalized medicine, as they will in the new trial.
In the study, the PDX mice will be pure patient stand-ins, indicating that patients are likely to be sensitive to a particular treatment by simply showing themselves to be sensitive.
"The best predictor of response is response," Haluska said in his presentation, adding that he believes genotyping is still "too complex" in ovarian cancer to be used to drive therapy.
However, he said in his email, researchers will also collect and track genomic data on the avatars, as well as patients’ own tumors, in the new trial to attempt to identify any associations between molecular signatures and response to a particular treatment.
"I don’t think we will ever be at a point in ovarian cancer that we can say 'you have gene X mutated, gene Y amplified in the background of gene signature Z, so you should get drug A,’” Haluska wrote. “As I look at the profiles of these avatars, [as well as my patients], I am struck by how different they are from each other genetically. The scope of such genetic diversity continues to dampen my enthusiasm that such a profiling approach will work."
But, he wrote, "of course, we will collect genomic data on the PDX and then hopefully we can use this to identify a signature from actual responders."
In the trial, researchers will implant the resected tumors of participating patients in mice immediately after surgery. Then, as patients begin standard platinum chemotherapy, their avatars will also receive the same treatment.
Post-platinum, the mouse populations will be subdivided to receive one of several possible second-line treatments including topotecan, gemcitabine, doxorubicin, and paclitaxel.
If a patient’s cancer recurs within six months, they will be considered platinum resistant and will receive whichever follow-on therapy showed the best response in their personal avatars. If they respond longer to initial platinum therapy, they will be re-treated with platinum after recurrence up until the point where they are deemed resistant. Meanwhile, data from their avatars about what drug they are most likely to respond to next will be waiting in the wings.
"The major problem we have in platinum-resistant ovarian cancer is that currently … you have the choice of several drugs that really all have only a modest response rate," Haluska said. "But if you know which women are likely to respond to which of these drugs, you can potentially increase the effective response rate."
Apart from the new treatment trial, Mayo researchers are also using genomically defined mouse avatar populations to explore signatures to predict response to targeted therapies. Haluska shared some data from the team's research into predicting response to PARP inhibition during his presentation.
A standing hypothesis, he said, has been that deficiency versus proficiency of the homologous recombination repair or HR pathway might be associated with response to PARP inhibition in ovarian cancer.
But according to Haluska, data from Mayo Clinic PDX mice has challenged this dogma and may reveal alternative molecular response signatures.
In another study in collaboration with Mayo Clinic Florida researcher Alan Fields, Haluska’s group is also using avatars to look at whether high levels of Protein kinase C iota type, or PRKCI, can predict response to PRKCI inhibitors.
The Mayo Clinic is not the only group looking to mouse avatars to help develop personalized treatment strategies in ovarian cancer.
In another presentation at the session, Clare Scott of Australia's Royal Melbourne Hospital highlighted her institution's efforts using PDX mice in studies of whether molecular markers can predict response to platinum therapy.
Her team has found that they can divide PDX models of high-grade serous ovarian cancers neatly into three categories: platinum-responsive, platinum-resistant, and platinum-refractory. These response rates also remained stable as the group developed and implanted tumors into progressive generations of mice, Scott said.
Looking at molecular markers of impaired DNA repair and oncogene overexpression, the team has been investigating whether they can predict response to platinum therapy, with some indication that oncogene-overexpressing tumors represent a subset that is particularly unresponsive to platinum.
Mouse avatars are also being used by the Mayo Clinic to investigate other cancers, namely in a trial studying drug resistance in breast cancer.
In addition, the Jackson Laboratory is collaborating with Hartford Hospital and Connecticut Children's Medical Center to use mouse avatars to explore potential new treatments for cancer.
And a team of researchers led by the Spanish National Cancer Research Center, CNIO, in Madrid has also been exploring whether a combination of tumor exome sequencing with drug testing in PDX mice can lead to personalized cancer treatments that improve the outcome of patients.