NEW YORK (GenomeWeb) – The Icahn School of Medicine at Mount Sinai has launched a project in which researchers will assess how closely the molecular characteristics, disease progression, and treatment responses of triple-negative breast cancer patients track with the experience of mouse avatars that have a piece of their tumors growing on them.
"The primary aim is to establish whether the mouse avatar model, as modeled by these [patient-derived xenografts or PDX] mice accurately reflect not only the clinical response to cytotoxic agents that the patients get, but also the genomic correlations in terms of how they respond to these cytotoxic agents," Hanna Irie, lead investigator of the study told PGx Reporter.
The project is being coordinated by Mount Sinai's Tisch Cancer Institute and involves investigators from its Dubin Breast Center and Icahn Institute for Genomics. The researchers will work with Champions Oncology to graft tumor samples from 100 triple-negative breast cancer patients onto mouse proxies. Irie noted that this is the largest study done to date testing out the feasibility of the mouse avatar model in cancer research.
Increasingly, cancer researchers are using avatar mice, living animal models on which they graft a piece of a human patient's tumor and allow it to grow. If this procedure is successful and the tumor in the mouse is molecularly similar to the patient's tumor, the idea is that researchers can screen drugs on these avatars and figure out the best option for the human patient. In this way, researchers and drugmakers can advance personalized treatment hypotheses while sparing human patients the toxicities from treatments they won't benefit from.
According to Irie, Mount Sinai is in the early stages of testing the viability of the mouse avatar approach in cancer research. "In this Phase I part of the study, we're not having the PDX mice guide clinical decision making," she said. "We take advantage of the neo-adjuvant pre-operative paradigm … to identify patients with triple-negative breast cancer who are eligible for neoadjuvant chemotherapy based on [tumor] size or high-risk status."
Upon enrollment into the Mount Sinai study, before patients receive any treatment, Irie and her colleagues with the help of Champions Oncology will take a sample from patients' initial tumor biopsies and attempt to grow it on mouse avatars. The patients and their pretreatment avatar mice will then receive the same neo-adjuvant (pre-surgery) chemotherapy. After neoadjuvant therapy, breast cancer patients will have their tumors resected, and investigators will analyze and compare samples from human subjects' tumors and their mouse avatars.
"The goal is to match the patient with their corresponding PDX mouse model and to assess whether a good response in a patient is also [reflected] as a good response in the PDX mouse, and … whether the lack of a response in the patient also manifests itself as lack of response or progressive disease in the mouse," Irie said. "We thought these were important first steps in validating the biological and genomic behavior of these tumors that grow in the PDX mice."
In small studies, researchers have identified similarities between patients' tumors and the tumors growing in avatar mice. For example, a study involving 14 pancreatic cancer patients published in Clinical Cancer Research in 2006 by Manuel Hidalgo from the Spanish National Cancer Research Center and others reported that the genomic alterations in the tumors growing in mice and patients' tumors were similar, but had some variations in gene expression.
However, there hasn't been a large-scale validation to date of whether these commonalities actually lead to similar disease progression or treatment responses in the human and its mouse proxy. "We're being very aggressive about collecting genetic and genomic information both from the patient and the mouse avatar, pre- and post-treatment, so we have a handle on … what's happening before and after cytotoxic drug treatment," Irie said. "Do they respond genetically and genomically with adaptive mechanisms in a similar way? So, the residual tumors in the mouse and the patient will be modeled, studied, and analyzed."
Eric Schadt, director of Mount Sinai's Icahn Institute for Genomics, and his group will analyze tumors samples via whole-exome sequencing and RNA-seq on Illumina platforms.
For Champions Oncology, the Mount Sinai project represents the largest trial in a specific cancer type where its mouse avatars are being utilized. The company on its website highlights that its mouse tumorgrafts have 94 percent genetic correlation to the patient tumor, and that approximately 70 percent of implantation tumors "take" in avatar mice.
By comparing the genomic profile of tumorgrafts in avatar mice with patient tumor samples at different points in their disease continuum, the Mount Sinai project will provide Champions further validation of its mouse avatars as a personalized medicine research tool. The study "is designed to show the high predictability of the mouse avatars for triple-negative breast cancer patients, as well as to further demonstrate the close resemblance of TumorGrafts to a patient's tumor, even over time," Champions Oncology President Ronnie Morris said in a statement.
More and more cancer centers are exploring whether mouse avatars can be used to generate precision medicine hypotheses. The Mayo Clinic is using mouse proxies to identify predictive biomarkers to guide therapeutic strategies for ovarian cancer patients and to study drug resistance in breast cancer patients. The Jackson Laboratory is also collaborating with Hartford Hospital and Connecticut Children's Medical Center to use mouse avatars to explore potential new treatments for cancer patients.
Still, mouse avatars are not commonly used in cancer research today because of cost and the lengthy timelines for growing the patient's tumor on to the animal. "Patient-derived xenograft models can suffer from long latency periods after engraftment and variable engraftment rates," wrote Despina Siolas of New York University Cancer Institute and Gregory Hannon of Cold Spring Harbor Laboratory last year in an article published in Cancer Research.
They noted that the time between implantation of the tumor graft onto the mouse and the development of the tumor in the animal can take between two months and a year. Irie said her group expects it will take around four months for mouse avatars to grow triple-negative breast tumors. But this lag won't impact patient care since study subjects will receive neoadjuvant chemotherapy independent of the mouse model.
Furthermore, rates of successful engraftments vary, between 23 percent and 75 percent, with higher engraftment rates reported in patients with aggressive cancers. "Indeed, patients whose cancers gave higher engraftment rates had poorer overall survival with increased metastatic potential," Siolas and Hannon wrote in their paper. "Correlations between poor prognosis and engraftment rates were so marked that it has been suggested to be predictive of disease course."
This is one reason Mount Sinai researchers chose to conduct the mouse avatar study in triple-negative breast cancer, a biologically aggressive form of the disease. Past studies conducted by Champions Oncology and others suggest that tumor engraftments from triple-negative breast cancer patients grow particularly well in immunodeficient mice.
When creating PDX models, researchers use immunodeficient mice so the animals' immune systems won't readily attack the tumor cells. Still, there are multiple other factors that can hinder a mouse avatar's ability to grow a patient's tumor. For example, tumors grafted onto mice lack the kind of stroma or tissues that tumors are surrounded by in a human breast. But because triple-negative breast cancer patients have highly proliferative and aggressive tumors, their "intrinsic biology makes them able to overcome many of the barriers to engraftment," Irie said.
According to Champions Oncology's research, ability of avatar mice to successfully grow triple-negative breast tumors is around 70 percent. "If we had take rates of around 25 percent, we would have to recruit many more hundreds of women," Irie said.
Champions Oncology's mouse avatars have been used in a number of clinical investigations to date. A study published this year in Clinical Cancer Research, also by Hidalgo, used both Champions Oncology's mouse avatars and next-generation exome sequencing to guide personalized treatment strategies. In this study, researchers successfully sequenced the tumors of 23 out of 25 cancer patients and achieved tumor grafts in mice for 10 out of 14 patients.
"In occasions actionable alterations,such as mutations in NF1, PI3KA and DDR2, failed to provide any benefit when a targeted drug was tested in the avatar, and accordingly, treatment of the patients with these drugs was not effective," the researchers reported. "Prior testing of candidate treatments in Avatar models correlated with clinical response and helped to select empirical treatments in some patients with no actionable mutations." In the study, 13 patients received personalized treatments and six achieved durable, partial remissions.
It is reasonable to expect that in the Mount Sinai study, some patients' tumors won't successfully be modeled in a mouse avatar. Researchers will learn from these cases, as well. "We will learn … what makes a mouse model for a particular patient not a good mirror of what's going on in the human patient," Irie said.
"It could be that those tumors that grow in the mouse, that don't correspond well to the patient, are those that have infiltration by immune cells for example," she noted. "Since we're using immunodeficient mice, if a particular tumor requires human immune cells to modify, grow, or respond to chemotherapy, then clearly, that's not being accurately or sufficiently modeled by the PDX mice."
Irie and her colleagues will bank the tumorgraft samples, which can be regrown and tested again if the patient's cancer gets worse or comes back. Patients who have residual disease will have another avatar mice created so that researchers can study the resistant tumor. "We're hoping to understand whether the resistant tumors grow differently from the primary tumors," Irie explained.
With a better understanding of the types of cancer patients and the disease stages that are best modeled in PDX mice, and the instances in which this model fails, Irie and her colleagues are hoping to eventually use avatar mice to screen drugs before giving them to human patients. Although Irie couldn't provide an estimate for how much it will cost to conduct this study, she said the project is being jointly funded by Champions Oncology and Mount Sinai.