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Jackson Lab Collecting Cancer Mutation Data in Mouse Avatars to Support PGx Studies

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The Jackson Laboratory's patient-derived xenograft, or PDX, mouse program has begun sequencing samples from a growing collection of mice implanted with human tumor tissue to support studies of molecularly targeted drugs.

The Jax PDX mice are currently used to test drug efficacy and mechanism of action, but the lab hopes that these mouse avatars will serve in the future as a way to test therapies in real time to personalize patient treatment.

So far the project has engrafted about 500 different patients' tumors into mouse models that can be maintained and expanded for drug studies. The group recently began sequencing the grafted tumor samples to provide mutation data for each model to help groups choose models to test drugs with molecular targets like EGFR, KRAS, and P53.

Neal Goodwin, director of the lab's PDX mouse project, told PGx Reporter this week that though the lab has been using microarrays to collect genomic data on the grafted mice, the team has received strong feedback that the sequencing data will provide crucial new information for choosing PDX mice for studies of targeted therapies.

"[Mutation status] is probably the number one thing that people look at when determining which models they want to use for which purpose," he said.

The PDX mouse models are created by progressively increasing a patient's tumor tissue by grafting it in larger and larger numbers of mice. A single grafted-mouse can grow enough tumor to engraft another ten mice, which each then lend tumor material to another ten mice, and so on.

Having had initial success sequencing a pilot set of 20 tumor samples using a targeted cancer panel from Illumina, the Jax lab group is now planning to collect the same set of sequence data from all remaining and future samples, Goodwin said.

The group used Illumina's MiSeq desktop sequencer and the company's TruSeq cancer panel, which was launched earlier this year and covers mutational hotspots on 48 genes.

"We're sequencing these 48 genes, identifying all the mutations that pass filters and then whittling those down to ones that are likely impactful in those genes," Doug Hinerfled, who is in charge of the sequencing part of the PDX mouse project, told PGx Reporter. "That data is then available to anyone who might want access to these models – to see if they have mutations in P53, or KRAS, EGFR, or whatever their interest is."

"The idea is that the data can be used for the purpose of selecting which tumor models are best for which drugs … so people can then access the [sequencing data] and find a cancer with a particular mutation … [that] might be a good model to use in [a particular] drug study," Hinerfeld said.

In the team's pilot group of 20 tumors, results of the cancer panel marked 12 samples as having potentially damaging mutations — several in genes that are the subject of targeted drug development research.

While Goodwin could not disclose specific companies or drugs the lab has been working with, he did say that the PDX mice have been used in a range of academic and private-sector studies, mainly of drug efficacy and "predictive tumor response."

Goodwin said the program has been "very well received" by the biopharmaceutical industry and that the Jackson lab currently distributes PDX models for groups to use in their own research and also contracts with private sector partners to do in-house studies through the JAX cancer services lab. Right now, he said most of that research is related to testing efficacy or mechanism of action.

"It is exciting to see [in co-clinical studies] … the PDX tumor drug response seemingly matches what is going on clinically," he said.

Tumors for the PDX mouse populations have come from a consortium of institutions and represent a wide range of tumor types, including lung cancer, colorectal cancer, breast cancer, and rarer tumor types.

Goodwin said that the lab has received many lung cancer samples from the University of California, Davis. "We've developed many models of UC Davis patients that are EGFR mutants," he said. "These models have been striking. And we're going at a feverish pace to genotype them and characterize their drug response to EGFR-targeted reagents [to try to] overcome drug resistance."

Goodwin said the project has also collected a number of KRAS mutant lung cancer samples, as well as some KRAS-mutant colorectal cancers, for studies of drug response, and many tumors with P53 mutations.

According to Goodwin, the group has also received more than 40 glioblastoma samples from its consortium partner, Seattle's Swedish Hospital. Of these 40, 25 have made it into PDX models so far. Of those, the team has found three to harbor EGFR v3 deletion mutations, which Goodwin said are important for testing EGFR-targeting molecules being developed as treatments for brain cancer.

The group has also had success building PDX populations harboring ER-positive breast cancer, he said.

According to Hinerfeld, the eventual hope is to gain a more comprehensive genomic picture for the mouse PDX mouse populations. He said that Edison Liu, the director of the Jackson Lab, eventually hopes for the mouse avatars to be able to serve as a testing ground for real-time personalized medicine, as a way of identifying the best therapies for patients currently undergoing cancer treatment.

"People are beginning to live long enough that the PDX models could catch up to the disease – and be used predictively," Goodwin explained.

Researchers from the Mayo Clinic are planning to use a similar approach in a larger study beginning this year called the Breast Cancer Genome Guided Therapy Study, which will attempt to personalize neoadjuvant chemotherapy treatment for high-risk, early-stage breast cancer patients. The group plans to create its own avatar mice to test high-risk treatments without harming patients (PGx Reporter 4/25/2012).

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