CHICAGO (GenomeWeb News) – A presentation at the annual American Society of Clinical Oncology meeting this weekend addressed the feasibility — and remaining challenges — of using so-called avatar mouse models to assess treatments targeting apparent driver mutations gleaned from cancer genome sequence data.
Speaking at a clinical science symposium on dose selection and targets in phase I trials, the Spanish National Cancer Research Center's Elena Garralda outlined the strategy that she and her colleagues from Spain and the US are using to test potentially actionable alterations uncovered through whole-exome sequencing in avatar mice transplanted with patients' tumor samples.
In general, the team filters tumor and normal exome sequence data to tally up tumor-specific somatic mutations, before identifying those that are recurrent in multiple tumors from the same cancer type, and using computational approaches — Polyphen and SIFT software for the current study — to narrow in on potential cancer drivers, Garralda noted.
From there, the researchers try to garner further molecular evidence that alterations they might want to target therapeutically are authentic contributors to a given patient's cancer.
At that stage, the group has been turning to in vivo assays using avatar mice — immunocompromised rodents engrafted with tumor samples from patients for whom personalized cancer treatment options are being considered.
Once these xenograft tumors 'take' in the mouse, Garralda said, researchers can try various targeted therapies to see which, if any, prompt a tumor response. That information would ideally help guide treatment with an existing drug, she noted, or to prioritize patients for enrollment in an appropriate trial of a proposed targeted treatment, if possible.
To test that notion, Garralda and her colleagues looked at a set of 30 individuals with various types of solid tumors, such as melanoma, pancreatic cancer, glioblastoma, or lung cancer.
The group managed to get whole-exome sequence data on tumor and matched normal samples from 28 of the individuals. Of the 19 cases for which avatar mouse models were attempted, 13 were successful, Garralda said.
All told, 16 patients have received personalized treatment based on information available from the exome sequencing analysis and/or experiments using the avatar mice. The remaining 14 patients received the standard treatment for their cancers instead.
In cases where a patient's tumor contained mutations affecting two potentially targetable genes — such as a pancreatic cancer patient whose tumor harbored a PIK3CA point mutation and amplification of a gene that interacts with the MAP-kinase signaling pathway — researchers could use avatar mice to test targeted treatments against each of the alterations to see if either halted xenograft tumor growth.
For at least one patient, a woman with small cell lung cancer, the researchers did not uncover an actionable mutation by exome sequencing, Garralda noted. But by testing multiple drugs in the corresponding avatar mouse model, they found a promising treatment that subsequently appeared to produce a good response in the patient.
In still other instances, the team found that a failed response to treatments targeting apparently actionable mutations in the mouse model corresponded to poor outcomes in patients, supporting the notion that the xenograft and patient tumors have comparable biology.
The use of genomics and avatar mice in personalized cancer treatment is challenging, Garralda noted, particularly for individuals whose tumors contain several suspicious mutations or — at the other extreme — no actionable mutations.
Still, based on their findings so far, she and her colleagues say the avatar mice show promise as an accurate, in vivo means of testing personalized treatment strategies.
"The use of full genomic analysis for cancer care is promising, but presents important challenges that will need to be solved for broad clinical application," they wrote in the abstract accompanying the study.
"Avatar models are a powerful investigational platform for therapeutic decision making and help to guide cancer treatment in the clinic," the study's authors added. "While limitations still exist, this strategy should be tested in prospective randomized clinical trials."
In a discussion of Garralda's ASCO presentation during the same session, Translational Genomics Research Institute researcher John Carpten said the Spanish-led study highlights the power of using tumor ex-plants in pre-clinical assessments of therapies.
Nevertheless, Carpten noted that more research is needed to understand how well various xenografts take in avatar mice — a process may or may not vary by tumor type — and to determine whether clones that successfully engraft in avatar mice represent those most relevant to each individual's disease.
He also cautioned that the timeline of the genomics-plus-avatar strategy is far longer than desired by most oncologists, who generally want access to information on their patients within a couple of weeks from the time of biopsy.
With their current methods, Garralda said her group is receiving exome sequence data for each patient within two to three weeks, though it has been taking four to five months to generate the avatar animals.
Given that time frame, she said, the current research strategy is to start patients on first-line treatments initially, while attempting to use genomics and avatar mouse-based tests to find more targeted treatments in case of cancer progression.