Pediatric AML Preclinical Pipeline Boosted by Xenograft Models

Patient-derived xenograft (PDX) models can provide an important preclinical tool for studying the treatment of pediatric acute myeloid leukemia (pAML) and can help close gaps in the preclinical pipeline for treatment and addressing chemotherapy resistance, according to a study published in Biomedicines.

Unlike adult patients who have patients, pediatric patients have notable differences in their biological and genetic makeup, which makes it essential to develop specific agents that can treat their disease. PDX models are considered the gold standard for evaluating potential novel agents in the preclinical setting.

Too many white blood cells due to leukemia

Image credit: Sebastian Kaulitzki-stock.adobe.com

These models are created by transplanting human cancer cells into immunodeficient mice (IDM), which allows for the replication of a human tumor in a live animal model. These models have been shown to be more predictive of patient responses to therapy than traditional cell line models due to their retaining of heterogeneity and genetic complexity of the original tumor from the patient, the investigators wrote.

Although they have been successful with various other cancer subtypes, creating models for patients with AML—pediatric patients in particular—-has been difficult, according to the investigators. Some of the reasons behind this difficulty include limited number of patients, a lack of specialized expertise to generate models, and little financial incentives to create models for a rare disease, the investigators discussed.

Recently, researchers at Texas Children’s Hospital at Baylor College of Medicine (TCH BCM) have had success in generating multiple pAML PDX models, facilitated by many patients and using existing banking protocols. The investigators presented the collection and protocols they used to create and validate these PDX models for pAML.

Samples for the study were obtained from the Children’s Oncology Group (COG) bank of samples and locally banked samples from children who received their diagnosis at TCH, the investigators wrote. Mice were obtained from Jackson Laboratories and bred in-house, and 2 IDM strains were used: NSG (NOD-Scid-IL-2Rγcnull) and NSGS (NOD-scidIL2Rgnull-3/GM/SF). The use of NSGS mice was prioritized since they were commercially available.

A total of 174 samples were collected from 154 patients, of which 49 resulted in a primary engraftment and 26 were successful in transplanting serially. The investigators found that cells from pheresis product were slightly more likely to produce a stable PDX model, which was possibly due to the enrichment of these samples for KMT2A rearrangements.

The PDX models were all validated using short tandem repeat. Importantly, DNA next-generation sequencing panel testing revealed that pAML PDX models retained similar variant allele frequencies vs their source patient material, the investigators found. This was essential given the frequent concerns surrounding subclone loss after the passage of patient samples.

“When a patient sample was known to harbor a high-need mutation or genetic anomaly, the sample was also trialed for engraftment in MISTRG or MISTRG6 if mice were available,” the authors wrote.

Through their trials, the investigators found that among the 26 serially transplanted models, only 2 (AML007 and AML008) serially transplanted in the MISTRG strain of mice. This led to the discovery that many genetic subtypes of pAML do not engraft well in a primary passage and do not serially transplant well either, the investigators wrote.

They noted that this is likely due to the supportive conditions within the host microenvironment that allow pAML to establish itself and expand, and that work is continuing to optimize the engraftment of rare subtypes of pAML. Overall, however, their developed models have been able to address the gap in the preclinical pipeline and allow for the testing of promising new agents.

“Our systematic approach to developing pAML PDX models has been successful thus far and is providing a renewable resource for pAML researchers at TCH/BCM and elsewhere. It is our hope that establishing this publicly available resource will speed the identification, testing, and selection of the most promising new targets and drugs for pAML,” the investigators concluded.

Reference

Stevens A M, Terrell M, Rashid R, et al. Addressing a pre-clinical pipieline gap: development of the pediatric acute myeloid leukemia patient-derived xenograft program at Texas Children’s Hospital at Baylor College of Medicine. Biomedicines. 2024;12(2):394. doi:10.3390/biomedicines12020394