# Impact of Genetic Diversity on Human Xenograft Tumor Growth

> **NIH NIH R33** · JACKSON LABORATORY · 2021 · $423,300

## Abstract

PROJECT SUMMARY/ABSTRACT
Patient derived xenograft (PDX) mouse models are an essential tool for the study of cancer biology, biomarker
development, drug screening, and the preclinical evaluation of personalized medicine strategies for many
types of cancers. However, xenograft failure rates due to host rejection, even in immunocompromised hosts, is
between ~20% and 100% depending on tumor type. Such failure often results in a lost sample and a lost
opportunity to obtain clinically relevant data for that patient or tumor type. Emerging evidence suggests that
host genetic background underlies much of this variability in xenograft establishment as well as tumor
response to drugs. To advance the clinical relevance of the PDX model system, an innovative alternative is to
utilize genetic diversity of the host PDX mice as a tool to substantially improve tumor engraftment. The
Collaborative Cross (CC) and Diversity Outbred (DO) are complementary sets of recombinant inbred and
strains, respectively, that derive from eight parental inbred strains, and combine high genetic diversity with
balanced population structures ideal for genetic trait mapping. The CC inbred strains provide a high degree of
genetic variability and potentially a genetically tractable platform for sustained and reproducible in vivo PDX
studies. DO provides the most genetic variability in outbred genomes with high levels of heterozygosity similar
to the human population, and is ideal for characterizing the full range of potential effects of host genetic
background variation on tumor cell expansion. To establish a PDX mouse, the host immune system must be
suppressed for xenograft acceptance. The challenge in the proposed studies is to suppress the immune
system in individual immunocompetent mice with different genetic backgrounds. In Aim 1, the immune
system will be suppressed in CC mice by knocking out the Rag1 gene using a novel CRISPR-Cas9
base editing system. In Aim 2, the immune system will be suppressed in genetically unique DO mice
using a novel oral immunosuppressant drug. This study is significant because it will provide the genetic
diversity necessary for the growth of any type of tumor, expanding the PDX platform to sustain cancers that
have previously been impossible to xenograft. This study is conceptually innovative because it will introduce
genetic diversity into the PDX platform. This study is technically innovative because it will compromise the
immune system in multiple genetically diverse mice by state-of-the-art CRISPR-Cas9 Base Editor technology
(Aim 1) or using a novel chemical immunosuppressant in the drinking water (Aim 2). The state-of-the-art Base
Editor system in Aim 1 will produce identical mutations in all mice with little or no collateral genetic alterations.
Development of these novel platforms has risks that will be rewarded with the generation of PDX engraftment
of “difficult” tumors, enabling a greater understanding of cancer biology and development of nov...

## Key facts

- **NIH application ID:** 10168486
- **Project number:** 5R33CA247669-02
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** Muneer Gulamhusein Hasham
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,300
- **Award type:** 5
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168486

## Citation

> US National Institutes of Health, RePORTER application 10168486, Impact of Genetic Diversity on Human Xenograft Tumor Growth (5R33CA247669-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10168486. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*