Oncology Drug Development 

A lack of reliable preclinical models has hampered progress in oncology drug development. A recent increase in the use of patient-derived tumor xenografts (PDTX) engrafted into immunocompromised mice such as athymic nude or NOD/SCID mice for preclinical modeling aims to address these shortcomings. In terms of global gene-expression patterns, mutational status, metastatic potential, drug responsiveness, and tumor architecture, many tumor-specific PDTX models have been established. These models are biologically stable when passaged in mice. 

Due to robust xenogeneic immune rejection, human cancer cells cannot engraft into immune-competent rodents. Several genes related to immune cells’ development, survival, and function have been disrupted to develop immunodeficient mice. Producing humanized mice for evaluating human cancer development relies heavily on the ability to create these immunodeficient animals.  

Immunodeficient mice rejected human cancer cells via their adaptive (T and B cells) and innate (NK cells and macrophages) immune responses. When mice lack the Foxn1 gene, the recombination activating gene 1, the recombination activating gene 2, the protein kinase gene, and the DNA activated and catalytic polypeptide (Prkdc) gene, they develop T and B cell deficiencies. By selecting a non-obese diabetic (NOD) mouse background or knocking in human or NOD Sirpa genes, mice NK cells are absent or functionally impaired. In contrast, mouse macrophages cannot phagocytose IL2rg or B2m if those genes are deleted.