Development of patient-derived models for pre-clinical studies in breast cancer
In collaboration with our clinical colleagues at the Huntsman Cancer Hospital, we have generated PDX (patient derived xenograft) and PDX organoid models of several subtypes of breast cancer that facilitates many avenues of cancer research. These models also allow testing of new drugs for breast cancer in vitro and in vivo, and should contribute to the evolution of functional precision medicine, whereby a patient could receive a treatment based on the specific phenotype, genotype, and drug responsiveness of their tumor. Please see our list of available models along with their general characteristics. PDX-derived organoids are also available for the lines indicated. More specific details for each model can be found here. Models are distributed through the HCI Preclinical Research Resource core.
To request models, please complete the MTA Request form. Once the MTA is completed, contact the PRR to arrange model shipment: prr@hci.utah.edu.
For more information on these models please see our publications:
- Breast cancer PDxO cultures for drug discovery and functional precision oncology
- A human breast cancer-derived xenograft and organoid platform for drug discovery and precision oncology
- Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes
- Patient-derived models of human breast cancer: protocols for in vitro and in vivo applications in tumor biology and translational medicine
Mechanisms by which metastatic breast tumors escape the immune system
Our latest research in tumor-immune interaction is focused on a novel “immune checkpoint” that is different from classic immune checkpoints but still serves to restrict T cell activity in metastatic breast tumors in mouse models. Blocking Ron kinase activity restricts metastasis and works remarkably well in combination with one of the classic immunotherapies (anti-CTLA-4; Oncoimmunology 2018). We are investigating the mechanism of how the anti-tumor immune response is regulated by Ron kinase. We found that blocking a particular isoform of Ron kinase robustly expands a stem-like CD4+ T helper cell population that leads to swarming of metastatic lesions by T cells, and continues to fuel the immune response when, normally, exhaustion would occur (Cancer Discovery 2021). Since Ron kinase inhibitors have been in clinical trials and are well-tolerated, this finding paves the way for a new immunotherapy strategy in breast cancer. We have also generated an immune-humanized model of endocrine resistant, ER+ metastatic breast cancer (Breast Cancer Research 2021) for future studies of immune regulation in patient-derived models.
Mechanisms by which MSP preferentially induces metastasis to bone
We observed that MSP facilitates metastasis of breast cancer to bone and induces osteolysis, a common problem in human breast cancer. Our data suggest that MSP promotes bone metastasis by activating osteoclasts and causing bone resorption, which promotes further tumor growth. We are now identifying important downstream effectors of MSP that promote tumor growth in bone.
Pre-clinical studies of MSP inhibitors for treatment of metastatic breast cancer
Our studies showed that MSP not only promotes metastasis in mouse models of breast cancer, but also is significantly associated with metastasis and death in human breast cancer. We are currently testing inhibitors of the MSP signaling pathway in mouse models for efficacy in blocking or reducing metastasis. We are also testing these inhibitors on primary human breast cancer cells in patient-derived tumor grafts or xenografts (PDX).
