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MYB-activated models for testing therapeutic agents in adenoid cystic carcinoma
Yue Jiang1, Ruli Gao2, Chunxia Cao1
1Department Medicine, University of Florida, Gainesville, FL 32608, USA.
Objective:
There are no effective systemic therapies for adenoid cystic cancer (ACC) and lack of tumor lines and mouse models have hindered drug development.We aim to develop MYB-activated models for testing new therapeutic agents.
Materials And Methods:
We studied new ACC patient-derived xenograft (PDX) models and generated a matched cell line from one patient. In addition, we generated a genetically-engineered MYB-NFIB mouse model (GEMM) that was crossed with Ink4a+/-/Arf+/- mice to study tumor spectrum and obtain tumor lines. Using human and murine ACC-like tumor lines, we analyzed MYB expression by RNA-Seq and immunoblot and tested efficacy of new MYB inhibitors.
Results:
We detected MYB-NFIB transcripts in both UFH1 and UFH2 PDX and observed tumor inhibition by MYB depletion using shRNA in vivo. We observed rapid loss of MYB expression when we cultured UFH1 in vitro, but were able to generate a UFH2 tumor cell line that retained MYB expression for 6 months. RNA-Seq expression detected an ACC-like mRNA signature in PDX samples and we confirmed an identical KMT2A/MLL variant in UFH2 PDX, matched cell line, and primary biopsy. Although the predominant phenotype of the MYB-NFIB GEMM was B-cell leukemia, we also generated a MYB-activated ACC-like mammary tumor cell line. We observed tumor inhibition using a novel MYB peptidomimetic in both human and murine tumor models.
Conclusions:
We generated and studied new murine and human MYB-activated tumor samples and detected growth inhibition with MYB peptidomimetics. These data provide tools to define treatment strategies for patients with advanced MYB-activated ACC.
Insights
New MYB-activated models, including patient-derived xenografts and genetically engineered mice, were developed for adenoid cystic cancer (ACC). These models showed promise for testing novel MYB inhibitors, offering new therapeutic strategies for advanced ACC.
Area of Science:
- Oncology
- Cancer Biology
- Drug Development
Background:
- Adenoid cystic cancer (ACC) lacks effective systemic therapies, hindering drug development due to a scarcity of suitable tumor models.
- Targeting MYB activation is a potential therapeutic strategy for ACC.
Purpose of the Study:
- To develop MYB-activated models for adenoid cystic cancer (ACC) to facilitate the testing of new therapeutic agents.
- To investigate the efficacy of novel MYB inhibitors in preclinical ACC models.
Main Methods:
- Generation of patient-derived xenograft (PDX) models and matched cell lines from ACC patients.
- Creation of a MYB-NFIB genetically-engineered mouse model (GEMM), crossed with Ink4a/Arf deficient mice.
- Analysis of MYB expression via RNA-Seq and immunoblotting in human and murine ACC models.
- Testing of novel MYB inhibitors, including peptidomimetics, for anti-tumor activity.
Main Results:
- MYB-NFIB transcripts were detected in PDX models, with MYB depletion showing tumor inhibition.
- A stable MYB-expressing ACC cell line (UFH2) was established from a PDX model.
- A MYB-activated ACC-like mammary tumor cell line was generated from the GEMM.
- A novel MYB peptidomimetic demonstrated tumor inhibition in both human and murine ACC models.
Conclusions:
- New MYB-activated tumor models (murine and human) for ACC have been successfully generated and characterized.
- These models provide a platform for evaluating therapeutic strategies targeting MYB in advanced ACC.
- The study demonstrates the potential of MYB peptidomimetics as a treatment approach for MYB-activated ACC.
