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Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma
Published on: March 30, 2018
Therapeutic efficacy of RAS inhibitor trametinib using a juvenile myelomonocytic leukemia patient-derived xenograft
Alex Q Lee1, Hiroaki Konishi1, Masami Ijiri1
1Department of Pediatrics, UC Davis School of Medicine, Sacramento, California, USA.
Abstract:
Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric leukemia with few effective treatments and poor outcomes even after stem cell transplantation, the only current curative treatment. We developed a JMML patient-derived xenograft (PDX) mouse model and demonstrated the in vivo therapeutic efficacy and confirmed the target of trametinib, a RAS-RAF-MEK-ERK pathway inhibitor, in this model. A PDX model was created through transplantation of patient JMML cells into mice, up to the second generation, and successful engraftment was confirmed using flow cytometry. JMML PDX mice were treated with trametinib versus vehicle control, with a median survival of 194 days in the treatment group versus 124 days in the control group (p = 0.02). Trametinib's target as a RAS pathway inhibitor was verified by showing inhibition of ERK phosphorylation using immunoblot assays. In conclusion, trametinib monotherapy significantly prolongs survival in our JMML PDX model by inhibiting the RAS pathway. Our model can be effectively used for assessment of novel targeted treatments, including potential combination therapies, to improve JMML outcomes.
Insights
Trametinib significantly improved survival in a juvenile myelomonocytic leukemia (JMML) mouse model by targeting the RAS pathway. This new model aids in developing better treatments for this aggressive pediatric cancer.
Area of Science:
- Oncology
- Pediatric Hematology-Oncology
- Cancer Therapeutics
Background:
- Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric cancer with limited treatment options and poor prognosis.
- Current curative treatment, stem cell transplantation, has limited efficacy for many patients.
Purpose of the Study:
- To develop and validate a patient-derived xenograft (PDX) mouse model for JMML.
- To evaluate the therapeutic efficacy of trametinib, a MEK inhibitor, in the JMML PDX model.
- To confirm trametinib's mechanism of action as a RAS-RAF-MEK-ERK pathway inhibitor.
Main Methods:
- Established a JMML PDX mouse model by transplanting patient cells through two generations.
- Confirmed successful engraftment using flow cytometry.
- Administered trametinib or vehicle control to JMML PDX mice and assessed survival and pathway inhibition via immunoblot assays.
Main Results:
- Trametinib treatment significantly prolonged median survival in JMML PDX mice (194 days vs. 124 days, p=0.02).
- Trametinib effectively inhibited ERK phosphorylation, confirming its action on the RAS-RAF-MEK-ERK pathway.
- The PDX model demonstrated successful engraftment and response to targeted therapy.
Conclusions:
- Trametinib monotherapy significantly improves survival in a JMML PDX model.
- The developed JMML PDX model is a valuable tool for evaluating novel targeted therapies.
- This model can accelerate the development of improved treatments to enhance outcomes for JMML patients.
