PP2A Inhibition Sensitizes Cancer Stem Cells to ABL Tyrosine Kinase Inhibitors in BCR-ACL+ Human Leukemia
This week we profile a recent publication in Science Translational Medicine from the lab of
Dr. Xiaoyan Jiang (second from left, front) at the BC Cancer Agency.
Can you provide a brief overview of your lab’s current research focus?
The focus of our translational leukemia research is to identify key molecules and pathways that will lead to new, rationally designed, more effective, less toxic, personalized molecularly targeted therapies. In particular, we are extremely interested in developing mechanism-based combination therapeutic strategies that can directly target drug-insensitive blood cancer stem cells, leading to curative therapies for human leukemia.
What is the significance of the findings in this publication?
We have uncovered protein phosphatase 2A (PP2A) as a critical therapeutic target in drug-resistant blood cancer cells, including blood cancer stem cells from chronic myeloid leukemia (CML) patients. ABL tyrosine kinase inhibitor (TKI) monotherapy is the current standard-of-care treatment for CML, which allows most patients to remain in clinical remission, but early relapse and resistant disease prevent many patients from being cured. In particular, CML cancer stem cells are insensitive to the TKI monotherapy, which is thought to be the root cause of drug resistance and disease relapse in patients. We have now demonstrated that the clinically validated PP2A inhibitors LB100 and LB102, in combination with TKIs, preferentially sensitize treatment-naïve drug-insensitive stem and progenitor cells to elimination by TKIs, while not being toxic to healthy bone marrow cells. This new combination therapy may lead to more effective disease eradication, especially in patients at high risk of drug resistance and disease progression.
What are the next steps for this research?
A phase 1 clinical trial of the PP2A inhibitor LB100 for the treatment of relapsed solid tumors (NCT01837667) has been successfully completed, without safety issues, which opens a promising avenue for combination cancer therapies. An additional clinical trial of LB100 for treatment of brain tumors has also been initiated (NCT03027388). A potential clinical trial for CML treatment has been discussed with our industry partners, based on our significant findings. If these results can be replicated in the clinic, this combination strategy will improve the effectiveness of CML therapy and may also apply to other malignancies where PP2A activity is highly increased.
This project was supported by:
This work was supported by the Canadian Institutes of Health Research, the Canadian Cancer Society, the Leukemia & Lymphoma Society of Canada and the Cancer Research Society. Two post-doctoral fellows (J. Su and K. Rothe) were supported by MITACS Elevate postdoctoral fellowships.