The target is protein phosphatase 2A (PP2A) — a ubiquitous enzyme that regulates multiple cell signaling networks important to cell growth, division and death. This new finding has recently been published in the journal Science Translation Medicine.
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. Thus life-long treatment is required, with potential side-effects and a high cost. In some patients, the cancer returns in a form that is untreatable. Studies from Dr. Jiang's group and others have extensively demonstrated that CML cancer stem cells are insensitive to TKI monotherapy, which contributes to the root cause of drug resistance and disease relapse in patients.
Dr. Jiang's group has now demonstrated that the clinically validated PP2A inhibitors LB100 and LB102, in combination with TKIs, preferentially sensitize cancer stem cells, from drug-resistant patients and in preclinical xenotransplant animal models, to elimination by TKIs, while not being toxic to healthy bone marrow cells. This new combination treatment approach may lead to more effective disease eradication, especially in patients at high risk of drug resistance and disease progression.
"A phase 1 clinical trial of the PP2A inhibitor LB100 for the treatment of relapsed solid tumors has been successfully completed, without safety issues, which opens up a promising avenue for combination cancer therapies," said Dr. Jiang. "If the results of our study 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".
Indeed, a novel role for PP2A in B cells, a type of blood cell producing antibodies in the human immune system, and its abnormal activity in B cell-derived tumors have recently been discovered and the results have been published simultaneously in the journal Cell. The research was conducted by a team of researchers led by City of Hope's Dr. Markus Muschen, and Dr. Jiang is a collaborator and co-author of the paper.
Confocal microscopy image showing that PP2A inhibitor (LB100) can disrupt cell cycle control and induce abnormal formation of mitotic spindles in drug resistant CML cells.
All cells need energy to survive, but the team discovered that abnormal activity of PP2A can redirect energy metabolites from sugars into a pathway that generates antioxidants to protect cells from damage during metabolism, leading to uncontrolled cancer growth, specifically in B cell tumors, and drug resistance. Importantly, a series of studies in animal models uncovered that dual inhibition of the abnormal activity of PP2A by LB100 and a G6PD-mediated metabolic pathway can effectively inhibit B-cell tumor development and overcome drug resistance.
"Thus, these two studies both point to critical roles of PP2A as a vital therapeutic target in blood cancers," Dr. Jiang said. "Understanding precisely the biological functions of key cancer drivers such as PP2A will facilitate the development of new combination cancer therapies, which will offer promising approaches to shortening the duration of therapy to achieve a cure. If successful, such approaches will greatly improve patient outcomes and the cost savings could also be significant."
Joining senior author Dr. Jiang, the CML study lead authors are Damian Lai, a graduate student, and Dr. Min Chen a Research Associate. Other authors from Dr. Jiang's team include Drs. Jiechuang Su, Xiaohu Liu, Katharina Rothe and Kaiji Hu. Collaborators include Dr. Donna Forrest, Leukemia/Bone Marrow Transplant Program of BC; Dr. Connie Eaves, Terry Fox Laboratory; and Dr. Gregg Morin, Michael Smith Genome Science Centre, BC Cancer.
This work was supported by the Canadian Institutes of Health Research and in part by 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.
Lai D, Chen M, Su J, Liu X, Rothe K, Hu K, Forrest DL, Eaves CJ, Morin GB & Jiang X. PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL+human leukemia. Sci Transl Med, 10, eaan8735, 2018.
Xiao G, Chan LN, Klemm L, Braas D, Chen Z, Geng H, Zhang QC, Aghajanirefah A, Cosgun KN, Sadras T, Lee J, Mirzapoiazova T, Salgia R, Ernst T, Hochhaus A, Jumaa H, Jiang X, Weinstock DM, Graeber TG & Müschen M. B-lymphoid transcriptional repression of the pentose phosphate pathway reveals a unique therapeutic vulnerability of B cell malignancies. Cell, 2018 (Mar 6, Epub ahead of print).