Inhibition of leukemic stem cells by PP2A activating agents
Inventors
Perrotti, Danilo • Neviani, Paolo
Assignees
National Institutes of Health NIH • Ohio State Innovation Foundation • US Department of Health and Human Services
Publication Number
US-9220706-B2
Publication Date
2015-12-29
Expiration Date
2033-05-31
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Abstract
A method of inhibiting the growth of leukemic hematopoietic stem cells in a subject with leukemia is described. The method includes administering a therapeutically effective amount of a composition including a compound of formula I: I wherein R1 is independently selected from hydrogen and methyl; R2 is selected from the group consisting of 4,8-dimethyl-non-1-enyl, 4,8-dimethyl-nonyl, non-1-enyl, and nonanyl groups; X is a carboxyl, phosphonic, or sulfonic moiety, and n is an integer from 1 to 6, or a compound of Formula II: II wherein R1 is a C6-C12 alkyl or C6-C12 alkoxy group; R2 is independently selected from the group consisting of hydrogen, methoxy, and hydroxyl; and R3 is an alkyl or cycloalkyl group; or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention provides a method of inhibiting the growth of leukemic hematopoietic stem cells (HSCs) in a subject with leukemia by administering a therapeutically effective amount of compositions comprising compounds of formula I or formula II, including FTY720 and its non-immunosuppressive derivatives. These compounds selectively suppress survival of leukemic but not normal quiescent hematopoietic stem cells by restoring PP2A activity, which is a tumor suppressor inhibited in chronic myeloid leukemia (CML) stem cells.
The background problem addressed is that chronic myeloid leukemia quiescent hematopoietic stem cells are resistant to tyrosine kinase inhibitors (TKIs) such as imatinib, and represent an active disease reservoir. While TKIs induce remission in most patients, these leukemic stem cells persist, leading to disease relapse. Existing therapies aiming at direct killing or induction of these quiescent cells carry uncertain safety and clinical benefits. Thus, there is a need for compounds able to treat TKI-resistant leukemic hematopoietic stem cells to eradicate the disease at the stem cell level.
The invention elucidates that BCR-ABL1 expression, independent of its kinase activity, is vital for survival of Ph+ quiescent HSCs by promoting JAK2 activation, which enhances β-catenin activity through SET-mediated inactivation of PP2A. The pharmaceutical compositions comprising PP2A activating agents such as FTY720 disrupt the SET-PP2A interaction, reactivating PP2A, leading to inhibition of JAK2 and β-catenin pathways, thus reducing survival and self-renewal of leukemic stem cells without adversely affecting normal HSCs. This provides a therapeutic advantage toward potential cure of CML patients by targeting TKI-resistant leukemic stem cells.
Claims Coverage
The patent contains one independent claim defining a method of inhibiting leukemic hematopoietic stem cell growth by administering a compound of Formula II; the inventive features focus on the composition and its therapeutic use.
Use of compounds of Formula II to inhibit leukemic hematopoietic stem cells
Administering a therapeutically effective amount of a composition including a compound of Formula II or a pharmaceutically acceptable salt thereof to inhibit growth of leukemic hematopoietic stem cells in a subject with leukemia.
Selection of specific substituents on Formula II compounds
Compounds wherein R1 is a C6-C12 alkyl or alkoxy group; R2 is hydrogen, methoxy, or hydroxyl; and R3 is an alkyl or cycloalkyl group, including specific selections such as C8 alkyl or C8 alkoxy for R1 and propyl, isopropyl, isobutyl, cyclopropyl methyl, or cyclobutyl methyl for R3.
Method applicable to Philadelphia chromosome-positive leukemia
The method is applicable specifically to Ph+ leukemias, including chronic myelogenous leukemia (CML).
Achieving cytotoxic effects on leukemic hematopoietic stem cells
The administered composition has a cytotoxic effect, killing leukemic hematopoietic stem cells to inhibit disease progression.
The independent claim establishes a therapeutic method targeting leukemic hematopoietic stem cells using compounds of Formula II with defined chemical substituents, focusing on treating Ph+ leukemias such as CML with cytotoxic efficacy.
Stated Advantages
Selective suppression of leukemic Ph+ quiescent hematopoietic stem cells without harming normal hematopoietic stem cells.
Ability to overcome tyrosine kinase inhibitor resistance in leukemic stem cells, which represent a reservoir for disease relapse.
Potential to induce long-term disease remission or cure in chronic myeloid leukemia patients by eradicating TKI-resistant leukemic stem cells.
Use of non-immunosuppressive derivatives of FTY720 that avoid lymphopenia while maintaining anti-leukemic activity.
Documented Applications
Treatment of chronic myelogenous leukemia (CML) including Ph+ leukemias by inhibiting TKI-resistant leukemic hematopoietic stem cells.
Use of PP2A activating agents such as FTY720 and derivatives for selective killing or growth inhibition of leukemic hematopoietic stem cells.
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