In about one quarter of acute leukemias and almost in all cases of chronic myeloid leukemia, the tumor cells are driven by an oncogenic tyrosine kinase. Current efforts of targetred therapy almost entirely focus on the development of new compounds that attenuate oncogenic signaling from these tyrosine kinase molecules. Targeting negative feedback regulators of oncogenic tyrosine kinases for the treatment leukemias seems counter intuitive because it represents effectively the opposite of current efforts to improve existing tyrosine kinase inhibitor (TKI)-therapies. However, our preliminary data using genetic mouse models and a small molecule inhibitor of inhibitory phosphatases demonstrate an unexpected dependence of TKD-tumor cells on negative feedback regulation. The central goal of this proposal is to build a fundamental understanding of how blockade of negative feedback mechanistically leads to cell death in TKD-malignancies (Aims 1-2), and to leverage this mechanistic information towards the development of a new therapy concept based on alternating treatment schedules between TKIs and pharmacological inhibitors of negative feedback (Aim 3).
Statement of Benefit to California:
In 2008, the California Cancer Registry expected 3,655 patients with newly diagnosed leukemia and at total of 2,185 death resulting from fatal leukemia. In addition, ~23,300 Californians lived with leukemia in 2008, which highlights that leukemia remains a frequent and life-threatening disease in the State of California despite substantial clinical progress. Here we propose the development of a fundamentally novel treatment approach that is directed at leukemia stem cells. While current treatment approaches effectively diminish the bulk of proliferating leukemia cells, they fail to eradicate the rare leukemia stem cells (LSC), which give rise to drug-resistance and recurrence of the disease. We propose a sequential targeting approach which combines targeted therapy of the leukemia-causing oncogene and blockade of inhibitory phosphatases. Tyrosine kinase inhibitors (TKI) effectively eliminate transient amplifying progenitors but not quiescent LSC. Here propose that pharmacological blockade of inhibitory phosphatases represents a conceptually novel approach to selectively induce eradication of LSC. To validate this concept, we are proposing three Aims to (1) reconstruct the pathway through which inhibitory phosphatases promote LSC self-renewal, (2) to determine whether LSC depletion results from forced differentiation or cell death and (3) to study pharmacological blockade of inhibitory phosphatases in patient-derived human leukemia samples.