Chronic Myelogenous Leukemia (CML) affects nearly 14,000 patients worldwide and is a disorder of the pluripotent hematopoietic stem cells with two distinct phases. The protracted myelopoliferative chronic phase is followed by a rapidly fatal blast crisis. In CML, a chromosomal translocation leads to production of the Philadelphia Chromosome (Ph1) in which the BCR protein is fused to the Abl kinase to form the BCR/ABL oncogene, a constitutively activated form of the Abl kinase. This constitutive activation of Abl has been shown to be sufficient for induction of chronic phase CML. Although progress has been made in treatment of CML with the introduction of Gleevec and other inhibitors of BCR/ABL, recently however, Gleevec resistant CML has been reported and is a growing concern. Patients that progress into blast phase also experience a resistance to Gleevec and other BCR/ABL inhibitors (i.e. dasatinib and nilotinib. Recently, Perrotti and coworkers demonstrated that increased levels of BCR/ABL activity also results in the overexpression of the protein SET in the blast phase of CML and in the PH1(+) acute lymphoblastic leukemia. Due to its potent inhibition of the tumor suppressor Protein Phosphatase 2A (PP2A) SET is known as Inhibitor-2 of Protein Phosphatase 2A (I2PP2A). Overexpression of SET results in strong inhibition of PP2A, thereby inhibiting the ability of PP2A to perform its regulatory role in deactivating signaling proteins by dephosphorylation. Oncotide Pharmaceuticals has developed novel compounds) that have potent anti-inflammatory activity in vitro and in vivo. In mechanistic studies we recently discovered that these peptides bind to SET and have the ability to activate PP2A enzymatic activity in the cell. Based on this data, we postulated that our lead compound (OP449) may provide therapeutic benefits in patients with CML and other hematologic and non-hematologic malignancies characterized by impaired PP2A activity. We have determined that OP449 suppresses proliferation and induces apoptosis in the BCR/ABL+ K562 CML line, inhibits colony formation by primary patient-derived CML cells, and does is not cytotoxic to normal CD34+ cells. We now seek to extend these studies to determine if OP449 is cytotoxic to drug-resistant CML cells and blast phase CML cells;evaluate the activatin of PP2A in these cells;determine the effect of OP449 treatment on phosphorylation of BCR/ABL, ERK, AKT and STAT5;an inhibit growth in an in vivo model of CML.
Chronic Myelogenous Leukemia (CML) effects nearly 14,000 patients worldwide and is a disorder of the pluripotent hematopoietic stem cells with two distinct phases. The protracted myelopoliferative chronic phase is followed by a rapidly fatal blast crisis. In CML, a chromosomal abnormality known as the Philadelphia Chromosome (Ph1) leads to a signal system in the cell being stuck in the on position instead of being able to be turned on and off. When stuck in the on position it causes CML. Although progress has been made in treatment of CML with the introduction of Gleevec and other inhibitors of the abnormal signal protein, recently however, Gleevec resistant CML has been reported and is a growing concern. While investigating the signals that are turned on in response to the stuck signal, it has been discovered that a protein known as SET accumulates in the CML cells and this disrupts the function of a protein known as PP2A that controls cell growth and proliferation. Recently we discovered small compounds that deactivate the protein SET and restore the normal function of PP2A and have found that these compounds block the growth of CML and other cancer cells. Based on these data, we hypothesize that Oncotide's compounds may provide a therapeutic benefit to patients with CML. The funds derived from this grant proposal will be utilized to determine if some of these compounds can inhibit growth of cancer cells from CML patients and stop the growth of cancer cells in a mouse model of CML.
|Agarwal, Anupriya; MacKenzie, Ryan J; Pippa, Raffaella et al. (2014) Antagonism of SET using OP449 enhances the efficacy of tyrosine kinase inhibitors and overcomes drug resistance in myeloid leukemia. Clin Cancer Res 20:2092-103|
|Farrell, Amy S; Allen-Petersen, Brittany; Daniel, Colin J et al. (2014) Targeting inhibitors of the tumor suppressor PP2A for the treatment of pancreatic cancer. Mol Cancer Res 12:924-39|