RESEARCH TRIANGLE PARK, NC, United States

Oncotide Pharmaceuticals, Inc.

www.oncotide.com
RESEARCH TRIANGLE PARK, NC, United States

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Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 300.00K | Year: 2013

DESCRIPTION (provided by applicant): Each year in the United States over 270,000 women will be diagnosed with breast cancer and over 40,000 will die from the disease. While multiple forms of breast cancer exist, a common theme in most of the forms involvesaberrations in signal transduction pathways that lead to inhibition of the programmed cell death process known as apoptosis. Apoptosis is a carefully regulated process in the normal healthy cell with many inducible positive and negative regulators of theprocess. In contrast, many types of cancer feature aberrant, constitutive activation of the Phosphatidylinositol-3 Kinase (PI- 3K)/Akt pathway and overexpression of the c-Myc oncogene. Together, this results in establishment of an anti-apoptotic environment in the cancer cell and correlates with poor outcome. This abnormal constitutive activation of the PI-3K/Akt pathways has lead to a great deal of effort being focused on development of inhibitors of this pathway as targeted anti-tumor agents. The naturalprocess for regulation of Akt signaling and c-Myc stabilization utilizes Protein Phosphatase 2A (PP2A) to remove the phosphate groups that either activate Akt or stabilize c-Myc. Unfortunately, PP2A activity is reduced in many breast cancer cells through genetic deletion or other mechanisms. We recently found that the SET oncoprotein, a potent PP2A inhibitor, is overexpressed in breast cancer cells relative to adjacent normal tissue. Additionally we have found potent antagonists of SET that activate PP2A, which leads to destabilization of c-Myc and deactivation of downstream signals from Akt. These compounds induce apoptosis in cancer cells with 90-200 nM potency but do not kill normal cells at doses up to 50-fold higher concentrations. This proposal provides for testing of COG compounds as anti-tumor agents for the treatment of breast cancer in murine xenograft models. If the proposed work is successful, it has the potential to add novel molecular targeted agents to the pharmacopeia for treatment of breast cancer. This would have a significant impact on treatment of breast cancer, and because molecular targeted therapies typically have fewer side effects, would have the potential to reduce the extreme physical burden on the cancer patient and could save thousands of lives each year. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Each year in the United States over 270,000 women will be diagnosed with breast cancer and over 40,000 will die from the disease. While multiple forms of breast cancer exist, a common theme in most of the forms involves aberrations in signal transduction pathways that lead to inhibition of the programmed cell death process known as apoptosis. Oncotide Pharmaceuticals has discovered novel compounds that antagonize the activity of an oncogene that is overexpressed in breast cancer cells relative to normal adjacent tissue and potently and selectively induce cell death in cancer cells with minimal effects in normal cells. This proposal provides for testing of the lead compound in this series as anti-tumor agents for the treatment of breast cancer in murine xenograft models. If the proposed work is successful, it has the potential to add novel molecular targeted agents to the pharmacopeia for treatment of breast cancer. This wouldhave a significant impact on treatment of breast cancer, and because molecular targeted therapies typically have fewer side effects, would have the potential to reduce the extreme physical burden on the cancer patient and could save thousands of lives each year.


PubMed | Oregon Health And Science University, Randall Childrens Hospital at Legacy Emanuel, Oncotide Pharmaceuticals, Inc., Dana-Farber Cancer Institute and University of Navarra
Type: Journal Article | Journal: Oncotarget | Year: 2016

Recent evidence suggests that inhibition of protein phosphatase 2A (PP2A) tumor suppressor activity via the SET oncoprotein contributes to the pathogenesis of various cancers. Here we demonstrate that both SET and c-MYC expression are frequently elevated in T-ALL cell lines and primary samples compared to healthy T cells. Treatment of T-ALL cells with the SET antagonist OP449 restored the activity of PP2A and reduced SET interaction with the PP2A catalytic subunit, resulting in a decrease in cell viability and c-MYC expression in a dose-dependent manner. Since a tight balance between phosphatases and kinases is required for the growth of both normal and malignant cells, we sought to identify a kinase inhibitor that would synergize with SET antagonism. We tested various T-ALL cell lines against a small-molecule inhibitor screen of 66 compounds targeting two-thirds of the tyrosine kinome and found that combined treatment of T-ALL cells with dovitinib, an orally active multi-targeted small-molecule receptor tyrosine kinase inhibitor, and OP449 synergistically reduced the viability of all tested T-ALL cell lines. Mechanistically, combined treatment with OP449 and dovitinib decreased total and phospho c-MYC levels and reduced ERK1/2, AKT, and p70S6 kinase activity in both NOTCH-dependent and independent T-ALL cell lines. Overall, these results suggest that combined targeting of tyrosine kinases and activation of serine/threonine phosphatases may offer novel therapeutic strategies for the treatment of T-ALL.


PubMed | Oregon Health And Science University and Oncotide Pharmaceuticals, Inc.
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

The transcription factor c-MYC is stabilized and activated by phosphorylation at serine 62 (S62) in breast cancer. Protein phosphatase 2A (PP2A) is a critical negative regulator of c-MYC through its ability to dephosphorylate S62. By inactivating c-MYC and other key signaling pathways, PP2A plays an important tumor suppressor function. Two endogenous inhibitors of PP2A, I2PP2A, Inhibitor-2 of PP2A (SET oncoprotein) and cancerous inhibitor of PP2A (CIP2A), inactivate PP2A and are overexpressed in several tumor types. Here we show that SET is overexpressed in about 50-60% and CIP2A in about 90% of breast cancers. Knockdown of SET or CIP2A reduces the tumorigenic potential of breast cancer cell lines both in vitro and in vivo. Treatment of breast cancer cells in vitro or in vivo with OP449, a novel SET antagonist, also decreases the tumorigenic potential of breast cancer cells and induces apoptosis. We show that this is, at least in part, due to decreased S62 phosphorylation of c-MYC and reduced c-MYC activity and target gene expression. Because of the ubiquitous expression and tumor suppressor activity of PP2A in cells, as well as the critical role of c-MYC in human cancer, we propose that activation of PP2A (here accomplished through antagonizing endogenous inhibitors) could be a novel antitumor strategy to posttranslationally target c-MYC in breast cancer.


Trakhtenberg E.F.,University of Miami | Morkin M.I.,University of Miami | Morkin M.I.,University of California at San Diego | Patel K.H.,University of Miami | And 15 more authors.
Journal of Biological Chemistry | Year: 2015

Set-β protein plays different roles in neurons, but the diversity of Set-β neuronal isoforms and their functions have not been characterized. The expression and subcellular localization of Set-β are altered in Alzheimer disease, cleavage of Set-β leads to neuronal death after stroke, and the full-length Set-β regulates retinal ganglion cell (RGC) and hippocampal neuron axon growth and regeneration in a subcellular localization-dependent manner. Here we used various biochemical approaches to investigate Set-β isoforms and their role in the CNS, using the same type of neurons, RGCs, across studies. We found multiple alternatively spliced isoforms expressed from the Set locus in purified RGCs. Set transcripts containing the Set-β-specific exon were the most highly expressed isoforms. We also identified a novel, alternatively spliced Set-β transcript lacking the nuclear localization signal and demonstrated that the full-length (∼39-kDa) Set-β is localized predominantly in the nucleus, whereas a shorter (∼25-kDa) Set-β isoform is localized predominantly in the cytoplasm. Finally, we show that an N-terminal Set-β cleavage product can induce neuronal death. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.


PubMed | The Prostate Center at Vancouver General Hospital Vancouver, Mount Sinai School of Medicine, Oncotide Pharmaceuticals, Inc. and Shanghai JiaoTong University
Type: | Journal: Scientific reports | Year: 2015

The PP2A signaling axis regulates multiple oncogenic drivers of castration resistant prostate cancer (CRPC). We show that targeting the endogenous PP2A regulator, SET (I2PP2A), is a viable strategy to inhibit prostate cancers that are resistant to androgen deprivation therapy. Our data is corroborated by analysis of prostate cancer patient cohorts showing significant elevation of SET transcripts. Tissue microarray analysis reveals that elevated SET expression correlates with clinical cancer grading, duration of neoadjuvant hormone therapy (NHT) and time to biochemical recurrence. Using prostate regeneration assays, we show that in vivo SET overexpression is sufficient to induce hyperplasia and prostatic intraepithelial neoplasia. Knockdown of SET induced significant reductions in tumorgenesis both in murine and human xenograft models. To further validate SET as a therapeutic target, we conducted in vitro and in vivo treatments using OP449 - a recently characterized PP2A-activating drug (PAD). OP449 elicits robust anti-cancer effects inhibiting growth in a panel of enzalutamide resistant prostate cancer cell lines. Using the Pten conditional deletion mouse model of prostate cancer, OP449 potently inhibited PI3K-Akt signaling and impeded CRPC progression. Collectively, our data supports a critical role for the SET-PP2A signaling axis in CRPC progression and hormone resistant disease.


Farrell A.S.,Oregon Health And Science University | Allen-Petersen B.,Oregon Health And Science University | Daniel C.J.,Oregon Health And Science University | Wang X.,Oregon Health And Science University | And 10 more authors.
Molecular Cancer Research | Year: 2014

Pancreatic cancer is a deadly disease that is usually diagnosed in the advanced stages when few effective therapies are available. Given the aggressive clinical course of this disease and lack of good treatment options, the development of new therapeutic agents for the treatment of pancreatic cancer is of the upmost importance. Several pathways that have shown to contribute to pancreatic cancer progression are negatively regulated by the tumor suppressor protein phosphatase 2A (PP2A). Here, the endogenous inhibitors of PP2A, SET (also known as I2PP2A) and cancerous inhibitor of PP2A (CIP2A), were shown to be overexpressed in human pancreatic cancer, contributing to decreased PP2A activity and overexpression and stabilization of the oncoprotein c-Myc, a key PP2A target. Knockdown of SET or CIP2A increases PP2A activity, increases c-Myc degradation, and decreases the tumorigenic potential of pancreatic cancer cell lines both in vitro and in vivo . Moreover, treatment with a novel SET inhibitor, OP449, pharmacologically recapitulates the phenotypes and significantly reduces proliferation and tumorigenic potential of several pancreatic cancer cell lines, with an accompanying attenuation of cell growth and survival signaling. Furthermore, primary cells from patients with pancreatic cancer were sensitive to OP449 treatment, indicating that PP2A-regulated pathways are highly relevant to this deadly disease. Implications: The PP2A inhibitors SET and CIP2A are overexpressed in human pancreatic cancer and are important for pancreatic cancer cell growth and transformation; thus, antagonizing SET and/or CIP2A may be an innovative approach for the treatment of human pancreatic cancer. ©2014 AACR.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 300.00K | Year: 2012

DESCRIPTION (provided by applicant): 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 Ablkinase. 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, Gleevecresistant 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 asInhibitor-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. Basedon 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. PUBLIC HEALTH RELEVANCE: 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 benefitto 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.


PubMed | Oncotide Pharmaceuticals, Inc., University of Miami, Wayne State University, Bascom Palmer Eye Institute and Interdisciplinary Stem Cell Institute and and 3 more.
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2015

Set- protein plays different roles in neurons, but the diversity of Set- neuronal isoforms and their functions have not been characterized. The expression and subcellular localization of Set- are altered in Alzheimer disease, cleavage of Set- leads to neuronal death after stroke, and the full-length Set- regulates retinal ganglion cell (RGC) and hippocampal neuron axon growth and regeneration in a subcellular localization-dependent manner. Here we used various biochemical approaches to investigate Set- isoforms and their role in the CNS, using the same type of neurons, RGCs, across studies. We found multiple alternatively spliced isoforms expressed from the Set locus in purified RGCs. Set transcripts containing the Set--specific exon were the most highly expressed isoforms. We also identified a novel, alternatively spliced Set- transcript lacking the nuclear localization signal and demonstrated that the full-length (39-kDa) Set- is localized predominantly in the nucleus, whereas a shorter (25-kDa) Set- isoform is localized predominantly in the cytoplasm. Finally, we show that an N-terminal Set- cleavage product can induce neuronal death.


Christensen D.J.,Oncotide Pharmaceuticals, Inc. | Christensen D.J.,Duke University | Chen Y.,Duke University | Oddo J.,Oncotide Pharmaceuticals, Inc. | And 15 more authors.
Blood | Year: 2011

B-cell chronic lymphocytic leukemia (CLL), an incurable leukemia, is characterized by defective apoptosis. We found that the SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A) tumor suppressor, is overexpressed in primary CLL cells and B-cell non-Hodgkin lymphoma (NHL) cell line cells. In CLL, increased levels of SET correlated significantly with disease severity (shorter time to treatment and overall survival). We developed SET antagonist peptides that bound SET, increased cellular PP2A activity, decreased Mcl-1 expression, and displayed selective cytotoxicity for CLL and NHL cells in vitro. In addition, shRNA for SET was cytotoxic for NHL cells in vitro. The SET antagonist peptide COG449 inhibited growth of NHL tumor xenografts in mice. These data demonstrate that SET is a new treatment target in B-cell malignancies and that SET antagonists represent novel agents for treatment of CLL and NHL.


B-cell chronic lymphocytic leukemia (CLL), an incurable leukemia, is characterized by defective apoptosis. We found that the SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A) tumor suppressor, is overexpressed in primary CLL cells and B-cell non-Hodgkin lymphoma (NHL) cell line cells. In CLL, increased levels of SET correlated significantly with disease severity (shorter time to treatment and overall survival). We developed SET antagonist peptides that bound SET, increased cellular PP2A activity, decreased Mcl-1 expression, and displayed selective cytotoxicity for CLL and NHL cells in vitro. In addition, shRNA for SET was cytotoxic for NHL cells in vitro. The SET antagonist peptide COG449 inhibited growth of NHL tumor xenografts in mice. These data demonstrate that SET is a new treatment target in B-cell malignancies and that SET antagonists represent novel agents for treatment of CLL and NHL.

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