Brittany Allen-Petersen

Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer

Significance Increased kinase activity and suppressed phosphatase activity are hallmarks of oncogenic signaling. The transcription factor c-MYC, a master driver of human cancer, is stabilized and activated by persistent serine 62 phosphorylation. The tumor suppressor protein phosphatase 2A (PP2A) targets this site and negatively regulates c-MYC. Here, we show that two cellular inhibitors of PP2A, the SET oncoprotein and cancerous inhibitor of PP2A (CIP2A), are overexpressed in breast cancer, and depletion or inhibition of SET or CIP2A reduces c-MYC expression and activity and decreases the tumorigenic potential of breast cancer cells. These findings strongly suggest that inhibiting SET or CIP2A to reactivate PP2A may be an effective therapeutic strategy for targeting c-MYC in breast cancer. 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.

Targeting Inhibitors of the Tumor Suppressor PP2A for the Treatment of Pancreatic Cancer

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. Mol Cancer Res; 12(6); 924–39. ©2014 AACR.

MYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemoresistance.

Intratumoral phenotypic heterogeneity has been described in many tumor types, where it can contribute to drug resistance and disease recurrence. We analyzed ductal and neuroendocrine markers in pancreatic ductal adenocarcinoma, revealing heterogeneous expression of the neuroendocrine marker Synaptophysin within ductal lesions. Higher percentages of Cytokeratin-Synaptophysin dual positive tumor cells correlate with shortened disease-free survival. We observe similar lineage marker heterogeneity in mouse models of pancreatic ductal adenocarcinoma, where lineage tracing indicates that Cytokeratin-Synaptophysin dual positive cells arise from the exocrine compartment. Mechanistically, MYC binding is enriched at neuroendocrine genes in mouse tumor cells and loss of MYC reduces ductal-neuroendocrine lineage heterogeneity, while deregulated MYC expression in KRAS mutant mice increases this phenotype. Neuroendocrine marker expression is associated with chemoresistance and reducing MYC levels decreases gemcitabine-induced neuroendocrine marker expression and increases chemosensitivity. Altogether, we demonstrate that MYC facilitates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma, contributing to poor survival and chemoresistance.Neuroendocrine differentiation of epithelial tumor cells can contribute to cancer cell resistance and survival. Here, the authors show that dysregulated c-Myc promotes neuroendocrine differentiation in pancreatic ductal adenocarcinoma, leading to poor survival and chemoresistance.

Abstract B51: Modeling the intrinsic and extrinsic influences on breast cancer phenotypic heterogeneity using mouse models and three-dimensional bioprinting

Breast cancer cells exhibit intertumoral and intratumoral heterogeneity due to both tumor cell intrinsic and extrinsic influence. We have been modeling phenotypic heterogeneity in breast cancer using multiple model systems to interrogate the causes of this heterogeneity as well as its effects on therapeutic resistance. Toward this end, we generated a novel, genetically-engineered mouse model of triple negative breast cancer driven by loss of PTEN in combination with low-level deregulated c-Myc expression. Expression of deregulated Myc significantly accelerates tumorigenesis in this model. Histologic and global gene expression analyses reveal that this model generates predominately two phenotypic groups within triple negative breast cancer. One group is composed of fibrotic tumors that have increased ECM deposition as well as increased alpha-Smooth Muscle Actin (SMA) and Fibroblast Associated Protein (FAP) expression in the stroma. These tumors express a Claudin-low molecular signature and have high p-SMAD3 expression. The second group is composed of adenocarcinomas that have less stromal involvement and decreased ECM deposition. In preliminary studies, the more fibrotic tumors exhibit increased resistance to targeted therapeutics. To better understand if this resistance is due to intrinsic or extrinsic influence, we are generating primary cultures of both the tumor and stromal cells from these mice. Through additional in vitro and in vivo studies, we will interrogate the mechanisms of therapeutic resistance. To build upon this approach, we are also utilizing three-dimensional bioprinting to model the heterogeneity of tumor/stroma interactions with human cell lines or primary cultures. For this model, we surround breast cancer cells with stromal cells of the tumor microenvironment, including fibroblasts and endothelial cells. As the structures mature over the course of 1-3 weeks, the cells within these tissues self-organize and respond to extrinsic signals. In this system, we can assess the contribution of distinct cell types to the overall histology of the tissues as well as interrogate the mechanisms driving specific phenotypes by manipulating either the tumor or stromal cells prior to printing. Together, analysis of both the mouse models and bioprinted human tissues will help reveal nodes of crosstalk between breast tumor cells and cells within the microenvironment that affect baseline phenotypic heterogeneity and/or therapeutic efficacy. Citation Format: Ellen M. Langer, Xiaoyan Wang, Juan Liang, Brittany L. Allen-Petersen, Nicholas D. Kendsersky, Tyler Risom, Carl Pelz, Rosalie C. Sears. Modeling the intrinsic and extrinsic influences on breast cancer phenotypic heterogeneity using mouse models and three-dimensional bioprinting. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B51.

Abstract B21: Protein phosphatase 2A (PP2A) activation functions synergistically with kinase inhibition in pancreatic cancer

The 5-year survival rate for pancreatic cancer patients is only 6%, the lowest of all major cancers, indicating a critical need for increased understanding of pancreatic cancer development and identification of new therapeutic targets. Several genetic mutations are associated with the progression of human pancreatic ductal adenocarcinoma, including KRAS, which is mutated in ~95% of all pancreatic ductal adenocarcinomas (PDAC). Targeted therapies, such as kinase inhibitors, provide a means to reduce oncogenic signaling pathways that drive pancreatic cancer; however, the presence of resistance mechanisms, through extensive feedback loops, reduces the clinical efficacy of single agent treatments. Protein Phosphatase 2A (PP2A) is a critical tumor suppressor that negatively regulates several key oncogenic pathways implicated in mediating therapeutic resistance, including the PI3K/Akt, RAS/ERK, and Myc pathways. The goal of this research is to identify the therapeutic benefit of combined phosphatase activation and kinase inhibition, as a means to attenuate resistance mechanisms, reduce pancreatic tumor growth, and improve therapeutic efficacy in pancreatic cancer patients. We have determined that SET, an endogenous inhibitor of PP2A, is overexpressed in pancreatic cancer cell lines and primary patient samples, suggesting that suppression of PP2A contributes to pancreatic oncogenic signaling. As a result, we have started investigating the therapeutic efficacy of two novel therapeutic agents that activate PP2A: OP449, a SET antagonist, and DT1154, a small molecule direct PP2A activator. Treatment of pancreatic cancer cell lines with these compounds results in increased PP2A activity, reduced MYC levels, and reduced tumorigenic potential both in vitro and in vivo. Since these compounds reduce oncogenic signals known to contribute to pancreatic cancer, we hypothesize that phosphatase activation will function synergistically with select kinase inhibitors, resulting in sustained attenuation of oncogenic signaling in pancreatic cancer cells. In order to identify pathways that function synergistically with PP2A activation, a panel of pancreatic cancer cell lines was plated with and without OP449 into a 384-well kinase inhibitor (KI) screen, which evaluates the efficacy of over 130 kinase inhibitors at seven serial dilutions spanning the predicted IC50. Several signaling nodes were found to be synergistic with OP449, with the PI3K/AKT/mTOR pathways being particularly susceptible. Specifically, the combination of OP449 with Ink128, an mTOR1/2 inhibitor, reduced pancreatic cancer cell survival, oncogenic signaling, and transformed phenotypes, over either drug alone. These results provide new insight into our understanding of the regulation of pancreatic oncogenic signaling by phosphatases and identify new combination therapies that reduce resistance mechanisms. Citation Format: Brittany L. Allen-Petersen, Amy S. Farrell, Zina P. Jenny, Colin J. Daniel, Zhiping Wang, Charles D. Lopez, Dale J. Christensen, Goutham Narla, Brett C. Sheppard, Rosalie C. Sears. Protein phosphatase 2A (PP2A) activation functions synergistically with kinase inhibition in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B21.

Abstract IA10: Post-translational regulation of MYC's oncogenic activity

In response to growth stimulatory signals in normal cells or in transformed cells with constitutive signaling, the c-Myc oncoprotein is post-translationally stabilized through enhanced phosphorylation at the conserved Serine 62 residue. In addition to increasing c-Myc stability, phosphorylation at Serine 62 (pS62-Myc), in conjunction with Proline 63 isomerization mediated by the Pin1 Proline Isomerase, also increases the rate of recruitment of newly synthesized c-Myc to its target genes involved in pro-proliferative phenotypes, enhancing their expression. In normal cells, phosphorylation of S62 primes phosphorylation at a second conserved residue, Threonine 58 (pT58), which then enhance c-Myc degradation by facilitating a second Pin1-mediated isomerization event, which promotes Protein Phosphatase 2A (PP2A-B56α)-mediated dephosphorylation of Serine 62 and recruits the E3 ubiquitin ligase, SCFFbw7. In cancer cell lines as well as patient tumor samples pS62-Myc is elevated relative to non-transformed cell lines or adjacent normal tissue. In order to study the role of pS62-Myc in vivo, we created c-Myc knock-in mice that express either Myc wild-type (WT) or the MycT58A or MycS62A phosphorylation mutant from the ROSA26 locus in response to Cre-recombinase. Analysis of these mice revealed increased tumorigenic potential of MycT58A, which has constitutive S62 phosphorylation as it is resistant to PP2A-mediated S62 dephosphorylation. Together, this research has revealed an important role for S62 phosphorylation and Pin1-mediated isomerization in the tumorigenic activity of c-Myc, which presents new strategies to target c-Myc by inhibiting these post-translational activation steps. Thus, we are currently testing the therapeutic efficacy of PP2A activation and Pin1 inhibition in mouse models of c-Myc-driven tumorigenesis. To create physiologically relevant c-Myc-driven tumor models that engage post-translational activation of c-Myc, we have crossed our ROSA-LSL-MycWT mice with mice carrying organ-relevant oncogenic signaling transgenes. Thus far, we have generated mouse models of Her2+ and Triple Negative breast cancer, and pancreatic cancer. We have demonstrated dramatic tumor growth inhibition with a novel, orally available small molecule PP2A activator drug in these mouse models. Citation Format: Rosalie Sears, Amy Farrell, Xiaoyan Wang, Juan Liang, Mahnaz Janghorban, Yulong Su, Brittany Allen-Petersen, Michael Ohlemeyer, Narla Goutham. Post-translational regulation of MYC9s oncogenic activity. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA10.

Abstract A104: Phosphatase activation and kinase inhibition as a novel therapeutic strategy for pancreatic cancer

The 5-year survival rate for pancreatic cancer patients is only 6%, the lowest of all major cancers, indicating a critical need for increased understanding of pancreatic cancer development and identification of new therapeutic targets. Several genetic mutations are associated with the progression of human pancreatic ductal adenocarcinoma, including KRAS, which is mutated in ~95% of all pancreatic ductal adenocarcinomas (PDAC). Targeted therapies, such as kinase inhibitors, provide a means to reduce oncogenic signaling pathways that drive pancreatic cancer; however, the presence of resistance mechanisms, through extensive feedback loops, reduces the clinical efficacy of single agent treatments. Protein Phosphatase 2A (PP2A) is a critical tumor suppressor that negatively regulates several key oncogenic pathways implicated in mediating therapeutic resistance, including the PI3K/Akt, RAS/ERK, and Myc pathways. The goal of this research is to identify the therapeutic benefit of combined phosphatase activation and kinase inhibition, as a means to attenuate resistance mechanisms, reduce pancreatic tumor growth, and improve therapeutic efficacy in pancreatic cancer patients. We have determined that SET, an endogenous inhibitor of PP2A, is overexpressed in pancreatic cancer cell lines and primary patient samples, suggesting that suppression of PP2A contributes to pancreatic oncogenic signaling. Therapeutic inhibition of SET utilizing a novel SET antagonist, OP449, leads to increased PP2A activity and significant cytotoxic activity in pancreatic cancer cells in vitro and in vivo. Importantly, these results correlate with reduced activation of pathways known to contribute to therapeutic resistance, including c-Myc and Akt. I hypothesize that phosphatase activation will function synergistically with select kinase inhibitors, resulting in sustained attenuation of oncogenic signaling in pancreatic cancer cells. In order to identify pathways that function synergistically with PP2A activation, a panel of pancreatic cancer cell lines was plated with and without OP449 into a 384-well kinase inhibitor (KI) screen, which evaluates the efficacy of over 130 kinase inhibitors at seven serial dilutions spanning the predicted IC50. Several signaling nodes were found to be synergistic with OP449, with the PI3K/AKT/mTOR pathways being particularly susceptible. Specifically, the combination of OP449 with Ink128, an mTOR1/2 inhibitor, reduced pancreatic cancer cell survival, oncogenic signaling, and transformed phenotypes, over either drug alone. These results provide new insight into our understanding of the regulation of pancreatic oncogenic signaling by phosphatases and identify new combination therapies that reduce resistance mechanisms. Citation Format: Brittany L. Allen-Petersen, Amy S. Farrell, Colin J. Daniel, Zhiping Wang, Charles D. Lopez, Dale J. Christensen, Brett C. Sheppard, Rosalie C. Sears. Phosphatase activation and kinase inhibition as a novel therapeutic strategy for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A104.

Abstract A89: Targeting the MYC activation and degradation pathway for the treatment of pancreatic cancer

Pancreatic cancer is a disease with a high rate of mortality, as it is generally diagnosed in the advanced stages when few effective treatments are available. Given the clinical aggressivity of this disease and lack of good treatment options, the development of new therapeutic agents is of the upmost importance. The c-MYC (MYC) oncoprotein is a critical transcription factor that regulates many diverse cellular functions by either activating or suppressing downstream target genes. High levels of MYC expression occur in a wide variety of human tumors, and animal models demonstrate MYC-induced tumorigenesis in many tissues. It has been shown that the MYC gene is frequently amplified in human pancreatic cancer and that MYC mRNA and/or protein are often overexpressed. However, what pathways contribute to this overexpression or whether MYC can be therapeutically targeted in pancreatic cancer is yet not known. Work in our laboratory has elucidated a complex signaling pathway that regulates MYC protein stability and transcriptional activity. RAS activation in early G1 leads to ERK-dependent phosphorylation of MYC at Serine62 (pS62-MYC), which stabilizes MYC. pS62-MYC is then recognized by the phosphorylation-directed Pin1 prolyl isomerase, which isomerizes Proline63 (P63) to cis , enhancing MYC’s recruitment to, and transactivation of, pro-growth target genes. Later in G1, when RAS activation decreases, GSK3β phosphorylates MYC at T58 (pT58-MYC). Following a second isomerization by Pin1, the trans -specific phosphatase PP2A-B56α removes the stabilizing S62 phosphate. pT58-MYC is then recognized by the E3 ubiquitin ligase SCF Fbw7 and degraded by the proteasome. We have found that this pathway is frequently deregulated in human cancer leading to elevated pS62, decreased pT58, and increased c-Myc stability and activity. Here, we show that MYC is overexpressed and stabilized in pancreatic cancer cells. Additionally, we find aberrant MYC phosphorylation in primary human pancreatic cancer tissue, suggesting that the pathway that controls MYC phosphorylation is deregulated in human pancreatic cancer. Therefore, we hypothesized that the pathways regulating MYC phosphorylation and activation might represent new therapeutic targets. We are pursuing two different approaches to target MYC in pancreatic cancer: 1) inhibiting Pin1, the prolyl isomerase that co-activates pS62-MYC, and 2) activation of PP2A, the phosphatase that destabilizes MYC protein. We have observed decreased PP2A activity in pancreatic cancer cells, and have found that two endogenous inhibitors of PP2A, SET and CIP2A, are frequently overexpressed in pancreatic cancer cells and primary patient samples. This overexpression correlates with aberrant phosphorylation and stabilization of MYC. Furthermore, knockdown of SET or CIP2A, or inhibition of SET using a peptide mimetic (OP449), increases PP2A activity and reduces the tumorigenic potential of pancreatic cancer cells both in vitro and in vivo. In addition to increased SET and CIP2A expression in pancreatic cancer, we also observe frequent overexpression of Pin1 in human pancreatic cancer cell lines and primary patient tumor tissue and find that Pin1 knockdown or inhibition reduces the oncogenic potential of pancreatic cancer cells both in vitro and in vivo. Together, these findings suggest that MYC may play an important role in pancreatic cancer, and that targeting the pathway that regulates MYC activity and protein stability may be a viable therapeutic approach for human pancreatic cancer. Citation Format: Amy S. Farrell, Brittany Allen-Petersen, Colin J. Daniel, Xiaoyan Wang, Zhiping Wang, Dale J. Christensen, Brett Sheppard, Rosalie C. Sears. Targeting the MYC activation and degradation pathway for the treatment of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A89.

Abstract B118: Developing a molecular and cellular atlas of pancreatic disease

Experimental results generated from human pancreatic ductal adenocarcinoma (PDAC) specimens have produced a broad knowledge of pancreatic tumors. However, successful personalized treatment of pancreatic disease will require an exceptionally deep knowledge of the molecular and cellular diversity of tumors, as well as their evolution through the course of disease progression, therapeutics, relapse, and terminal disease burden. To address this need, we have conducted diverse but complementary experimental analyses on adjacent regions of fresh tumor specimens collected from over 70 primary pancreas specimens obtained during Whipple and RAMPS procedures. Coordination between surgical and research teams has ensured that only a minimum time elapses between surgical resection and specimen processing, thus limiting potential degradation by pancreatic enzymes. Researchers with diverse cancer biology expertise obtain adjacent dissections from three regions (i.e., tumor, dysplastic, and normal) within each pancreas specimen. An annotated image of the whole pancreas specimen records the location of each dissected portion relative to one another. Fresh tissues are immediately used to 1) characterize the phenotypic diversity of tumor and non-tumor cells in the microenvironment, 2) isolate and culture cancer stem cells, 3) perform high resolution imaging including 3D-SEM, 4) “bioprint” and culture three-dimensional, multi-cell-type structures, and 5) propagate tumors in mouse avatars. Genomics, epigenomics, and transcriptomics analyses are also performed on laser-captured specimens. In addition to primary PDAC tumors, other fresh pancreatic cancer specimens are being added to the collection including core needle biopsies obtained from treatment-naive patients, metastases removed during primary tumor resection or recurrence, and tumor specimens from a rapid autopsy program. Importantly, all specimens are fully clinically annotated as patients are followed through the course of their disease. By comprehensively characterizing individual pancreatic tumors from many patients we hope to produce a unique body of information – an “Atlas” of pancreatic disease – that will inform the research community of new molecular and cellular features that contribute to the progression and therapeutic resistance of this devastating disease. Research data and clinical information in the Atlas will be accessible through a user-friendly customizable database. We hope that this resource will support the development of molecularly targeted early detection, therapeutics, and prevention in order to improve patient care. Funding for this initiative comes from philanthropic support to the Brenden-Colson Center for Pancreatic Care at Oregon Health and Science University. Citation Format: Jason M. Link, Brittany Allen-Petersen, Andrew Gunderson, Danielle Jorgens, Craig Dorrell, Jody Hooper, Philip Streeter, Markus Grompe, Lisa Coussens, Joe Gray, Hope Hardaker, Charles D. Lopez, Rosalie C. Sears, Brett C. Sheppard. Developing a molecular and cellular atlas of pancreatic disease. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B118.

Abstract 1976: Targeting the PP2A tumor suppressor for the treatment of human pancreatic cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Pancreatic cancer is a disease with a high rate of mortality, as it is generally diagnosed in the advanced stages when few effective treatments are available. Given the clinical aggressivity of this disease and the lack of good treatment options, the development of new therapeutic agents for the treatment of pancreatic cancer is of the upmost importance. Recent reports have suggested that disruption of several key signal transduction pathways is important for the development of pancreatic cancer. Many of these pathways are negatively regulated by PP2A, a phosphatase that plays a role in many cellular processes, and whose inhibition is essential for cell transformation. PP2A inhibition can occur through inactivation by viral oncogenes, mutation of specific subunits, or by overexpression of endogenous inhibitors, including SET (also known as I2PP2A) and Cellular Inhibitor of PP2A (CIP2A). Here, we show that SET and CIP2A are frequently overexpressed in human pancreatic cancer cells and primary patient samples. This overexpression results in decreased PP2A activity, and overexpression and stabilization of a key PP2A target, c-Myc. Knockdown of SET or CIP2A increases PP2A activity and reduces tumorigenic potential. Furthermore, inhibition of SET using a peptide mimetic (OP449) in pancreatic cancer cell lines increases PP2A activity, reduces migration and invasion, and decreases tumorigenic potential. Thus, antagonizing SET and CIP2A could be an innovative approach for the treatment of human pancreatic cancer. Citation Format: Amy Farrell, Colin Daniel, Zhiping Wang, Brittany Allen-Petersen, Dale Christensen, Brett Sheppard, Charles D. Lopez, Rosalie Sears. Targeting the PP2A tumor suppressor for the treatment of human pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1976. doi:10.1158/1538-7445.AM2013-1976