Stephen H Parsons

Publications (5)38.88 Total impact

• Article: Therapeutic inhibition of MAP kinase interacting kinase blocks eukaryotic initiation factor 4E phosphorylation and suppresses outgrowth of experimental lung metastases.

  Bruce W Konicek, Jennifer R Stephens, Ann M McNulty, Nathaniel Robichaud, Robert B Peery, Chad A Dumstorf, Michele S Dowless, Philip W Iversen, Stephen Parsons, Karen E Ellis, Denis J McCann, Jerry Pelletier, Luc Furic, Jonathan M Yingling, Louis F Stancato, Nahum Sonenberg, Jeremy R Graff
  [show abstract] [hide abstract]
  ABSTRACT: Activation of the translation initiation factor 4E (eIF4E) promotes malignant transformation and metastasis. Signaling through the AKT-mTOR pathway activates eIF4E by phosphorylating the inhibitory 4E binding proteins (4E-BP). This liberates eIF4E and allows binding to eIF4G. eIF4E can then be phosphorylated at serine 209 by the MAPK-interacting kinases (Mnk), which also interact with eIF4G. Although dispensable for normal development, Mnk function and eIF4E phosphorylation promote cellular proliferation and survival and are critical for malignant transformation. Accordingly, Mnk inhibition may serve as an attractive cancer therapy. We now report the identification of a potent, selective and orally bioavailable Mnk inhibitor that effectively blocks 4E phosphorylation both in vitro and in vivo. In cultured cancer cell lines, Mnk inhibitor treatment induces apoptosis and suppresses proliferation and soft agar colonization. Importantly, a single, orally administered dose of this Mnk inhibitor substantially suppresses eIF4E phosphorylation for at least 4 hours in human xenograft tumor tissue and mouse liver tissue. Moreover, oral dosing with the Mnk inhibitor significantly suppresses outgrowth of experimental B16 melanoma pulmonary metastases as well as growth of subcutaneous HCT116 colon carcinoma xenograft tumors, without affecting body weight. These findings offer the first description of a novel, orally bioavailable MNK inhibitor and the first preclinical proof-of-concept that MNK inhibition may provide a tractable cancer therapeutic approach.
  Cancer Research 01/2011; 71(5):1849-57. · 7.86 Impact Factor
• Article: Modulation of 4E-BP1 function as a critical determinant of enzastaurin-induced apoptosis.

  Chad A Dumstorf, Bruce W Konicek, Ann M McNulty, Stephen H Parsons, Luc Furic, Nahum Sonenberg, Jeremy R Graff
  [show abstract] [hide abstract]
  ABSTRACT: Enzastaurin (LY317615.HCl) is currently in a phase III registration trial for diffuse large B-Cell lymphoma and numerous phase II clinical trials. Enzastaurin suppresses angiogenesis and induces apoptosis in multiple human tumor cell lines by inhibiting protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/AKT pathway signaling. PI3K/AKT pathway signaling liberates eukaryotic translation initiation factor 4E (eIF4E) through the hierarchical phosphorylation of eIF4E binding proteins (4E-BP). When hypophosphorylated, 4E-BPs associate with eIF4E, preventing eIF4E from binding eIF4G, blocking the formation of the eIF4F translation initiation complex. Herein, we show that enzastaurin treatment impacts signaling throughout the AKT/mTOR pathway leading to hypophosphorylation of 4E-BP1 in cancer cells of diverse lineages (glioblastoma, colon carcinoma, and B-cell lymphoma). Accordingly, enzastaurin treatment increases the amount of eIF4E bound to 4E-BP1 and decreases association of eIF4E with eIF4G, thereby reducing eIF4F translation initiation complex levels. We therefore chose to evaluate whether this effect on 4E-BP1 was involved in enzastaurin-induced apoptosis. Remarkably, enzastaurin-induced apoptosis was blocked in cancer cells depleted of 4E-BP1 by siRNAs, or in 4EBP1/2 knockout murine embryonic fibroblasts cells. Furthermore, eIF4E expression was increased and 4E-BP1 expression was decreased in cancer cells selected for reduced sensitivity to enzastaurin-induced apoptosis. These data highlight the importance of modulating 4E-BP1 function, and eIF4F complex levels, in the direct antitumor effect of enzastaurin and suggest that 4E-BP1 function may serve as a promising determinant of enzastaurin activity.
  Molecular Cancer Therapeutics 10/2010; 9(12):3158-63. · 5.23 Impact Factor
• Article: eIF4E activation is commonly elevated in advanced human prostate cancers and significantly related to reduced patient survival.

  Jeremy R Graff, Bruce W Konicek, Rebecca L Lynch, Chad A Dumstorf, Michele S Dowless, Ann M McNulty, Stephen H Parsons, Leslie H Brail, Bruce M Colligan, Jonathan W Koop, Bernadette M Hurst, James A Deddens, Blake L Neubauer, Louis F Stancato, Harry W Carter, Larry E Douglass, Julia H Carter
  [show abstract] [hide abstract]
  ABSTRACT: Elevated eukaryotic translation initiation factor 4E (eIF4E) function induces malignancy in experimental models by selectively enhancing translation of key malignancy-related mRNAs (c-myc and BCL-2). eIF4E activation may reflect increased eIF4E expression or phosphorylation of its inhibitory binding proteins (4E-BP). By immunohistochemical analyses of 148 tissues from 89 prostate cancer patients, we now show that both eIF4E expression and 4E-BP1 phosphorylation (p4E-BP1) are increased significantly, particularly in advanced prostate cancer versus benign prostatic hyperplasia tissues. Further, increased eIF4E and p4E-BP1 levels are significantly related to reduced patient survival, whereas uniform 4E-BP1 expression is significantly related to better patient survival. Both immunohistochemistry and Western blotting reveal that elevated eIF4E and p4E-BP1 are evident in the same prostate cancer tissues. In two distinct prostate cancer cell models, the progression to androgen independence also involves increased eIF4E activation. In these prostate cancer cells, reducing eIF4E expression with an eIF4E-specific antisense oligonucleotide currently in phase I clinical trials robustly induces apoptosis, regardless of cell cycle phase, and reduces expression of the eIF4E-regulated proteins BCL-2 and c-myc. Collectively, these data implicate eIF4E activation in prostate cancer and suggest that targeting eIF4E may be attractive for prostate cancer therapy.
  Cancer Research 05/2009; 69(9):3866-73. · 7.86 Impact Factor
• Article: Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity.

  Jeremy R Graff, Bruce W Konicek, Thomas M Vincent, Rebecca L Lynch, David Monteith, Spring N Weir, Phil Schwier, Andrew Capen, Robin L Goode, Michele S Dowless, [......], Lillian Sams, Sandaruwan Geeganage, Larry E Douglass, Blake Lee Neubauer, Nicholas M Dean, Kerry Blanchard, Jianyong Shou, Louis F Stancato, Julia H Carter, Eric G Marcusson
  [show abstract] [hide abstract]
  ABSTRACT: Expression of eukaryotic translation initiation factor 4E (eIF4E) is commonly elevated in human and experimental cancers, promoting angiogenesis and tumor growth. Elevated eIF4E levels selectively increase translation of growth factors important in malignancy (e.g., VEGF, cyclin D1) and is thereby an attractive anticancer therapeutic target. Yet to date, no eIF4E-specific therapy has been developed. Herein we report development of eIF4E-specific antisense oligonucleotides (ASOs) designed to have the necessary tissue stability and nuclease resistance required for systemic anticancer therapy. In mammalian cultured cells, these ASOs specifically targeted the eIF4E mRNA for destruction, repressing expression of eIF4E-regulated proteins (e.g., VEGF, cyclin D1, survivin, c-myc, Bcl-2), inducing apoptosis, and preventing endothelial cells from forming vessel-like structures. Most importantly, intravenous ASO administration selectively and significantly reduced eIF4E expression in human tumor xenografts, significantly suppressing tumor growth. Because these ASOs also target murine eIF4E, we assessed the impact of eIF4E reduction in normal tissues. Despite reducing eIF4E levels by 80% in mouse liver, eIF4E-specific ASO administration did not affect body weight, organ weight, or liver transaminase levels, thereby providing the first in vivo evidence that cancers may be more susceptible to eIF4E inhibition than normal tissues. These data have prompted eIF4E-specific ASO clinical trials for the treatment of human cancers.
  Journal of Clinical Investigation 10/2007; 117(9):2638-48. · 15.39 Impact Factor
• Article: Discovery of non-covalent dipeptidyl peptidase IV inhibitors which induce a conformational change in the active site.

  Scott M Sheehan, Hans-Juergen Mest, Brian M Watson, Valentine J Klimkowski, David E Timm, Annick Cauvin, Stephen H Parsons, Qing Shi, Emily J Canada, Michael R Wiley, [......], Brandon J Margolis, Graham N Wishart, Beatrice Renson, Dirk Hankotius, Michael Mohr, Johann-Christian Zechel, J Michael Kalbfleisch, Elizabeth A Dingess-Hammond, Andre Boelke, Andreas G Weichert
  [show abstract] [hide abstract]
  ABSTRACT: A series of non-covalent inhibitors of the serine protease dipeptidyl peptidase IV (DPP-IV) were found to adopt a U-shaped binding conformation in X-ray co-crystallization studies. Remarkably, Tyr547 undergoes a 70 degrees side-chain rotation to accommodate the inhibitor and allows access to a previously unexposed area of the protein backbone for hydrogen bonding.
  Bioorganic & Medicinal Chemistry Letters 04/2007; 17(6):1765-8. · 2.55 Impact Factor