Austin N Kirschner1, Jie Wang1, Riet van der Meer1, Philip D Anderson1, Omar E Franco-Coronel1, Max H Kushner1, Joel H Everett1, Omar Hameed1, Erika K Keeton1, Miika Ahdesmaki1, Shaun E Grosskurth1, Dennis Huszar1, Sarki A Abdulkadir2. 1. Department of Radiation Oncology (ANK), Department of Pathology, Microbiology and Immunology (JW, RvdM, JHE, OH, SAA), Department of Urology (OEFC), Department of Cancer Biology (SAA), Vanderbilt University Medical Center, Nashville, TN; Department of Biological Sciences, Salisbury University, Salisbury, MD (PDA); Department of Biological Sciences, Vanderbilt University, Nashville, TN (MHK); AstraZeneca, Oncology iMED, Waltham, MA (EKK, SEG, DH); AstraZeneca, R&D Information, Macclesfield, Cheshire, UK (MA); Currently at Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL (SAA). 2. Department of Radiation Oncology (ANK), Department of Pathology, Microbiology and Immunology (JW, RvdM, JHE, OH, SAA), Department of Urology (OEFC), Department of Cancer Biology (SAA), Vanderbilt University Medical Center, Nashville, TN; Department of Biological Sciences, Salisbury University, Salisbury, MD (PDA); Department of Biological Sciences, Vanderbilt University, Nashville, TN (MHK); AstraZeneca, Oncology iMED, Waltham, MA (EKK, SEG, DH); AstraZeneca, R&D Information, Macclesfield, Cheshire, UK (MA); Currently at Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL (SAA). sarki.abdulkadir@northwestern.edu.
Abstract
BACKGROUND: PIM1 kinase is coexpressed with c-MYC in human prostate cancers (PCs) and dramatically enhances c-MYC-induced tumorigenicity. Here we examine the effects of a novel oral PIM inhibitor, AZD1208, on prostate tumorigenesis and recurrence. METHODS: A mouse c-MYC/Pim1-transduced tissue recombination PC model, Myc-CaP allografts, and human PC xenografts were treated with AZD1208 (n = 5-11 per group). Androgen-sensitive and castrate-resistant prostate cancer (CRPC) models were studied as well as the effects of hypoxia and radiation. RNA sequencing was used to analyze drug-induced gene expression changes. Results were analyzed with χ(2) test. Student's t test and nonparametric Mann-Whitney rank sum U Test. All statistical tests were two-sided. RESULTS: AZD1208 inhibited tumorigenesis in tissue recombinants, Myc-CaP, and human PC xenograft models. PIM inhibition decreased c-MYC/Pim1 graft growth by 54.3 ± 39% (P < .001), decreased cellular proliferation by 46 ± 14% (P = .016), and increased apoptosis by 326 ± 170% (P = .039). AZD1208 suppressed multiple protumorigenic pathways, including the MYC gene program. However, it also downregulated the p53 pathway. Hypoxia and radiation induced PIM1 in prostate cancer cells, and AZD1208 functioned as a radiation sensitizer. Recurrent tumors postcastration responded transiently to either AZD1208 or radiation treatment, and combination treatment resulted in more sustained inhibition of tumor growth. Cell lines established from recurrent, AZD1208-resistant tumors again revealed downregulation of the p53 pathway. Irradiated AZD1208-treated tumors robustly upregulated p53, providing a possible mechanistic explanation for the effectiveness of combination therapy. Finally, an AZD1208-resistant gene signature was found to be associated with biochemical recurrence in PC patients. CONCLUSIONS: PIM inhibition is a potential treatment for MYC-driven prostate cancers including CRPC, and its effectiveness may be enhanced by activators of the p53 pathway, such as radiation.
BACKGROUND:PIM1 kinase is coexpressed with c-MYC in humanprostate cancers (PCs) and dramatically enhances c-MYC-induced tumorigenicity. Here we examine the effects of a novel oral PIM inhibitor, AZD1208, on prostate tumorigenesis and recurrence. METHODS: A mousec-MYC/Pim1-transduced tissue recombination PC model, Myc-CaP allografts, and human PC xenografts were treated with AZD1208 (n = 5-11 per group). Androgen-sensitive and castrate-resistant prostate cancer (CRPC) models were studied as well as the effects of hypoxia and radiation. RNA sequencing was used to analyze drug-induced gene expression changes. Results were analyzed with χ(2) test. Student's t test and nonparametric Mann-Whitney rank sum U Test. All statistical tests were two-sided. RESULTS:AZD1208 inhibited tumorigenesis in tissue recombinants, Myc-CaP, and human PC xenograft models. PIM inhibition decreased c-MYC/Pim1 graft growth by 54.3 ± 39% (P < .001), decreased cellular proliferation by 46 ± 14% (P = .016), and increased apoptosis by 326 ± 170% (P = .039). AZD1208 suppressed multiple protumorigenic pathways, including the MYC gene program. However, it also downregulated the p53 pathway. Hypoxia and radiation induced PIM1 in prostate cancer cells, and AZD1208 functioned as a radiation sensitizer. Recurrent tumors postcastration responded transiently to either AZD1208 or radiation treatment, and combination treatment resulted in more sustained inhibition of tumor growth. Cell lines established from recurrent, AZD1208-resistant tumors again revealed downregulation of the p53 pathway. Irradiated AZD1208-treated tumors robustly upregulated p53, providing a possible mechanistic explanation for the effectiveness of combination therapy. Finally, an AZD1208-resistant gene signature was found to be associated with biochemical recurrence in PC patients. CONCLUSIONS:PIM inhibition is a potential treatment for MYC-driven prostate cancers including CRPC, and its effectiveness may be enhanced by activators of the p53 pathway, such as radiation.
Authors: M J Scian; E H Carchman; L Mohanraj; K E R Stagliano; M A E Anderson; D Deb; B M Crane; T Kiyono; B Windle; S P Deb; S Deb Journal: Oncogene Date: 2007-11-05 Impact factor: 9.867
Authors: Kathryn A O'Donnell; Duonan Yu; Karen I Zeller; Jung-Whan Kim; Frederick Racke; Andrei Thomas-Tikhonenko; Chi V Dang Journal: Mol Cell Biol Date: 2006-03 Impact factor: 4.272
Authors: Philip A Watson; Katharine Ellwood-Yen; Jennifer C King; John Wongvipat; Michelle M Lebeau; Charles L Sawyers Journal: Cancer Res Date: 2005-12-15 Impact factor: 12.701
Authors: Andrew Macdonald; David G Campbell; Rachel Toth; Hilary McLauchlan; C James Hastie; J Simon C Arthur Journal: BMC Cell Biol Date: 2006-01-10 Impact factor: 4.241
Authors: Atish D Choudhury; Anna C Schinzel; Maura B Cotter; Rosina T Lis; Katherine Labella; Ying Jie Lock; Francesca Izzo; Isil Guney; Michaela Bowden; Yvonne Y Li; Jinal Patel; Emily Hartman; Steven A Carr; Monica Schenone; Jacob D Jaffe; Philip W Kantoff; Peter S Hammerman; William C Hahn Journal: Cancer Res Date: 2016-11-29 Impact factor: 12.701
Authors: Sabina Luszczak; Christopher Kumar; Vignesh Krishna Sathyadevan; Benjamin S Simpson; Kathy A Gately; Hayley C Whitaker; Susan Heavey Journal: Signal Transduct Target Ther Date: 2020-01-31
Authors: Rahul Aggarwal; Spencer C Behr; Pamela L Paris; Charles Truillet; Matthew F L Parker; Loc T Huynh; Junnian Wei; Byron Hann; Jack Youngren; Jiaoti Huang; Gayatri Premasekharan; Nimna Ranatunga; Emily Chang; Kenneth T Gao; Charles J Ryan; Eric J Small; Michael J Evans Journal: Mol Cancer Res Date: 2017-06-07 Impact factor: 5.852
Authors: Dai Horiuchi; Roman Camarda; Alicia Y Zhou; Christina Yau; Olga Momcilovic; Sanjeev Balakrishnan; Alexandra N Corella; Henok Eyob; Kai Kessenbrock; Devon A Lawson; Lindsey A Marsh; Brittany N Anderton; Julia Rohrberg; Ratika Kunder; Alexey V Bazarov; Paul Yaswen; Michael T McManus; Hope S Rugo; Zena Werb; Andrei Goga Journal: Nat Med Date: 2016-10-24 Impact factor: 53.440
Authors: Leslie A Crews; Larisa Balaian; Nathaniel P Delos Santos; Heather S Leu; Angela C Court; Elisa Lazzari; Anil Sadarangani; Maria A Zipeto; James J La Clair; Reymundo Villa; Anna Kulidjian; Rainer Storb; Sheldon R Morris; Edward D Ball; Michael D Burkart; Catriona H M Jamieson Journal: Cell Stem Cell Date: 2016-08-25 Impact factor: 24.633