title: PIM kinase inhibitor AZD1208 for treatment of MYC-driven prostate cancer.
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.
authors.affiliation: 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).
authors.forename: Austin N
authors.initials: AN
authors.lastname: Kirschner
authors.affiliation: 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).
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: 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).
authors.forename: Riet
authors.initials: R
authors.lastname: van der Meer
authors.affiliation: 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).
authors.forename: Philip D
authors.initials: PD
authors.lastname: Anderson
authors.affiliation: 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).
authors.forename: Omar E
authors.initials: OE
authors.lastname: Franco-Coronel
authors.affiliation: 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).
authors.forename: Max H
authors.initials: MH
authors.lastname: Kushner
authors.affiliation: 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).
authors.forename: Joel H
authors.initials: JH
authors.lastname: Everett
authors.affiliation: 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).
authors.forename: Omar
authors.initials: O
authors.lastname: Hameed
authors.affiliation: 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).
authors.forename: Erika K
authors.initials: EK
authors.lastname: Keeton
authors.affiliation: 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).
authors.forename: Miika
authors.initials: M
authors.lastname: Ahdesmaki
authors.affiliation: 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).
authors.forename: Shaun E
authors.initials: SE
authors.lastname: Grosskurth
authors.affiliation: 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).
authors.forename: Dennis
authors.initials: D
authors.lastname: Huszar
authors.affiliation: 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.
authors.forename: Sarki A
authors.initials: SA
authors.lastname: Abdulkadir
mesh_terms: D000284:Administration, Oral; D064591:Allografts; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D053778:Thiazolidines / Q000008:administration & dosage / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C587575:AZD1208; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D047428:Protein Kinase Inhibitors; D053778:Thiazolidines; D016159:Tumor Suppressor Protein p53; C496634:PIM1 protein, human; C496636:Pim1 protein, mouse; D051573:Proto-Oncogene Proteins c-pim-1