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Grant Details

Grant Number: 5R01CA141298-04 Interpret this number
Primary Investigator: Stampfer, Meir
Organization: Brigham And Women'S Hospital
Project Title: Growth Factors and Lethal Prostate Cancer Signature
Fiscal Year: 2013
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Abstract

DESCRIPTION (provided by applicant): A central issue in prostate cancer (PCa) is to recognize potentially lethal cancer at diagnosis, and to identify the causes and underlying mechanisms that distinguish lethal from indolent disease. Using a case-only design, we will develop a molecular signature for potentially lethal PCa by comparing the RNA expression profiles of tumor tissue from subsequently lethal PCa cases to tumor tissue from men without known lethal disease. Collaborating with researchers at the Broad Institute of Harvard University/MIT, we propose to apply a novel but proven high-throughput profiling technology to assess RNA expression in archival tumor tissue using a 24,000 gene platform. Our previous work provided converging evidence of a key role of the insulin-like growth factor (IGF) system in PCa risk and progression. We have already assembled an extensive prospective clinical and serological database on PCa with up to 26 years of follow-up. Germline polymorphisms and plasma levels of the IGF axis have been assayed in many cases who provided a prediagnostic blood sample. We now propose to extend this work with additional IGF/insulin components, including germline variations and tumor expression, in relation to PCa progression and mortality. Using a case-only design, we will assess circulating biomarkers and tagging germline polymorphisms in the IGF/insulin axis, comparing lethal cases to men without known lethal disease. We will also assess alterations of IGF/insulin signaling in PCa tissue (RNA and protein expression) in relation to fatal PCa, and will integrate plasma and genetic biomarkers with tumor tissue data to illuminate gene pathways that are dysregulated. Based on intriguing preliminary data, we will characterize tumor samples for presence of the common gene translocation, the TMPRSS2:ERG fusion, and address whether fusion positive tumors are more likely to progress when exposed to high levels of IGF/insulin signaling. The research will be conducted in the Physicians' Health Study (PHS) and Health Professionals Follow-up Study (HPFS) cohorts among incident PCa cases diagnosed from 1982-2008. We have assembled a PCa tumor repository of 1,600 cases (178 fatal) for tissue marker assays and are constructing high-density tissue microarrays for quantitative immunohistochemistry and FISH assays. We will have levels of circulating biomarkers measured in plasma (N=1,881) and SNPs assayed on extracted DNA (N=2,281). All men with PCa are followed intensively for information on treatment, PSA rise, metastases and cause of death with complete follow-up through 2012. The RNA expression data will greatly enhance our understanding of the influence of the IGF/insulin dependent and independent pathways on development of lethal PCa, which will aid in designing targeted therapy and prevention strategies. Most studies of PCa progression are based on elevations of PSA levels. A major strength of our proposal is that we use the most clinically relevant endpoint, lethal PCa. From the molecular signature of lethal PCa, we can identify a small number of highly predictive markers that could be ultimately assessed in biopsy samples. Thus, the findings can be translated to clinical practice, enabling clinicians to identify with confidence which tumors require aggressive therapy. Use of this rich resource of existing data and infrastructure permits a highly cost-efficient study, and the cross-disciplinary team of collaborators with a longstanding record of working together will ensure success of this project.

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Publications

Physical activity and prostate tumor vessel morphology: data from the Health Professionals Follow-up Study.
Authors: Van Blarigan EL, Gerstenberger JP, Kenfield SA, Giovannucci EL, Stampfer M, Jones LW, Clinton SK, Chan JM, Mucci LA
Source: Cancer Prev Res (Phila), 2015 Aug 14;null, p. null.
EPub date: 2015 Aug 14.
PMID: 26276753
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Measuring PI3K Activation: Clinicopathologic, Immunohistochemical, and RNA Expression Analysis in Prostate Cancer.
Authors: Martin NE, Gerke T, Sinnott JA, Stack EC, Andren O, Andersson SO, Johansson JE, Fiorentino M, Finn S, Fedele G, Stampfer M, Kantoff PW, Mucci LA, Loda M
Source: Mol Cancer Res, 2015 Jun 29;null, p. null.
EPub date: 2015 Jun 29.
PMID: 26124442
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Fat intake after prostate cancer diagnosis and mortality in the Physicians' Health Study.
Authors: Van Blarigan EL, Kenfield SA, Yang M, Sesso HD, Ma J, Stampfer MJ, Chan JM, Chavarro JE
Source: Cancer Causes Control, 2015 Aug;26(8), p. 1117-26.
EPub date: 2015 Jun 6.
PMID: 26047644
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Dietary patterns after prostate cancer diagnosis in relation to disease-specific and total mortality.
Authors: Yang M, Kenfield SA, Van Blarigan EL, Batista JL, Sesso HD, Ma J, Stampfer MJ, Chavarro JE
Source: Cancer Prev Res (Phila), 2015 Jun;8(6), p. 545-51.
PMID: 26031631
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Prediagnostic Obesity and Physical Inactivity Are Associated with Shorter Telomere Length in Prostate Stromal Cells.
Authors: Joshu CE, Peskoe SB, Heaphy CM, Kenfield SA, Van Blarigan EL, Mucci LA, Giovannucci EL, Stampfer MJ, Yoon G, Lee TK, Hicks JL, De Marzo AM, Meeker AK, Platz EA
Source: Cancer Prev Res (Phila), 2015 Aug;8(8), p. 737-42.
EPub date: 2015 May 19.
PMID: 25990087
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Replication of a genetic variant for prostate cancer-specific mortality.
Authors: Penney KL, Shui IM, Feng Z, Sesso HD, Stampfer MJ, Stanford JL
Source: Prostate Cancer Prostatic Dis, 2015 Sep;18(3), p. 260-3.
EPub date: 2015 May 5.
PMID: 25939514
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Comparing Platforms for Messenger RNA Expression Profiling of Archival Formalin-Fixed, Paraffin-Embedded Tissues.
Authors: Tyekucheva S, Martin NE, Stack EC, Wei W, Vathipadiekal V, Waldron L, Fiorentino M, Lis RT, Stampfer MJ, Loda M, Parmigiani G, Mucci LA, Birrer M
Source: J Mol Diagn, 2015 Jul;17(4), p. 374-81.
EPub date: 2015 Apr 30.
PMID: 25937617
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Molecular differences in transition zone and peripheral zone prostate tumors.
Authors: Sinnott JA, Rider JR, Carlsson J, Gerke T, Tyekucheva S, Penney KL, Sesso HD, Loda M, Fall K, Stampfer MJ, Mucci LA, Pawitan Y, Andersson SO, Andrén O
Source: Carcinogenesis, 2015 Jun;36(6), p. 632-8.
EPub date: 2015 Apr 13.
PMID: 25870172
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Tumor expression of adiponectin receptor 2 and lethal prostate cancer.
Authors: Rider JR, Fiorentino M, Kelly R, Gerke T, Jordahl K, Sinnott JA, Giovannucci EL, Loda M, Mucci LA, Finn S, Transdisciplinary Prostate Cancer Partnership (ToPCaP)
Source: Carcinogenesis, 2015 Jun;36(6), p. 639-47.
EPub date: 2015 Apr 11.
PMID: 25863129
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The TMPRSS2:ERG fusion and response to androgen deprivation therapy for prostate cancer.
Authors: Graff RE, Pettersson A, Lis RT, DuPre N, Jordahl KM, Nuttall E, Rider JR, Fiorentino M, Sesso HD, Kenfield SA, Loda M, Giovannucci EL, Rosner B, Nguyen PL, Sweeney CJ, Mucci LA, Transdisciplinary Prostate Cancer Partnership ToPCaP
Source: Prostate, 2015 Jun 15;75(9), p. 897-906.
EPub date: 2015 Mar 1.
PMID: 25728532
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The high prevalence of undiagnosed prostate cancer at autopsy: implications for epidemiology and treatment of prostate cancer in the Prostate-specific Antigen-era.
Authors: Jahn JL, Giovannucci EL, Stampfer MJ
Source: Int J Cancer, 2014 Dec 29;null, p. null.
EPub date: 2014 Dec 29.
PMID: 25557753
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Selenium supplementation and prostate cancer mortality.
Authors: Kenfield SA, Van Blarigan EL, DuPre N, Stampfer MJ, L Giovannucci E, Chan JM
Source: J Natl Cancer Inst, 2015 Jan;107(1), p. 360.
EPub date: 2014 Dec 12.
PMID: 25505227
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Circadian clock genes and risk of fatal prostate cancer.
Authors: Markt SC, Valdimarsdottir UA, Shui IM, Sigurdardottir LG, Rider JR, Tamimi RM, Batista JL, Haneuse S, Flynn-Evans E, Lockley SW, Czeisler CA, Stampfer MJ, Launer L, Harris T, Smith AV, Gudnason V, Lindstrom S, Kraft P, Mucci LA
Source: Cancer Causes Control, 2015 Jan;26(1), p. 25-33.
EPub date: 2014 Nov 12.
PMID: 25388799
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Association of prostate cancer risk variants with gene expression in normal and tumor tissue.
Authors: Penney KL, Sinnott JA, Tyekucheva S, Gerke T, Shui IM, Kraft P, Sesso HD, Freedman ML, Loda M, Mucci LA, Stampfer MJ
Source: Cancer Epidemiol Biomarkers Prev, 2015 Jan;24(1), p. 255-60.
EPub date: 2014 Nov 4.
PMID: 25371445
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Prediagnostic plasma IGFBP-1, IGF-1 and risk of prostate cancer.
Authors: Cao Y, Nimptsch K, Shui IM, Platz EA, Wu K, Pollak MN, Kenfield SA, Stampfer MJ, Giovannucci EL
Source: Int J Cancer, 2015 May 15;136(10), p. 2418-26.
EPub date: 2014 Nov 10.
PMID: 25348852
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Circulating fatty acids and prostate cancer risk: individual participant meta-analysis of prospective studies.
Authors: Crowe FL, Appleby PN, Travis RC, Barnett M, Brasky TM, Bueno-de-Mesquita HB, Chajes V, Chavarro JE, Chirlaque MD, English DR, Gibson RA, Giles GG, Goodman GE, Henning SM, Kaaks R, King IB, Kolonel LN, Kristal AR, Neuhouser ML, Park SY, Severi G, Siddiq A, Stampfer MJ, Stattin P, Tangen CM, Tjřnneland A, Trichopoulos D, Tumino R, Wilkens LR, Key TJ, Allen NE, Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group
Source: J Natl Cancer Inst, 2014 Sep;106(9), p. null.
EPub date: 2014 Sep 10.
PMID: 25210201
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Vasectomy and risk of aggressive prostate cancer: a 24-year follow-up study.
Authors: Siddiqui MM, Wilson KM, Epstein MM, Rider JR, Martin NE, Stampfer MJ, Giovannucci EL, Mucci LA
Source: J Clin Oncol, 2014 Sep 20;32(27), p. 3033-8.
PMID: 25002716
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Androgen receptor CAG repeat polymorphism and risk of TMPRSS2:ERG-positive prostate cancer.
Authors: Yoo S, Pettersson A, Jordahl KM, Lis RT, Lindstrom S, Meisner A, Nuttall EJ, Stack EC, Stampfer MJ, Kraft P, Brown M, Loda M, Giovannucci EL, Kantoff PW, Mucci LA
Source: Cancer Epidemiol Biomarkers Prev, 2014 Oct;23(10), p. 2027-31.
EPub date: 2014 Jun 12.
PMID: 24925673
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Genetic variation across C-reactive protein and risk of prostate cancer.
Authors: Markt SC, Rider JR, Penney KL, Schumacher FR, Epstein MM, Fall K, Sesso HD, Stampfer MJ, Mucci LA
Source: Prostate, 2014 Jul;74(10), p. 1034-42.
EPub date: 2014 May 20.
PMID: 24844401
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Insulin-like growth factor pathway genetic polymorphisms, circulating IGF1 and IGFBP3, and prostate cancer survival.
Authors: Cao Y, Lindström S, Schumacher F, Stevens VL, Albanes D, Berndt S, Boeing H, Bueno-de-Mesquita HB, Canzian F, Chamosa S, Chanock SJ, Diver WR, Gapstur SM, Gaziano JM, Giovannucci EL, Haiman CA, Henderson B, Johansson M, Le Marchand L, Palli D, Rosner B, Siddiq A, Stampfer M, Stram DO, Tamimi R, Travis RC, Trichopoulos D, Willett WC, Yeager M, Kraft P, Hsing AW, Pollak M, Lin X, Ma J
Source: J Natl Cancer Inst, 2014 Jun;106(6), p. dju085.
PMID: 24824313
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Plasma antioxidants, genetic variation in SOD2, CAT, GPX1, GPX4, and prostate cancer survival.
Authors: Van Blarigan EL, Ma J, Kenfield SA, Stampfer MJ, Sesso HD, Giovannucci EL, Witte JS, Erdman JW Jr, Chan JM, Penney KL
Source: Cancer Epidemiol Biomarkers Prev, 2014 Jun;23(6), p. 1037-46.
EPub date: 2014 Apr 7.
PMID: 24711484
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SPINK1 protein expression and prostate cancer progression.
Authors: Flavin R, Pettersson A, Hendrickson WK, Fiorentino M, Finn S, Kunz L, Judson GL, Lis R, Bailey D, Fiore C, Nuttall E, Martin NE, Stack E, Penney KL, Rider JR, Sinnott J, Sweeney C, Sesso HD, Fall K, Giovannucci E, Kantoff P, Stampfer M, Loda M, Mucci LA
Source: Clin Cancer Res, 2014 Sep 15;20(18), p. 4904-11.
EPub date: 2014 Mar 31.
PMID: 24687926
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Association of C-peptide and leptin with prostate cancer incidence in the Health Professionals Follow-up Study.
Authors: Lai GY, Giovannucci EL, Pollak MN, Peskoe SB, Stampfer MJ, Willett WC, Platz EA
Source: Cancer Causes Control, 2014 May;25(5), p. 625-32.
EPub date: 2014 Mar 25.
PMID: 24664287
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