|Grant Number:||5R01CA141298-03 Interpret this number|
|Primary Investigator:||Stampfer, Meir|
|Organization:||Brigham And Women'S Hosp., Inc.|
|Project Title:||Growth Factors and Lethal Prostate Cancer Signature|
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. PUBLIC HEALTH RELEVANCE: Prostate cancer is among the most common cancers in men, and a major cause of cancer death. A central problem is that with PSA screening, many men are diagnosed with a cancer that would not cause them harm, and they undergo therapy unnecessarily. We propose to use an exciting innovative technology to identify a molecular tumor signature to distinguish prostate cancers that are indolent, and can safely be left untreated, from those that are potentially lethal and require aggressive therapy. We also plan to extend our work to identify the causes of lethal prostate cancer as they relate to the growth factor pathway.
Dietary lycopene, angiogenesis, and prostate cancer: a prospective study in the prostate-specific antigen era.
Authors: Zu K, Mucci L, Rosner BA, Clinton SK, Loda M, Stampfer MJ, Giovannucci E
Source: J Natl Cancer Inst, 2014 Feb;106(2), p. djt430.
EPub date: 2014 Jan 24.
Modification of the association between obesity and lethal prostate cancer by TMPRSS2:ERG.
Authors: Pettersson A, Lis RT, Meisner A, Flavin R, Stack EC, Fiorentino M, Finn S, Graff RE, Penney KL, Rider JR, Nuttall EJ, Martin NE, Sesso HD, Pollak M, Stampfer MJ, Kantoff PW, Giovannucci EL, Loda M, Mucci LA
Source: J Natl Cancer Inst, 2013 Dec 18;105(24), p. 1881-90.
EPub date: 2013 Nov 30.
Mounting evidence for prediagnostic use of statins in reducing risk of lethal prostate cancer.
Authors: Mucci LA, Stampfer MJ
Source: J Clin Oncol, 2014 Jan 1;32(1), p. 1-2.
EPub date: 2013 Nov 25.
Prostate-specific membrane antigen protein expression in tumor tissue and risk of lethal prostate cancer.
Authors: Kasperzyk JL, Finn SP, Flavin R, Fiorentino M, Lis R, Hendrickson WK, Clinton SK, Sesso HD, Giovannucci EL, Stampfer MJ, Loda M, Mucci LA
Source: Cancer Epidemiol Biomarkers Prev, 2013 Dec;22(12), p. 2354-63.
EPub date: 2013 Oct 15.
Blood levels of saturated and monounsaturated fatty acids as markers of de novo lipogenesis and risk of prostate cancer.
Authors: Chavarro JE, Kenfield SA, Stampfer MJ, Loda M, Campos H, Sesso HD, Ma J
Source: Am J Epidemiol, 2013 Oct 15;178(8), p. 1246-55.
EPub date: 2013 Aug 28.
Protein expression of PTEN, insulin-like growth factor I receptor (IGF-IR), and lethal prostate cancer: a prospective study.
Authors: Zu K, Martin NE, Fiorentino M, Flavin R, Lis RT, Sinnott JA, Finn S, Penney KL, Ma J, Fazli L, Gleave ME, Bismar TA, Stampfer MJ, Pollak MN, Loda M, Mucci LA, Giovannucci E
Source: Cancer Epidemiol Biomarkers Prev, 2013 Nov;22(11), p. 1984-93.
EPub date: 2013 Aug 27.
Gleason grade progression is uncommon.
Authors: Penney KL, Stampfer MJ, Jahn JL, Sinnott JA, Flavin R, Rider JR, Finn S, Giovannucci E, Sesso HD, Loda M, Mucci LA, Fiorentino M
Source: Cancer Res, 2013 Aug 15;73(16), p. 5163-8.
Prostate cancer cell telomere length variability and stromal cell telomere length as prognostic markers for metastasis and death.
Authors: Heaphy CM, Yoon GS, Peskoe SB, Joshu CE, Lee TK, Giovannucci E, Mucci LA, Kenfield SA, Stampfer MJ, Hicks JL, De Marzo AM, Platz EA, Meeker AK
Source: Cancer Discov, 2013 Oct;3(10), p. 1130-41.
EPub date: 2013 Jun 18.
Fat intake after diagnosis and risk of lethal prostate cancer and all-cause mortality.
Authors: Richman EL, Kenfield SA, Chavarro JE, Stampfer MJ, Giovannucci EL, Willett WC, Chan JM
Source: JAMA Intern Med, 2013 Jul 22;173(14), p. 1318-26.
Partnerships for promoting prevention.
Authors: Stampfer M, Jahn JL
Source: Circulation, 2013 Mar 26;127(12), p. 1267-9.
EPub date: 2013 Mar 18.
A single nucleotide polymorphism in inflammatory gene RNASEL predicts outcome after radiation therapy for localized prostate cancer.
Authors: Schoenfeld JD, Margalit DN, Kasperzyk JL, Shui IM, Rider JR, Epstein MM, Meisner A, Kenfield SA, Martin NE, Nguyen PL, Kantoff PW, Giovannucci EL, Stampfer MJ, Mucci LA
Source: Clin Cancer Res, 2013 Mar 15;19(6), p. 1612-9.
EPub date: 2013 Feb 4.
Prediagnostic circulating sex hormones are not associated with mortality for men with prostate cancer.
Authors: Gershman B, Shui IM, Stampfer M, Platz EA, Gann PH, Sesso HL, DuPre N, Giovannucci E, Mucci LA
Source: Eur Urol, 2014 Apr;65(4), p. 683-9.
EPub date: 2013 Jan 11.
Whole milk intake is associated with prostate cancer-specific mortality among U.S. male physicians.
Authors: Song Y, Chavarro JE, Cao Y, Qiu W, Mucci L, Sesso HD, Stampfer MJ, Giovannucci E, Pollak M, Liu S, Ma J
Source: J Nutr, 2013 Feb;143(2), p. 189-96.
EPub date: 2012 Dec 19.
Selenoprotein P genetic variants and mrna expression, circulating selenium, and prostate cancer risk and survival.
Authors: Penney KL, Li H, Mucci LA, Loda M, Sesso HD, Stampfer MJ, Ma J
Source: Prostate, 2013 May;73(7), p. 700-5.
EPub date: 2012 Nov 5.
Common genetic variation of the calcium-sensing receptor and lethal prostate cancer risk.
Authors: Shui IM, Mucci LA, Wilson KM, Kraft P, Penney KL, Stampfer MJ, Giovannucci E
Source: Cancer Epidemiol Biomarkers Prev, 2013 Jan;22(1), p. 118-26.
EPub date: 2012 Nov 2.
Aspirin use after a prostate cancer diagnosis and cancer survival in a prospective cohort.
Authors: Dhillon PK, Kenfield SA, Stampfer MJ, Giovannucci EL, Chan JM
Source: Cancer Prev Res (Phila), 2012 Oct;5(10), p. 1223-8.
EPub date: 2012 Sep 7.
Choline intake and risk of lethal prostate cancer: incidence and survival.
Authors: Richman EL, Kenfield SA, Stampfer MJ, Giovannucci EL, Zeisel SH, Willett WC, Chan JM
Source: Am J Clin Nutr, 2012 Oct;96(4), p. 855-63.
EPub date: 2012 Sep 5.
The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis.
Authors: Pettersson A, Graff RE, Bauer SR, Pitt MJ, Lis RT, Stack EC, Martin NE, Kunz L, Penney KL, Ligon AH, Suppan C, Flavin R, Sesso HD, Rider JR, Sweeney C, Stampfer MJ, Fiorentino M, Kantoff PW, Sanda MG, Giovannucci EL, Ding EL, Loda M, Mucci LA
Source: Cancer Epidemiol Biomarkers Prev, 2012 Sep;21(9), p. 1497-509.
EPub date: 2012 Jun 26.
Seasonal variation in expression of markers in the vitamin D pathway in prostate tissue.
Authors: Epstein MM, Andrén O, Kasperzyk JL, Shui IM, Penney KL, Fall K, Rider JR, Stampfer MJ, Andersson SO, Giovannucci E, Mucci LA
Source: Cancer Causes Control, 2012 Aug;23(8), p. 1359-66.
EPub date: 2012 Jun 19.
Vitamin D-related genetic variation, plasma vitamin D, and risk of lethal prostate cancer: a prospective nested case-control study.
Authors: Shui IM, Mucci LA, Kraft P, Tamimi RM, Lindstrom S, Penney KL, Nimptsch K, Hollis BW, Dupre N, Platz EA, Stampfer MJ, Giovannucci E
Source: J Natl Cancer Inst, 2012 May 2;104(9), p. 690-9.
EPub date: 2012 Apr 12.