|Grant Number:||5R01CA127435-04 Interpret this number|
|Primary Investigator:||Colditz, Graham|
|Project Title:||Prospective Evaluation of Igf and IL-6 Dysregulation and Multiple Myeloma|
DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a malignancy with poor survival and without known modifiable risk factors. Thus, prospective studies are needed to characterize the etiology of MM to inform the development of prevention strategies. Laboratory research has described important roles for the IGF-1 and IL-6 pathways in MM pathogenesis. With a collaborative study that includes a total of at least 498 MM cases and 996 controls with prospectively collected biospecimens, we are uniquely situated to conduct the first examination of the role of IGF-1 and IL-6 in MM etiology. This application addresses the following specific hypotheses: 1. Insulin-like growth factor (IGF)-1 pathway a. Circulating levels of IGF-1, IGF binding protein (IGFBP)-1, IGFBP-3, acid labile subunit (ALS), and C- peptide are related to increased incidence of MM b. Specific polymorphisms and haplotypes in the IGF-I, IGFBP-1,-2, and -3, IGF-I receptor (IGF-IR), and insulin receptor substrate (IRS)-1 and -2 genes are associated with increased risk of MM 2. Interleukin (IL)-6 upregulation and B-cell stimulation a. Plasma levels of IL-6, slL-6R, and C-reactive protein are positively associated with MM. b. Specific polymorphisms and haplotypes in the IL-6 pathway increase risk of MM. We will conduct pooled prospective studies with incident cases of MM from nine large cohorts with archived, prospectively acquired plasma and DNA specimens: the Women's Health Initiative, the Nurses' Health Study, the Health Professionals' Follow-up Study, the Women's Health Study, the Physician's Health Study, and the Singapore Chinese Cohort. From the intramural program at NCI, we have PLCO and ATBC and from Australia, we have the Melbourne Collaborative Cohort. We will utilize a prospective nested case- control design to examine the associations of the serologic and genetic biomarkers with incident MM. In secondary analyses, we will explore whether the association of a given IGF-1- or IL-6-related marker with MM varies by status of known or suggested risk factors, including age, gender, MGUS status, or body mass index. Each cohort is represented by a senior investigator (or study PI) who will oversee the case-control identification from that study, and then participate in the planning and interpretation of data analyses. The team is led from by Drs. Colditz and Anderson and is supported by a senior statistician (Dr. Rosner) and a study director (Dr. Birmann) who is funded, in part, through a K award.
Development of extramedullary myeloma in the era of novel agents: no evidence of increased risk with lenalidomide-bortezomib combinations.
Authors: Varga C, Xie W, Laubach J, Ghobrial IM, O'Donnell EK, Weinstock M, Paba-Prada C, Warren D, Maglio ME, Schlossman R, Munshi NC, Raje N, Weller E, Anderson KC, Mitsiades CS, Richardson PG
Source: Br J Haematol, 2015 Jun;169(6), p. 843-50.
Therapeutic landscape of carfilzomib and other modulators of the ubiquitin-proteasome pathway.
Authors: Mitsiades CS
Source: J Clin Oncol, 2015 Mar 1;33(7), p. 782-5.
EPub date: 2015 Jan 20.
Regular aspirin use and risk of multiple myeloma: a prospective analysis in the health professionals follow-up study and nurses' health study.
Authors: Birmann BM, Giovannucci EL, Rosner BA, Colditz GA
Source: Cancer Prev Res (Phila), 2014 Jan;7(1), p. 33-41.
EPub date: 2013 Nov 26.
TRIM13 (RFP2) downregulation decreases tumour cell growth in multiple myeloma through inhibition of NF Kappa B pathway and proteasome activity.
Authors: Gatt ME, Takada K, Mani M, Lerner M, Pick M, Hideshima T, Carrasco DE, Protopopov A, Ivanova E, Sangfelt O, Grandér D, Barlogie B, Shaughnessy JD Jr, Anderson KC, Carrasco DR
Source: Br J Haematol, 2013 Jul;162(2), p. 210-20.
EPub date: 2013 May 7.
Prediagnosis biomarkers of insulin-like growth factor-1, insulin, and interleukin-6 dysregulation and multiple myeloma risk in the Multiple Myeloma Cohort Consortium.
Authors: Birmann BM, Neuhouser ML, Rosner B, Albanes D, Buring JE, Giles GG, Lan Q, Lee IM, Purdue MP, Rothman N, Severi G, Yuan JM, Anderson KC, Pollak M, Rifai N, Hartge P, Landgren O, Lessin L, Virtamo J, Wallace RB, Manson JE, Colditz GA
Source: Blood, 2012 Dec 13;120(25), p. 4929-37.
EPub date: 2012 Oct 16.
Insulin-like growth factor-1- and interleukin-6-related gene variation and risk of multiple myeloma.
Authors: Birmann BM, Tamimi RM, Giovannucci E, Rosner B, Hunter DJ, Kraft P, Mitsiades C, Anderson KC, Colditz GA
Source: Cancer Epidemiol Biomarkers Prev, 2009 Jan;18(1), p. 282-8.