Our overall Program is focused on understanding the oncogenomic changes in myeloma central to disease pathogenesis which impact clinical outcome. We have proposed two large clinical trials;first to evaluate the role of transplant in the era of novel therapies;and second to evaluate progression from MGUS/SMM to active MM, which will accrue 1000 patients and 1210 patients, respectively, both in France and the United States. A critical aspect of obtaining robust ongenomic data is to have centralized and uniform processing and analysis of samples with established SOPs. Specifically, samples will be obtained from patients enrolled on the randomized trial evaluating lenalidomide bortezomib and dexamethasone (RVD) with or without high dose therapy and autotransplant at time of diagnosis (Project 2) and at relapse (Project 4);and from patients with monoclonal gammopathy of undetermined significance/smoldering MM (MGUS/SMM) at time of study entry and progression (Project 2). In each case, tumor cells versus normal cells will be isolated in Core B using well established procedures. Core C will perform DNA, RNA, and microRNA analyses on these samples. In addition, this Core will perform genomic analyses on preclinical samples, specifically evaluating changes in RNA and miRNA resulting from gain and loss of gene function, as well as before and after novel targeted therapies. This Core will provide a detailed catalog of gains or losses in DNA by using Genome Wide Human SNP 6.0 array. Levels of mRNA expression and splicing of all genes will be assessed using whole transcript GeneChip? Human Exon 1.0 ST array. Micro RNA (miRNA) profile will be established using qPCR-based miRNA arrays. This core has also interacted closely with investigators in Core E for bioinformatic support and data analysis, which is essential for the success of our proposed studies. This core has and will continue to help identify novel targets and validate targeted therapies in preclinical studies in Project 3. The following 3 Specific Aims will be pursued: to assess changes in DNA by high density SNP array analysis (Specific Aim 1);to evaluate expression profile and alternate splicing using Exon 1.0 ST array (Specific Aim 2);to profile miRNA using high density qPCR array (Specific Aim 3). Core C is therefore an essential and integral component to meet our goals.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA155258-03
Application #
8566975
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$269,712
Indirect Cost
$69,590
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Gullà, Annamaria; Di Martino, Maria Teresa; Gallo Cantafio, Maria Eugenia et al. (2016) A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells. Clin Cancer Res 22:1222-33
Prabhala, R H; Fulciniti, M; Pelluru, D et al. (2016) Targeting IL-17A in multiple myeloma: a potential novel therapeutic approach in myeloma. Leukemia 30:379-89
Magrangeas, Florence; Kuiper, Rowan; Avet-Loiseau, Hervé et al. (2016) A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Patients with Multiple Myeloma. Clin Cancer Res 22:4350-5
Ohguchi, Hiroto; Hideshima, Teru; Bhasin, Manoj K et al. (2016) The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival. Nat Commun 7:10258
Dimopoulos, Meletios A; Orlowski, Robert Z; Facon, Thierry et al. (2015) Retrospective matched-pairs analysis of bortezomib plus dexamethasone versus bortezomib monotherapy in relapsed multiple myeloma. Haematologica 100:100-6
Bianchi, Giada; Munshi, Nikhil C (2015) Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood 125:3049-58
Jagannathan, S; Vad, N; Vallabhapurapu, S et al. (2015) MiR-29b replacement inhibits proteasomes and disrupts aggresome+autophagosome formation to enhance the antimyeloma benefit of bortezomib. Leukemia 29:727-38
Hu, Y; Song, W; Cirstea, D et al. (2015) CSNK1α1 mediates malignant plasma cell survival. Leukemia 29:474-82
Hebraud, Benjamin; Magrangeas, Florence; Cleynen, Alice et al. (2015) Role of additional chromosomal changes in the prognostic value of t(4;14) and del(17p) in multiple myeloma: the IFM experience. Blood 125:2095-100
Mitsiades, Constantine S (2015) Therapeutic landscape of carfilzomib and other modulators of the ubiquitin-proteasome pathway. J Clin Oncol 33:782-5

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