A prominent feature of multiple myeloma (MM) is significant genomic instability, which leads to genetic changes resulting in acquisition of drug resistance and progression of disease. An emerging focus of investigation has therefore been to define the molecular basis for evolving genetic changes associated with disease progression. In this Project, we will delineate molecular mechanisms and clinical consequences of genomic instability. We will also, develop therapeutic strategies based upon inhibiting these underlying mechanisms to avoid or delay genomic changes and their sequelae. In preliminary studies, we have evaluated the role of homologous recombination (HR) as a mechanism for genomic instability in MM. We have observed that: HR activity is significantly higher in MM cells compared to normal plasma cells; MM cell lines and primary patient MM cells acquire newer genetic changes overtime; inhibition of HR activity reduces acquisition of new genetic changes; and conversely, induction of HR leads to increased genetic instability in MM, associated with the development of drug resistance. These and other preliminary data form the basis for our hypothesis that elevated HR mediates DNA instability in MM and may therefore contribute to development of drug resistance and disease progression, thereby providing the framework for targeting HR in novel therapeutics. In this Project, we will investigate the genomic changes evolving at the time of relapse compared to diagnosis and evaluate their clinical significance (Sp Aim 1). We will evaluate the role of elevated HR, a key mediator of genomic instability, as a marker of prognosis (Sp Aim 2), and preclinically evaluate the ability of inhibitors of HR to prevent evolution of genomic changes (Sp Aim 3). The proposed studies will improve our understanding of progression of MM and may facilitate the development of prognostic tests for disease progression, as well as identity novel therapeutic strategies.

Public Health Relevance

The proposed studies in this project will improve our understanding of genomic changes associated with disease relapse and its clinical relevance, identify role of homolgous recombination (HR) activity in predicting prognosis in myeloma and develop therapies targeting HR to inhibit genomic evolution These studies may facilitate the development of prognostic tests for disease progression as well as identify novel therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA155258-05
Application #
8931919
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
2017-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
5
Fiscal Year
2015
Total Cost
$205,369
Indirect Cost
$52,889
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
O'Donnell, Elizabeth K; Laubach, Jacob P; Yee, Andrew J et al. (2018) A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Br J Haematol 182:222-230
Guo, Guangwu; Raje, Noopur S; Seifer, Charles et al. (2018) Genomic discovery and clonal tracking in multiple myeloma by cell-free DNA sequencing. Leukemia 32:1838-1841
Szalat, R; Samur, M K; Fulciniti, M et al. (2018) Nucleotide excision repair is a potential therapeutic target in multiple myeloma. Leukemia 32:111-119
Nair, Shiny; Sng, Joel; Boddupalli, Chandra Sekhar et al. (2018) Antigen-mediated regulation in monoclonal gammopathies and myeloma. JCI Insight 3:
Gullà, A; Hideshima, T; Bianchi, G et al. (2018) Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. Leukemia 32:996-1002
Mazzotti, Céline; Buisson, Laure; Maheo, Sabrina et al. (2018) Myeloma MRD by deep sequencing from circulating tumor DNA does not correlate with results obtained in the bone marrow. Blood Adv 2:2811-2813
Miannay, Bertrand; Minvielle, Stéphane; Magrangeas, Florence et al. (2018) Constraints on signaling network logic reveal functional subgraphs on Multiple Myeloma OMIC data. BMC Syst Biol 12:32
Samur, Mehmet Kemal; Minvielle, Stephane; Gulla, Annamaria et al. (2018) Long intergenic non-coding RNAs have an independent impact on survival in multiple myeloma. Leukemia 32:2626-2635
Singh, Irtisha; Lee, Shih-Han; Sperling, Adam S et al. (2018) Widespread intronic polyadenylation diversifies immune cell transcriptomes. Nat Commun 9:1716
Xu, Yan; Deng, Shuhui; Mao, Xuehan et al. (2018) Tolerance, Kinetics, and Depth of Response for Subcutaneous Versus Intravenous Administration of Bortezomib Combination in Chinese Patients With Newly Diagnosed Multiple Myeloma. Clin Lymphoma Myeloma Leuk 18:422-430

Showing the most recent 10 out of 218 publications