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.
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.
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|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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