A clinically distinguishing feature of multiple myeloma (MM) is focal tumor growth detectable by MRI as focal lesions;this tumor growth is associated with increased resistance to chemotherapy and often osteolytic bone disease. Our preliminary work suggests that focal lesions, osteolytic bone disease, and dissemination to extramedullary disease are associated with molecular events resulting from suppression of Wnt/Beta-catenin signaling and from interactions between p-catenin and cadherin that mediate cell adhesion. Our long-term objective is to thoroughly understand the relationship between Wnt/Beta-catenin signaling and myeloma pathogenesis, with the ultimate goal of uncovering novel therapeutic approaches to control myeloma growth and improve survival and quality of life of patients with MM. We hypothesize that deregulation of Wnt/Beta-catenin signaling in both the microenvironment and the myeloma tumor cell is a fundamental and critical event in the natural history of MM. Therefore, control of this signaling axis may represent a paradigm shift in myeloma therapy. We will pursue this broad hypothesis through the following specific aims:
(Aim 1) Verify that elevated transcription of DKKI in myeloma tumor cells is related to polymorphisms/mutations in the DKKI promoter;
(Aim 2) Examine the roles of E- and N-cadherin and their interactions with Beta-catenin in MM pathogenesis and determine if they represent viable therapeutic targets;
(Aim 3) Determine whether bone-anabolic effects of bortezomib treatment result from induction of Beta-catenin signaling in mesenchymal stem cells and osteoblasts;
(Aim 4) Establish the derivation of a novel CYR61 isoform in MM and determine the in vitro and In vivo effects of this and native CYR61 on myeloma growth and bone disease. Comprehensive understanding of the molecular events surrounding dysregulation of Wnt/Beta-catenin signaling in MM will potentially provide the foundation for innovative therapeutic strategies to control growth of myeloma.

Public Health Relevance

Deregulation of Wnt/Beta-catenin signaling is central to myeloma biology and pathogenesis, so it may provide molecular therapeutic targets. Myeloma tumors aberrantly produce molecules that disrupt specific aspects of the Beta-catenin signaling axis, leading to enhanced tumor growth and bone destruction early in the disease and greater cell proliferation and metastases later in the disease. By thoroughly investigating the Beta-catenin signaling axis in myeloma. Project 3 will provide the framework for innovative therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA055819-19
Application #
8566717
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
19
Fiscal Year
2013
Total Cost
$372,828
Indirect Cost
$115,359
Name
University of Arkansas for Medical Sciences
Department
Type
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Alagpulinsa, David A; Ayyadevara, Srinivas; Yaccoby, Shmuel et al. (2016) A Cyclin-Dependent Kinase Inhibitor, Dinaciclib, Impairs Homologous Recombination and Sensitizes Multiple Myeloma Cells to PARP Inhibition. Mol Cancer Ther 15:241-50
McDonald, James E; Kessler, Marcus M; Gardner, Michael W et al. (2016) Assessment of Total Lesion Glycolysis by 18F FDG PET/CT Significantly Improves Prognostic Value of GEP and ISS in Myeloma. Clin Cancer Res :
VÃ¥tsveen, Thea Kristin; Sponaas, Anne-Marit; Tian, Erming et al. (2016) Erythropoietin (EPO)-receptor signaling induces cell death of primary myeloma cells in vitro. J Hematol Oncol 9:75
Pawlyn, Charlotte; Kaiser, Martin F; Heuck, Christoph et al. (2016) The Spectrum and Clinical Impact of Epigenetic Modifier Mutations in Myeloma. Clin Cancer Res 22:5783-5794
Weinhold, Niels; Ashby, Cody; Rasche, Leo et al. (2016) Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma. Blood 128:1735-44
Jethava, Yogesh; Mitchell, Alan; Epstein, Joshua et al. (2016) Adverse metaphase cytogenetics can be overcome by adding bortezomib and thalidomide to fractionated melphalan transplants. Clin Cancer Res :
Weinhold, N; Heuck, C J; Rosenthal, A et al. (2016) Clinical value of molecular subtyping multiple myeloma using gene expression profiling. Leukemia 30:423-30
Pawlyn, C; Fowkes, L; Otero, S et al. (2016) Whole-body diffusion-weighted MRI: a new gold standard for assessing disease burden in patients with multiple myeloma? Leukemia 30:1446-8
Heuck, C J; Jethava, Y; Khan, R et al. (2016) Inhibiting MEK in MAPK pathway-activated myeloma. Leukemia 30:976-80
Mitchell, Jonathan S; Li, Ni; Weinhold, Niels et al. (2016) Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. Nat Commun 7:12050

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