The proposed research seeks to elucidate the roles of various cells in the bone marrow (BM) microenvironment in the pathogenesis of multiple myeloma (MM), a once rare but increasingly more common hematologic malignancy that currently afflicts nearly 14,000 people in the U.S. each year. Despite treatment advances, MM remains incurable. The central hypothesis is that myeloma cells alter the cellular and cytokine milieu in the BM microenvironment to their growth and survival advantage. We will identify cellular elements critical for supporting the growth of MM, as well as other cell types that may restrain tumor growth. We recently developed the SCID-hu host system for primary human myeloma. In this in vivo system, primary myeloma cells grow exclusively in a human BM environment. As in patients, interaction of myeloma cells with the human BM microenvironment is associated with typical MM manifestations, providing an excellent tool for studying this interaction mechanism. In this study, we will concentrate on the role of osteoclasts and osteoblasts in the MM disease process.
Our Specific Aims i nclude the following:
Specific Aim 1 : Elucidate the reciprocal relationship between myeloma cells and osteoclasts. Myeloma cells induce osteoclastogenesis. We will test whether osteoclast activity is required for the growth of primary myeloma by treating myeloma-bearing SCID-hu hosts with osteoclast inhibitors. Using both in vitro and in vivo approaches, we will also test the ability of isolated osteoclasts to support myeloma growth.
Specific Aim 2 : Unravel the molecular mechanisms by which myeloma cells and osteoblasts affect each other. We hypothesize that osteoblasts produce factors that interfere with myeloma growth. We will test the ability of osteoblasts to affect the growth and survival of myeloma cells in vitro and in SCID-hu hosts. We will also test the effect of myeloma cells on the survival of osteoblasts in myelomatous bone, and examine the effect of these cells on the differentiation pathways of mesenchymal stem cells. By its conclusion, work under this study will have determined the importance of increased osteoclast activity to myeloma cell growth and survival, and whether interfering with myeloma-induced osteoclastogenesis will prevent and control MM. It will also have determined the involvement of osteoblasts in MM, and whether increasing bone formation in myelomatous bones will affect myeloma progression. This study will help develop an effective treatment for patients with MM or at risk of it, as well as its prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093897-03
Application #
6779054
Study Section
Special Emphasis Panel (ZRG1-PTHC (01))
Program Officer
Mufson, R Allan
Project Start
2002-08-01
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2004
Total Cost
$252,760
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Other Clinical Sciences
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Bam, Rakesh; Khan, Sharmin; Ling, Wen et al. (2015) Primary myeloma interaction and growth in coculture with healthy donor hematopoietic bone marrow. BMC Cancer 15:864
Bam, R; Venkateshaiah, S U; Khan, S et al. (2014) Role of Bruton's tyrosine kinase (BTK) in growth and metastasis of INA6 myeloma cells. Blood Cancer J 4:e234
Bam, Rakesh; Ling, Wen; Khan, Sharmin et al. (2013) Role of Bruton's tyrosine kinase in myeloma cell migration and induction of bone disease. Am J Hematol 88:463-71
Li, Xin; Ling, Wen; Khan, Sharmin et al. (2012) Therapeutic effects of intrabone and systemic mesenchymal stem cell cytotherapy on myeloma bone disease and tumor growth. J Bone Miner Res 27:1635-48
Li, Xin; Ling, Wen; Pennisi, Angela et al. (2011) Human placenta-derived adherent cells prevent bone loss, stimulate bone formation, and suppress growth of multiple myeloma in bone. Stem Cells 29:263-73
Jia, Dan; Koonce, Nathan A; Halakatti, Roopa et al. (2010) Repression of multiple myeloma growth and preservation of bone with combined radiotherapy and anti-angiogenic agent. Radiat Res 173:809-17
Yaccoby, Shmuel (2010) Advances in the understanding of myeloma bone disease and tumour growth. Br J Haematol 149:311-21
Pennisi, Angela; Ling, Wen; Li, Xin et al. (2010) Consequences of daily administered parathyroid hormone on myeloma growth, bone disease, and molecular profiling of whole myelomatous bone. PLoS One 5:e15233
Yaccoby, Shmuel (2010) Osteoblastogenesis and tumor growth in myeloma. Leuk Lymphoma 51:213-20
Pennisi, Angela; Li, Xin; Ling, Wen et al. (2009) Inhibitor of DASH proteases affects expression of adhesion molecules in osteoclasts and reduces myeloma growth and bone disease. Br J Haematol 145:775-87

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