Myeloma is characterized by the accumulation of malignant plasma cells in the bone marrow and is accompanied by severe bone disease. Myeloma afflicts more than 14,000 people in the US each year;despite advances in treatment, myeloma remains incurable, highlighting the importance of developing novel interventions for this disease. We demonstrated the interdependence between myeloma bone disease and tumor progression. Therefore, we propose an innovative treatment paradigm based on creating an inhospitable bone marrow environment for myeloma through stimulating bone formation, increasing antitumor osteoblastic factors, and blocking activity of osteoclastic factors that promote myeloma. This therapeutic concept is supported by clinical observations and by our previous and preliminary studies demonstrating that osteoblasts inhibit myeloma growth and that osteoblast-activating agents induce bone formation while also reducing myeloma burden in vivo. Moreover, osteoblasts produce high levels of small-leucine-rich-proteoglycans (SLRPs), which are essential for proper bone remodeling and, notably, also inhibit some tumor types;our preliminary study revealed that SLRPs suppress myeloma growth. We also showed that osteoclasts support myeloma growth via physical contact, and we identified fibroblast activation factor (FAP) as a critical microenvironmental factor involved in this processes. Our overall hypothesis is that factors upregulated on osteoclasts in myelomatous bone promote myeloma cell survival and that bone-building factors produced by osteoblasts negate myeloma progression. We will exploit our unique in vivo and ex vivo systems for primary myeloma to study three Specific Aims. We will (Aim 1) determine the involvement of SLRPs in osteoblast-induced myeloma growth inhibition and unravel anti-myeloma molecular mechanisms of these proteoglycans ex vivo and in vivo. We will test the effect of blocking SLRPs on osteoblast-induced myeloma growth inhibition, unravel SLRPs molecular mechanisms, and test their anti-myeloma efficacy. We will (Aim 2) determine the effects of the potent osteoblast-activating factors, dickkopf-1 (DKK1) neutralizing antibody, parathyroid hormone (PTH) and bortezomib on myeloma bone disease and myeloma development and progression in primary myelomatous SCID-rab mice. We will (Aim 3) determine the role of FAP in myeloma pathogenesis and as a potential microenvironment-targeted therapy;using recombinant FAP, specific FAP inhibitors and short-interfering RNA approaches we will unravel direct and indirect effects of FAP on myeloma progression in vitro and in vivo. Work under this study will validate novel microenvironmental-targeted therapies associated with activation of osteoclasts and explore the use of bone-anabolic agents and SLRPs as effective and safe strategies to improve patients'quality of life and control myeloma. Project Narrative: Malignant myeloma cells manifest in the bone marrow and cause severe, painful bone disease. Our main goal is to create a hostile environment for tumor cells by controlling myeloma-induced bone destruction. Our study will increase knowledge of myeloma pathogenesis, which will help develop new approaches to treat myeloma bone disease and tumor progression simultaneously, improve patients'quality of life, and prevent myeloma development in individuals who are at risk for developing this incurable disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093897-09
Application #
8196715
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Howcroft, Thomas K
Project Start
2001-12-01
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
9
Fiscal Year
2012
Total Cost
$257,868
Indirect Cost
$80,028
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
Venkateshaiah, Sathisha Upparahalli; Khan, Sharmin; Ling, Wen et al. (2013) NAMPT/PBEF1 enzymatic activity is indispensable for myeloma cell growth and osteoclast activity. Exp Hematol 41:547-557.e2
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

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