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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Microenvironment Study Section (TME)
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Howcroft, Thomas K
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University of Arkansas for Medical Sciences
Other Clinical Sciences
Schools of Medicine
Little Rock
United States
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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
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
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
Yaccoby, Shmuel (2010) Osteoblastogenesis and tumor growth in myeloma. Leuk Lymphoma 51:213-20
Pennisi, Angela; Ling, Wen; Li, Xin et al. (2009) The ephrinB2/EphB4 axis is dysregulated in osteoprogenitors from myeloma patients and its activation affects myeloma bone disease and tumor growth. Blood 114:1803-12
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
van Rhee, Frits; Szmania, Susann M; Dillon, Myles et al. (2009) Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma. Mol Cancer Ther 8:2616-24
Pennisi, Angela; Li, Xin; Ling, Wen et al. (2009) The proteasome inhibitor, bortezomib suppresses primary myeloma and stimulates bone formation in myelomatous and nonmyelomatous bones in vivo. Am J Hematol 84:6-14
Li, Xin; Ling, Wen; Pennisi, Angela et al. (2009) Fenretinide inhibits myeloma cell growth, osteoclastogenesis and osteoclast viability. Cancer Lett 284:175-81

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