The common and typical induction of osteolytic bone disease in multiple myeloma (MM) led to the notion that bone disease is both a consequence and a necessity of MM progression and metastasis. Our reported and preliminary data suggest that osteoclasts support myeloma cell survival and metastasis through production of certain serine proteases known as dipeptidyl peptidase-IV activity and/or structure homolog (DASH) proteins and that inhibiting activity of osteoclasts or DASH proteases suppresses growth of medullary MM. Conversely, we found that osteoblasts reduce growth of myeloma cells through production of certain small leucine-rich proteoglycans and that increased osteoblast activity in myelomatous bones (from treating with osteoblast-activating agents [parathyroid hormone or anti-DKKI] or with cytotherapy [osteoprogenitor cells]) increases bone formation, creating an inhospitable microenvironment that attenuates MM progression in vivo. Based on these findings, we hypothesize that the microenvironment in existing focal lesions is a critical determinant of long-term survival and dissemination of myeloma cells;therefore, simultaneously inhibiting osteoclast activity and stimulating bone formation is critical for sustaining a patient's response to treatment and for preventing metastasis.
In Specific Aim 1, we will determine whether increased bone formation by bone-anabolic agents (e.g., PTH, anti-DKKI), with or without exogenous osteoblast precursors, will sustain remission induced by clinical agents (e.g., melphalan, dexamethasone, bortezomib, lenalidomide), and/or prevent tumor metastasis upon relapse. We will also investigate molecular mechanisms associated with these effects.
In Specific Aim 2, we will determine whether osteoclast-produced DASH proteases contribute to MM-induced bone disease, support survival of MM in osteolytic lesions, and stimulate metastasis directly by signaling through caveolae and indirectly through reduced retention of myeloma cells by inactivating the central chemokine SDF-1.
In Specific Aim 3, we will determine whether combining treatments to increase activity of osteoblasts and inhibit activity of DASH proteases has superior effects on controlling MM growth and dissemination and on preventing relapse than either individual therapeutic approach. Through interactions with all projects and cores, using our SCID-hu model and coculture systems with primary samples and myeloma cell lines, we will unravel antitumor and antimetastatic effects of factors associated with bone anabolism, as well as molecular mechanisms of DASH proteases in MM using gain-and-loss approaches, specific inhibitors, and recombinant proteins.

Public Health Relevance

Achieving sustained remission and preventing new osteolytic lesions upon relapse are critical goals for improving survival and quality of life of patients with myeloma. Osteoclasts and osteoblasts play critical roles in behavior of myeloma cells during the disease's active and inactive states. Therefore, unraveling the consequences of altered activities of osteoclasts and osteoblasts on tumor dissemination, and understating molecular mechanisms involved, will help in developing novel interventions for myeloma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA055819-19
Application #
8566718
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
$205,465
Indirect Cost
$63,574
Name
University of Arkansas for Medical Sciences
Department
Type
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Rasche, L; Alapat, D; Kumar, M et al. (2018) Combination of flow cytometry and functional imaging for monitoring of residual disease in myeloma. Leukemia :
Went, Molly; Sud, Amit; Försti, Asta et al. (2018) Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nat Commun 9:3707
Mehdi, Syed J; Johnson, Sarah K; Epstein, Joshua et al. (2018) Mesenchymal stem cells gene signature in high-risk myeloma bone marrow linked to suppression of distinct IGFBP2-expressing small adipocytes. Br J Haematol :
Rasche, Leo; Angtuaco, Edgardo J; Alpe, Terri L et al. (2018) The presence of large focal lesions is a strong independent prognostic factor in multiple myeloma. Blood 132:59-66
Rasche, Leo; Angtuaco, Edgardo; McDonald, James E et al. (2017) Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma. Blood 130:30-34
Mikulasova, Aneta; Wardell, Christopher P; Murison, Alexander et al. (2017) The spectrum of somatic mutations in monoclonal gammopathy of undetermined significance indicates a less complex genomic landscape than that in multiple myeloma. Haematologica 102:1617-1625
Stein, Caleb K; Pawlyn, Charlotte; Chavan, Shweta et al. (2017) The varied distribution and impact of RAS codon and other key DNA alterations across the translocation cyclin D subgroups in multiple myeloma. Oncotarget 8:27854-27867
Chavan, S S; He, J; Tytarenko, R et al. (2017) Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker. Blood Cancer J 7:e535
Went, M; Sud, A; Law, P J et al. (2017) Assessing the effect of obesity-related traits on multiple myeloma using a Mendelian randomisation approach. Blood Cancer J 7:e573
McDonald, James E; Kessler, Marcus M; Gardner, Michael W et al. (2017) Assessment of Total Lesion Glycolysis by 18F FDG PET/CT Significantly Improves Prognostic Value of GEP and ISS in Myeloma. Clin Cancer Res 23:1981-1987

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