The overall objective of this program project is to understand MM growth in the context of its interaction with the bone marrow microenvironment (ME) in order to translate and exploit this knowledge into smarter MM growth control in patients. A concerted effort by a team of basic and clinical scientists is aimed at further overcoming the tremendous obstacles posed by MM's extensive genetic heterogeneity. We hypothesize that MM subjugates various ME components, perhaps in a MM subtypespecific manner, and that such MM-induced ME imprints may become an irreversible force contributing to MM's defiance of cure. In light of our theme of growth control in MM, toward achieving cure in an increasingly higher proportion of patients, investigators of 4 projects and 5 cores will continue to collaborate in a highly integrated and synergistic fashion. Project 1 plans to achieve better growth control via risk-based treatment strategies in an effort to reduce treatment-related toxicities in low-risk disease while accelerating outcome improvement in high-risk disease. Translational work will interrogate the MM-ME interaction and elucidate, through examination of serial gene expression profiling (GEP) samples, how this interaction affects growth control. Project 2 postulates to achieve better growth control in the relapsed setting by optimizing the clinical activity of haplo-identical NK cells via combination therapy with bortezomib and CS1 antibody. Basic research will examine the antimyeloma activity of human NK cells activated/expanded with K562 cells transfected with membrane-bound interleukin-15 (IL-15) and the co-stimulatory molecule 4-1BBL, in combination with bortezomib and CS1 Ab, in a murine model. Projects 3 and 4 deal with the role of bone, disease in MM pathogenesis. Project 3 will focus on fundamental observations relevant to DKK1 suppression of Wnt/beta-catenin signaling and the interaction of beta-catenin/cadherin cell adhesion with focal lesions, osteolytic bone disease, and MM dissemination to extramedullary disease, in an effort to harness the molecular MM-ME interaction therapeutically pertinent to MM pathogenesis, allowing us to investigate growth control via another avenue (by reduction of tumor cell adhesion). Project 4 will shed light on the biological mechanisms by which osteoblasts and osteoclasts affect myeloma cell growth and dissemination. By unraveling the consequences of altered activities of osteoclasts and osteoblasts on MM dissemination, and understanding the mechanisms involved, novel therapeutic interventions for MM can be developed. This work will be accomplished with access to 5 shared resource cores.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA055819-18
Application #
8324018
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Program Officer
Merritt, William D
Project Start
2000-06-05
Project End
2014-08-31
Budget Start
2012-09-11
Budget End
2013-08-31
Support Year
18
Fiscal Year
2012
Total Cost
$3,627,570
Indirect Cost
$1,124,532
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
Johnson, Sarah K; Stewart, James P; Bam, Rakesh et al. (2014) CYR61/CCN1 overexpression in the myeloma microenvironment is associated with superior survival and reduced bone disease. Blood 124:2051-60
Dhodapkar, Madhav V; Sexton, Rachael; Waheed, Sarah et al. (2014) Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood 123:78-85
Lapteva, Natalia; Szmania, Susann M; van Rhee, Frits et al. (2014) Clinical grade purification and expansion of natural killer cells. Crit Rev Oncog 19:121-32
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
Papanikolaou, X; Rosenbaum, E R; Tyler, L N et al. (2014) Hematopoietic progenitor cell collection after autologous transplant for multiple myeloma: low platelet count predicts for poor collection and sole use of resulting graft enhances risk of myelodysplasia. Leukemia 28:888-93
Sawyer, Jeffrey R; Tian, Erming; Heuck, Christoph J et al. (2014) Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease. Blood 123:2504-12
Tian, Erming; Sawyer, Jeffrey R; Heuck, Christoph J et al. (2014) In multiple myeloma, 14q32 translocations are nonrandom chromosomal fusions driving high expression levels of the respective partner genes. Genes Chromosomes Cancer 53:549-57
Waheed, Sarah; Mitchell, Alan; Usmani, Saad et al. (2013) Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data. Haematologica 98:71-8
Lamy, Laurence; Ngo, Vu N; Emre, N C Tolga et al. (2013) Control of autophagic cell death by caspase-10 in multiple myeloma. Cancer Cell 23:435-49
Sousa, Mirta M L; Zub, Kamila Anna; Aas, Per Arne et al. (2013) An inverse switch in DNA base excision and strand break repair contributes to melphalan resistance in multiple myeloma cells. PLoS One 8:e55493

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