Interactions between tumor cells and the microenvironment (TME) have a major impact on the biology of myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS). This application is a continuation of our prior work wherein we characterized several aspects of TME in MM. A theme from our prior work is that transition of MGUS to MM is associated with several changes in TME, with loss of anti-tumor immunity and progressive inflammation. Herein we will pursue the link between properties of tumor cells and changes in TME. Based on our preliminary studies, we posit that secretion of wnt inhibitors by tumor cells and the recruitment of myeloid cells play a major role in the altered balance of immunity and inflammation.
In Aim 1, we will pursue the effect of wnt inhibitors on the regulation of host immune response.
In Aim 2, we will further characterize the crosstalk between myeloid cells and myeloma in the regulation of genomic instability. These studies may provide several targets to restore the dysregulation of immunity versus inflammation and restrict genomic instability in this cancer.

Public Health Relevance

This work builds on our prior studies to better understand the changes in the properties of the tumor bed in myeloma. These studies may provide novel approaches to control tumor growth and achieve durable responses to therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA106802-09
Application #
8625711
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Howcroft, Thomas K
Project Start
2004-03-08
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
9
Fiscal Year
2014
Total Cost
$313,930
Indirect Cost
$125,383
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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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
Zhao, S; Choi, M; Heuck, C et al. (2014) Serial exome analysis of disease progression in premalignant gammopathies. Leukemia 28:1548-52
Sehgal, Kartik; Dhodapkar, Kavita M; Dhodapkar, Madhav V (2014) Targeting human dendritic cells in situ to improve vaccines. Immunol Lett 162:59-67
Dhodapkar, Madhav V (2013) Personalized immune-interception of cancer and the battle of two adaptive systems--when is the time right? Cancer Prev Res (Phila) 6:173-6
Richter, Joshua; Neparidze, Natalia; Zhang, Lin et al. (2013) Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma. Blood 121:423-30
Dhodapkar, Madhav V; Dhodapkar, Kavita M (2011) Vaccines targeting cancer stem cells: are they within reach? Cancer J 17:397-402
Dhodapkar, Madhav V; Richter, Joshua (2011) Harnessing natural killer T (NKT) cells in human myeloma: progress and challenges. Clin Immunol 140:160-6
Dhodapkar, Kavita M; Feldman, Darren; Matthews, Phillip et al. (2010) Natural immunity to pluripotency antigen OCT4 in humans. Proc Natl Acad Sci U S A 107:8718-23
Dhodapkar, Madhav V (2010) Immunity to stemness genes in human cancer. Curr Opin Immunol 22:245-50

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