Molecular Sequelae of Myeloma-Bone Marrow Interactions: Therapeutic Applications We have defined the molecular mechanisms whereby interactions of multiple myeloma (MM) cells with BM stromal cells (BMSCs) mediate growth, survival, migration, and drug resistance in the BM milieu using in vitro and in vivo models. We have then validated novel therapeutics targeting the MM cell and its BM microenvironment (bortezomib and lenalidomide), and rapidly translated these agents from bench to bedside and FDA approval. The current proposal will define the molecular, functional, and therapeutic relevance of interactions of MM cells with accessory cells (BMSCs, osteoblasts, osteoclasts, and endothelial cells) in the BM milieu. Our central hypothesis is that the biological behavior of MM cells in the BM microenvironment is modulated by their interactions with individual BM accessory cells, and that the molecular and functional sequelae of these interactions represent potential therapeutic targets. To address this hypothesis, we will characterize the molecular contribution of individual cellular components of the BM microenvironment on MM cell proliferation, survival, and drug resistance (Specific Aim 1);validate the functional significance and therapeutic relevance of molecular events triggered in vitro by the interaction of MM cells with BM microenvironment (Specific Aim 2);and validate the therapeutic implications of targeting molecular events triggered by MM-BM microenvironment interactions in vivo (Specific Aim 3). Our studies will provide the framework for a new treatment paradigm targeting MM cell-BM accessory cell interactions to overcome drug resistance and improve patient outcome.

Public Health Relevance

Multiple myeloma (MM) affects yearly 19,300 new individuals in the United States and remains incurable. Novel treatment strategies are therefore urgently needed. We have defined the molecular mechanisms whereby interactions of MM cells with bone marrow stromal cells (BMSCs) mediate growth, survival, migration, and drug resistance and validated and rapidly translated novel therapeutics (bortezomib and lenalidomide) from bench to bedside and FDA approval. The current proposal will define the molecular, functional, and therapeutic relevance of interactions of MM cells with accessory cells of the bone marrow (BM), and will provide the framework for a new treatment paradigm targeting these interactions to overcome drug resistance and improve patient outcome in MM.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA050947-20
Application #
8196885
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Howcroft, Thomas K
Project Start
1990-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
20
Fiscal Year
2012
Total Cost
$278,781
Indirect Cost
$112,998
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Das, D Sharma; Ray, A; Das, A et al. (2016) A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells. Leukemia 30:2187-2197
Ray, Arghya; Ravillah, Durgadevi; Das, Deepika S et al. (2016) A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. Br J Haematol 174:397-409
Gullà, Annamaria; Di Martino, Maria Teresa; Gallo Cantafio, Maria Eugenia et al. (2016) A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells. Clin Cancer Res 22:1222-33
Hideshima, Teru; Qi, Jun; Paranal, Ronald M et al. (2016) Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma. Proc Natl Acad Sci U S A 113:13162-13167
Cea, Michele; Cagnetta, Antonia; Adamia, Sophia et al. (2016) Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells. Blood 127:1138-50
Ohguchi, Hiroto; Hideshima, Teru; Bhasin, Manoj K et al. (2016) The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival. Nat Commun 7:10258
Ray, A; Das, D S; Song, Y et al. (2015) Targeting PD1-PDL1 immune checkpoint in plasmacytoid dendritic cell interactions with T cells, natural killer cells and multiple myeloma cells. Leukemia 29:1441-4
Hideshima, T; Cottini, F; Ohguchi, H et al. (2015) Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma. Blood Cancer J 5:e312
Suzuki, Rikio; Kikuchi, Shohei; Harada, Takeshi et al. (2015) Combination of a Selective HSP90α/β Inhibitor and a RAS-RAF-MEK-ERK Signaling Pathway Inhibitor Triggers Synergistic Cytotoxicity in Multiple Myeloma Cells. PLoS One 10:e0143847
Cottini, Francesca; Hideshima, Teru; Suzuki, Rikio et al. (2015) Synthetic Lethal Approaches Exploiting DNA Damage in Aggressive Myeloma. Cancer Discov 5:972-87

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