We have defined the molecular mechanisms whereby interactions of multiple myeloma (MM) cells with BM stromal cells (BMSCs) mediate growth, survival, 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, lenalidomide and combinations thereof), and rapidly translated these agents from bench to bedside and FDA approval. The current proposal will further define the molecular, functional, and therapeutic relevance of interactions of MM cells with accessory cells in the BM milieu. Our central hypothesis is that the interaction between MM cells and their surrounding accessory cells in the BM microenvironment is a bidirectional one, whereby MM cells prime the accessory cells to function as more potent inducers of MM cell proliferation, survival, and drug resistance. To address this hypothesis, we will characterize the molecular and functional impact of MM cells on BMSCs as accessory cells in the BM microenvironment (Specific Aim 1);define the role of MM-induced myeloid-derived suppressor cells (MDSCs) as candidate accessory cells directly supporting proliferation and drug resistance of MM cells in the BM (Specific Aim 2);and define the impact of MM cells on accessory cells in vivo and its therapeutic implications. Our studies will provide the framework for a new treatment paradigm, whereby the mechanism(s) of BM accessory cell priming by MM cells constitute bona fide target(s) for therapeutic interventions to overcome drug resistance and improve patient outcome.

Public Health Relevance

Multiple myeloma (MM) affects yearly 20,000 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 and drug resistance and validated and rapidly translated novel therapeutics (bortezomib and lenalidomide) and combinations regimens from bench to bedside and FDA approval. The current proposal will define the molecular mechanisms and therapeutic implications of how MM cells induce accessory cells of the bone marrow (BM) to more potently support MM cell proliferation and drug resistance. These studies will provide the basis for new treatment paradigms of 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 #
2R01CA050947-22A1
Application #
8697235
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mufson, R Allan
Project Start
1990-12-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
22
Fiscal Year
2014
Total Cost
$301,545
Indirect Cost
$121,545
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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