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 #
5R01CA050947-18
Application #
7743074
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
2009-12-01
Budget End
2010-11-30
Support Year
18
Fiscal Year
2010
Total Cost
$287,403
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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