TY - JOUR
T1 - CCR1 as a target for multiple myeloma
AU - Vallet, Sonia
AU - Anderson, Kenneth C
PY - 2011/9
Y1 - 2011/9
N2 - INTRODUCTION: By directing cell trafficking, differentiation and growth, chemokines modulate the immune response and are involved in the pathogenesis of autoimmune diseases and cancers, including multiple myeloma (MM). MM, the second most common hematological malignancy in the US, is characterized by disordered plasma cell growth within the bone marrow microenvironment. CCL3 and its receptors, CCR1 in particular, play a central role in the pathogenesis of MM and MM-induced osteolytic bone disease.AREAS COVERED: This review describes the functional role of CCR1 in MM and the preclinical results observed with CCR1 antagonists. CCL3 and CCR1 stimulate tumor growth, both directly and indirectly, via upregulation of cell adhesion and cytokine secretion. In addition, they modulate the osteoclast/osteoblast balance, by inducing osteoclast differentiation and inhibiting osteoblast function. Targeting either ligand or receptor reverses these effects, leading to in vivo tumor burden control and prevention of osteolysis, as confirmed in both murine and humanized mouse models.EXPERT OPINION: These promising data set the stage for clinical trials to assess the effects of CCR1 inhibitors in MM. The success of these studies depends on the development of novel antagonists with improved chemical/physical properties and careful selection of the patient population who may benefit the most from these agents.
AB - INTRODUCTION: By directing cell trafficking, differentiation and growth, chemokines modulate the immune response and are involved in the pathogenesis of autoimmune diseases and cancers, including multiple myeloma (MM). MM, the second most common hematological malignancy in the US, is characterized by disordered plasma cell growth within the bone marrow microenvironment. CCL3 and its receptors, CCR1 in particular, play a central role in the pathogenesis of MM and MM-induced osteolytic bone disease.AREAS COVERED: This review describes the functional role of CCR1 in MM and the preclinical results observed with CCR1 antagonists. CCL3 and CCR1 stimulate tumor growth, both directly and indirectly, via upregulation of cell adhesion and cytokine secretion. In addition, they modulate the osteoclast/osteoblast balance, by inducing osteoclast differentiation and inhibiting osteoblast function. Targeting either ligand or receptor reverses these effects, leading to in vivo tumor burden control and prevention of osteolysis, as confirmed in both murine and humanized mouse models.EXPERT OPINION: These promising data set the stage for clinical trials to assess the effects of CCR1 inhibitors in MM. The success of these studies depends on the development of novel antagonists with improved chemical/physical properties and careful selection of the patient population who may benefit the most from these agents.
KW - Animals
KW - Antineoplastic Agents/pharmacology
KW - Chemokine CCL3/antagonists & inhibitors
KW - Drug Delivery Systems
KW - Drug Design
KW - Drug Evaluation, Preclinical
KW - Humans
KW - Mice
KW - Multiple Myeloma/complications
KW - Osteolysis/prevention & control
KW - Receptors, CCR1/antagonists & inhibitors
UR - http://www.scopus.com/inward/record.url?scp=80051761546&partnerID=8YFLogxK
U2 - 10.1517/14728222.2011.586634
DO - 10.1517/14728222.2011.586634
M3 - Review article
C2 - 21609295
SN - 1472-8222
VL - 15
SP - 1037
EP - 1047
JO - Expert Opinion on Therapeutic Targets
JF - Expert Opinion on Therapeutic Targets
IS - 9
ER -