Date of Presentation

5-3-2018 8:00 AM

College

Cooper Medical School of Rowan University

Poster Abstract

Multiple myeloma (MM) is a neoplastic plasma-cell disorder. This is characterized by clonal proliferation of malignant plasma cells in the bone-marrow (BM) microenvironment, monoclonal protein in blood or urine, and associated organ dysfunction. The treatment options approved by FDA are immune-modulatory agents, proteasome inhibitors, and autologous stem cell transplantation (ASCT). Unfortunately, MM remains uniformly fatal owing to intrinsic or acquired drug resistance and the median survival time is 3 to 5 years. Thus, there is a great need for novel strategies to combat MM.

The intimate relationship of myeloma cells to BM microenvironment is “hallmark of myeloma”. The homing of MM cells to the BM, mediated by the chemokine stromal cell-derived factor-1α (SDF-1α) and its receptor CXCR4 has important functional sequelae. The BM microenvironment constituting cells secrete chemokines, cytokines, and growth factors such as interleukin 6 (IL6), vascular endothelial growth factor (VEGF), SDF-1α, and tumor necrosis factor α (TNFα) etc. These growth factors either secreted by MM or BM microenvironment cells (e.g. stromal cells) contribute in activation of several signaling pathways including nuclear factor-κB (NF-κB); phosphatidylinositol 3-kinase (PI3K)-Akt; Ras-Raf-MAPK kinase (MEK)-extracellular signal regulated kinase (ERK); and the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3). Activation of these pathways has been associated with increased expression of several anti-apoptotic proteins such as Bcl-2, Bcl-xL, Mcl-1, and XIAP. Collectively, these discoveries highlight that interaction of MM cells to BM microenvironment not only promote growth, survival and migration of MM cells, but also confer resistance to conventional chemotherapy.

We hypothesized that an agent capable of inhibiting the migration of myeloma cells to bone marrow and suppressing the expression of survival protein Mcl-1 would be a better option for MM treatment.We have synthesized a novel dual inhibitor of CXCR4 and Mcl-1. Our data suggests that this molecule inhibits the expression of CXCR4 and Mcl-1 and survival of MM cells.

Keywords

multiple myeloma, tumor microenvironment, bone marrow, antineoplastic agents, Myeloid Cell Leukemia Sequence 1 Protein, CXCR4

Disciplines

Amino Acids, Peptides, and Proteins | Chemicals and Drugs | Hematology | Medicine and Health Sciences | Neoplasms | Oncology

Share

COinS
 
May 3rd, 8:00 AM

Development of Novel Dual Inhibitor of Chemokine Receptor 4 and Mcl-1 Against Multiple Myeloma

Multiple myeloma (MM) is a neoplastic plasma-cell disorder. This is characterized by clonal proliferation of malignant plasma cells in the bone-marrow (BM) microenvironment, monoclonal protein in blood or urine, and associated organ dysfunction. The treatment options approved by FDA are immune-modulatory agents, proteasome inhibitors, and autologous stem cell transplantation (ASCT). Unfortunately, MM remains uniformly fatal owing to intrinsic or acquired drug resistance and the median survival time is 3 to 5 years. Thus, there is a great need for novel strategies to combat MM.

The intimate relationship of myeloma cells to BM microenvironment is “hallmark of myeloma”. The homing of MM cells to the BM, mediated by the chemokine stromal cell-derived factor-1α (SDF-1α) and its receptor CXCR4 has important functional sequelae. The BM microenvironment constituting cells secrete chemokines, cytokines, and growth factors such as interleukin 6 (IL6), vascular endothelial growth factor (VEGF), SDF-1α, and tumor necrosis factor α (TNFα) etc. These growth factors either secreted by MM or BM microenvironment cells (e.g. stromal cells) contribute in activation of several signaling pathways including nuclear factor-κB (NF-κB); phosphatidylinositol 3-kinase (PI3K)-Akt; Ras-Raf-MAPK kinase (MEK)-extracellular signal regulated kinase (ERK); and the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3). Activation of these pathways has been associated with increased expression of several anti-apoptotic proteins such as Bcl-2, Bcl-xL, Mcl-1, and XIAP. Collectively, these discoveries highlight that interaction of MM cells to BM microenvironment not only promote growth, survival and migration of MM cells, but also confer resistance to conventional chemotherapy.

We hypothesized that an agent capable of inhibiting the migration of myeloma cells to bone marrow and suppressing the expression of survival protein Mcl-1 would be a better option for MM treatment.We have synthesized a novel dual inhibitor of CXCR4 and Mcl-1. Our data suggests that this molecule inhibits the expression of CXCR4 and Mcl-1 and survival of MM cells.

 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.