Inhibiting fatty acid binding proteins decreases multiple myeloma cell proliferation and increases efficacy of dexamethasone

Multiple myeloma (MM) is an incurable cancer of the plasma cell and currently only has a 5 year survival rate of 53%. MM cells depend on a multitude of cells within the bone marrow microenvironment to flourish and resist treatment-induced cell death. Bone marrow adipocytes (BMAd), which increase in number with aging and obesity, have been shown to support myeloma cells by inducing proliferation, migration, and drug resistance, and ultimately contributing to myeloma patient relapse from remission. Herein we confirm the pro-myeloma effects of BMAd conditioned media (CM) and investigate the effects of the family of proteins termed the fatty acid binding proteins (FABPs), which are expressed both by adipocytes and tumor cells themselves. We found that high levels of FABP5 in patient myeloma cells corresponds to poor overall and relapse free survival for MM patients. Moreover, we found that pharmacologically inhibiting fatty acid binding proteins negatively impact tumor burden in vitro and in vivo,ultimately leading to increased survival of tumor-bearing mice. In addition, when combined with FABP inhibitors, dexamethasone, a common anti-myeloma treatment, has increased efficacy in vitro. Overall, these data suggest that FABPs are a novel target in myeloma and that this is a potential new cancer therapeutic target should be developed fuither

New Bone Cell Type Identified as Driver of Drug Resistance in Multiple Myeloma: The Bone Marrow Adipocyte

Multiple myeloma (MM) is a hematological malignancy that is characterized by clonal proliferation of transformed plasma cells within the bone marrow (BM) and severe bone disease. Although MM cells are initially sensitive to many therapies, patients eventually relapse with refractory disease. Because MM cells show a dependency on the BM microenvironment for survival and proliferation, and BM adipocytes (BMAs) demonstrate a unique, endocrine signaling capacity and lipid composition, it is likely that there is cross-talk between MM cells and BMAs that leads to tumor support. Unlike the influences of osteoblasts and osteoclasts, the effect of BMAs on MM cells is poorly understood and few studies have investigated the relationship between bone marrow adipose tissue (BMAT) and cancer. We predict there to be a strong link between MAT and MM, as obesity is a risk factor for MM and also correlates with increased MAT in humans. Moreover, MAT has been shown to support other tumors and correlates with bone diseases such as osteoporosis, anorexia, and aging. Thus, we explored here the novel hypothesis that BMAs induce drug resistance in MM cells through direct cell-cell contact signaling and/or secreted signaling molecules

Inhibiting Fatty Acid Binding Protein Family Members Decreases Multiple Myeloma Cell Proliferation Through Effecting the myc Pathway

FABP inhibition leads to increased survival of myeloma bearing mice and decreased cell growth by inhibiting MYC signaling.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1016/thumbnail.jp

Investigation of the relationship between obesity, weight cycling, and tumor progression in murine myeloma models

We investigated this relationship in two murine myeloma models with a high fat diet (HFD) to induce obesity, and a diet cycling (DC) regimen to model weight cycling.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1025/thumbnail.jp

Multiple myeloma cells Graphs and Figures inhibit adipogenesis, increase senescencerelated and inflammatory gene transcript expression, and alter metabolism in preadipocytes

Myeloma cells alter metabolism & induce senescence in adipocyte-lineage cells, suggesting that senescence-associated proteins are involved in multiple myeloma.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1032/thumbnail.jp

Soluble and Cell–Cell-Mediated Drivers of Proteasome Inhibitor Resistance in Multiple Myeloma

It is becoming clear that myeloma cell-induced disruption of the highly organized bone marrow components (both cellular and extracellular) results in destruction of the marrow and support for multiple myeloma (MM) cell proliferation, survival, migration, and drug resistance. Since the first phase I clinical trial on bortezomib was published 15 years ago, proteasome inhibitors (PIs) have become increasingly common for treatment of MM and are currently an essential part of any anti-myeloma combination therapy. PIs, either the first generation (bortezomib), second generation (carfilzomib) or oral agent (ixazomib), all take advantage of the heavy reliance of myeloma cells on the 26S proteasome for their degradation of excessive or misfolded proteins. Inhibiting the proteasome can create a crisis specifically for myeloma cells due to their rapid production of immunoglobulins. PIs have relatively few side effects and can be very effective, especially in combination therapy. If PI resistance can be overcome, these drugs may prove even more useful to a greater range of patients. Both soluble and insoluble (contact mediated) signals drive PI-resistance via activation of various intracellular signaling pathways. This review discusses the currently known mechanisms of non-autonomous (microenvironment dependent) mechanisms of PI resistance in myeloma cells. We also introduce briefly cell-autonomous and stress-mediated mechanisms of PI resistance. Our goal is to help researchers design better ways to study and overcome PI resistance, to ultimately design better combination therapies

Soluble and Cell–Cell-Mediated Drivers of Proteasome Inhibitor Resistance in Multiple Myeloma

It is becoming clear that myeloma cell-induced disruption of the highly organized bone marrow components (both cellular and extracellular) results in destruction of the marrow and support for multiple myeloma (MM) cell proliferation, survival, migration, and drug resistance. Since the first phase I clinical trial on bortezomib was published 15 years ago, proteasome inhibitors (PIs) have become increasingly common for treatment of MM and are currently an essential part of any anti-myeloma combination therapy. PIs, either the first generation (bortezomib), second generation (carfilzomib) or oral agent (ixazomib), all take advantage of the heavy reliance of myeloma cells on the 26S proteasome for their degradation of excessive or misfolded proteins. Inhibiting the proteasome can create a crisis specifically for myeloma cells due to their rapid production of immunoglobulins. PIs have relatively few side effects and can be very effective, especially in combination therapy. If PI resistance can be overcome, these drugs may prove even more useful to a greater range of patients. Both soluble and insoluble (contact mediated) signals drive PI-resistanc

Soluble and Cell-Cell-Mediated Drivers of Proteasome Inhibitor Resistance in Multiple Myeloma.

It is becoming clear that myeloma cell-induced disruption of the highly organized bone marrow components (both cellular and extracellular) results in destruction of the marrow and support for multiple myeloma (MM) cell proliferation, survival, migration, and drug resistance. Since the first phase I clinical trial on bortezomib was published 15 years ago, proteasome inhibitors (PIs) have become increasingly common for treatment of MM and are currently an essential part of any anti-myeloma combination therapy. PIs, either the first generation (bortezomib), second generation (carfilzomib) or oral agent (ixazomib), all take advantage of the heavy reliance of myeloma cells on the 26S proteasome for their degradation of excessive or misfolded proteins. Inhibiting the proteasome can create a crisis specifically for myeloma cells due to their rapid production of immunoglobulins. PIs have relatively few side effects and can be very effective, especially in combination therapy. If PI resistance can be overcome, these drugs may prove even more useful to a greater range of patients. Both soluble and insoluble (contact mediated) signals drive PI-resistanc

Investigating the Effect that Inhibiting Fatty Acid Binding Proteins 4 or 5 Have on Myeloma Cell Proliferation

In the bone marrow microenvironment, adipocytes and multiple myeloma cells have an intricate bidirectional relationship. Adipokines have been linked to shifting typical behavior in many cancers such as proliferation. Our previous research found that Fatty Acid Binding Protein (FABP) family expression changes in the presence of bone marrow adipocytes. To test the effect that FABPs may have on myeloma cell growth, a cell line was treated with inhibitors of FABP4, FABP5, and a co-treatment in cell culture. Bioluminescence imaging (BLI) was used to cell count the myeloma cells at time 0, 24, 48, and 72 hours. Analysis of the inhibitor spike in showed that myeloma cell growth was inhibited over time with the individual inhibitors and the co-inhibitor treatment. To test if external FABPs are important to myeloma cells, recombinant FABP4 or FABP5 was spiked into myeloma cell lines (MM1.S and OPM2) in serum and serum-free conditions. This data was cell counted using BLI. Analysis showed that there was no impact on cell growth with the spike in. Thus, external FABPs are not important to myeloma cells. A future direction is to test the effect that inhibiting internal FABPs may have on myeloma cells by knocking down FABP5 by using methods of lipofectamine transfection and nucleofection to transfect siRNA. The successful inhibition of FABP4, FABP5, or both may prove useful as a potential cancer therapeutic to stop multiple myeloma cell proliferation in the human body

Targeting bone marrow adipose tissue and the FABP family increases efficacy of dexamethasone in MM

• Multiple myeloma (MM) is an incurable cancer of plasma cells. Myeloma cells grow primarily in the bone marrow (BM) and home throughout the body to extramedullary locations. MM causes aberrant IgG production, renal failure, hypercalcemia, anemia, and bone destruction. MM patients almost always relapse with the disease; finding new ways to target drug resistant MM clones is a major clinical need. • Bone Marrow Adipocytes (BMAs) have been shown to be supportive of MM cells and are associated with the transitions of both MGUS to MM and remission to relapse, with a strong correlation between high BMI and poor treatment response (Liu et al, Sci. Transl. Med, 2019). • As BMAs have been shown to be supportive in other cancers, such as AML and prostate cancer, therapeutically targeting the BM adipocyte may prove to be revolutionary in the clinic for treating MM. • Fatty Acid Binding Protein (FABP) family members have been linked to increased fatty acid trafficking and act as signaling molecules in many different malignant cells (Furuhashi, Nature, 2007). • Objective: Determine the role of BMAs in MM disease progression and discover novel targets to overcome drug resistance and relapse in MM. • Hypotheses: 1) BMAs secrete soluble factors that alter normal MM signaling to induce proliferation and/or dexamethasone resistance; 2) fatty acid binding protein family signaling is involved in the response of MM cells to BMAs and may be a novel therapeutic avenue in MM