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

D\u27Amico, Anastasia

Fairfield, Heather

Falank, Carolyne

Farrell, Mariah

Murphy, Connor

Reagan, Michaela

English

MaineHealth Knowledge Connection

MaineHealth MaineHealth Knowledge Connection Costas T. Lambrew Research Retreat 2021 Costas T. Lambrew Research Retreat 2021 Inhibiting Fatty Acid Binding Protein Family Members Decreases Multiple Myeloma Cell Proliferation Through Effecting the myc Pathway Mariah Farrell Maine Medical Center Heather Fairfield Maine Medical Center Anastasia D'Amico Maine Medical Center Carolyne Falank Maine Medical Center Connor Murphy Maine Medical Center See next page for additional authors Follow this and additional works at: https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021  Part of the Medical Cell Biology Commons, and the Oncology Commons Recommended Citation Farrell, Mariah; Fairfield, Heather; D'Amico, Anastasia; Falank, Carolyne; Murphy, Connor; and Reagan, Michaela, "Inhibiting Fatty Acid Binding Protein Family Members Decreases Multiple Myeloma Cell Proliferation Through Effecting the myc Pathway" (2021). Costas T. Lambrew Research Retreat 2021. 12. https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/12 This Book is brought to you for free and open access by the Costas T. Lambrew Research Retreat at MaineHealth Knowledge Connection. It has been accepted for inclusion in Costas T. Lambrew Research Retreat 2021 by an authorized administrator of MaineHealth Knowledge Connection. Authors Mariah Farrell, Heather Fairfield, Anastasia D'Amico, Carolyne Falank, Connor Murphy, and Michaela Reagan This book is available at MaineHealth Knowledge Connection: https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/12 FABP inhibition leads to increased survival of myeloma bearing mice and decreased cell growth by inhibiting MYC signalingGraphs and FiguresInhibiting fatty acid binding protein family members decreases multiple myeloma cell proliferation through effecting the myc pathwayMariah Farrell, MS, Heather Fairfield, MS, Anastasia D’Amico, BS, Carolyne Falank, PhD, Connor Murphy,  Michaela Reagan, PhDIntroduction• Multiple myeloma (MM) is currently an incurable cancer of the plasma cells, and ultimately results in only 53% of patients surviving after 5 years.• FABP signaling is instrumental in various cancers leading to tumorigenesis, metastasis, and poor prognosis• FABP5 is the only family member to display a strong dependency in hundreds of cancer cell lines according to the Cancer Dependency Map database (Broad Institute).  Methods• Using OncoMine, the Zhan et al. dataset (GSE132604) was analyzed for FABP5 expression in patient MM cells and analyzed using Graphpad Prism.• MM patient cells were fixed and permeabilize prior to staining with CD38 (Biolegend), DAPI and FABP5/secondary AF647.• Myeloma cell number was measured using a bioluminescence imaging (BLI) assay, Cell Titre Glo, or RealTime Glo and measured on a GLOMAX microplate reader.• Eight-week old female Scid-beige mice were inoculated tail vein with 5 million Luc+MM1S cells. Next day, 5 mg/kg BMS309403, 1 mg/kg SBFI-26, and the combination were injected IP and continued 3x weekly for the duration of the study. BLI imaging started on day 12 and continued 2x weekly. • RNA sequencing was performed on MM1S samples that were exposed to vehicle, 50 μM BMS, SBFI or the combination for 24 hours. Sequencing was completed by VIGR to receive a list of counts per million and differentially expressed genes for each treatment group. Data was then submitted to Morpheus (Broad Institute) for heatmaps.Results• Primary patient myeloma cells that contain a high level of FABP5 is indicative of poor overall survival. • Most human and mouse myeloma cell lines have a dose dependent response to FABP inhibitors BMS309403 (BMS) and SBFI-26 (SBFI) after 72 hours of exposure. • Immunodeficient mice inoculated with Luc+ MM1S cells have reduced tumor burden and increased survival when treated with 5 mg/kg BMS, 1 mg/kg SBFI or the combination compared to the vehicle treated cohort. • RNA sequencing that the largest change in expression in the combination treatment was MYC, with similar trends in the single treatments. • Downstream MYC regulated genes are also have decreased expression with treatment, with the combination exhibiting the greatest decrease among the treatment groups. Discussion• Myeloma is currently an incurable cancer, and ultimately results in all patients succumbing to the disease. • While there has been an explosion in the amount of treatments in the past decade, all patients still relapse, demonstrating a need for new treatments• Clinical data reveals that FABP5 levels are indicative to patient outcomes and that inhibition in vivo or in vitro of FABPs lead to decrease tumor growth and increased survival. • This in part is due to decreased MYC signaling• Creating new treatments against FABP5 that can be used in MM patients could extend patient survival.0 2 0 4 0 6 0 8 005 01 0 0O v e ra ll  S u rv iv a lM o n th s% SurvivalL o w e s t 1 0 0  F A B P 5H ig h e s t 1 0 0  F A B P 5H R = 1 .3 7 4p = 0 .0 1 0 50 2 0 4 0 6 0 8 005 01 0 0O v e ra ll  S u rv iv a lM o n th s% Survival F A B P 5lowF A B P 5h ig hH R = 1 .3 2 2p = 0 .0 1 0 50 2 0 4 0 6 005 01 0 0R e la p s e -F r e e  S u rv iv a lW e e k s% SurvivalF A B P 5lowF A B P 5h ig hH R = 1 .9 1 7p = 0 .0 4 9 10 5 0 0 1 0 0 0 1 5 0 005 01 0 0O v e ra ll  S u rv iv a lD a y s% SurvivalL o w e s t 1 0 0  F A B P 5H ig h e s t 1 0 0  F A B P 5H R = 1 .3 7 p = 0 .0 0 5 8Blue = DAPIGreen = CD38 Red = FABP50 1 20 .00 .51 .01 .57 2 hS B F I D o s e  ( lo g M )Luciferase Activity (RLU)Relative to Control5 T G M 1-T KM M 1RU 266H 929O P M 2V k *M Y C0 1 20 .00 .51 .01 .57 2 hB M S  D o s e  ( lo g M )Luciferase Activity (RLU)Relative to Control5 T G M 1-T KM M 1RU 266H 929O P M 2V k *M Y C0 1 0 2 0 3 005 .01 0 71 .01 0 81 .51 0 82 .01 0 8T o ta l F lu xD a y sTotal Flux [p/s]V e h ic leB M S 3 0 9 4 0 3S B F I-2 6B M S 3 0 9 4 0 3  +  S B F I2 6Row 5Vehicle vs. BMS309403Vehicle vs. SBFI-26Vehicle vs. BMS309403 + SBFI26BMS309403 vs. SBFI-26BMS309403 vs. BMS309403 + SBFI26SBFI-26 vs. BMS309403 + SBFI26Row 6Vehicle vs. BMS309403Vehicle vs. SBFI-26Vehicle vs. BMS309403 + SBFI26BMS309403 vs. SBFI-26BMS309403 vs. BMS309403 + SBFI26SBFI-26 vs. BMS309403 + SBFI264.844e+0074.469e+0074.628e+007-3.749e+006-2.161e+0061.588e+0061.221e+0089.334e+0078.730e+007-2.878e+007-3.482e+007-6.040e+0062.559e+007 to 7.129e+0072.184e+007 to 6.754e+0072.342e+007 to 6.913e+007-2.660e+007 to 1.910e+007-2.501e+007 to 2.069e+007-2.126e+007 to 2.444e+0071.002e+008 to 1.440e+0087.146e+007 to 1.152e+0086.493e+007 to 1.097e+008-5.066e+007 to -6.899e+006-5.719e+007 to -1.245e+007-2.841e+007 to 1.633e+007YesYesYesNoNoNoYesYesYesYesYesNo************nsnsns*****************nsD a y  2 4D a y  2 8Vehicle BMS309403 SBFI-26 BMS + SBFI-26Day 28

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

https://knowledgeconnection.mainehealth.org/cgi/viewcontent.cgi?article=1016&context=lambrew-retreat-2021

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

Abstract

Similar works

Full text

Available Versions

MaineHealth Knowledge Connection