Contribution of osteocytes to the musculoskeletal effects of Multiple Myeloma

骨细胞对多发性骨髓瘤肌肉骨骼效应的贡献

• 批准号: 10744924
• 负责人: Teresita M. Bellido
• 金额: $ 44.98万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744924
• 关键词: Alpha Cell; Angiogenic Factor; Animal Model; Antibodies; Autocrine Communication; Binding; Bone Diseases; Bone Marrow; Bortezomib; Cell Communication; Cells; Clinical; Coculture Techniques; Cytokine Receptors; Development; Dexamethasone; Disease; Disease Progression; Drug resistance; Endocrine; Fibroblast Growth Factor Receptors; Foundations; Funding; Genes; Genetic; Goals; Growth; Growth Inhibitors; Homeostasis; Human; In Vitro; Kidney; Knowledge; Malignant - descriptor; Malignant Neoplasms; Marrow; Mediating; Mediator; Mining; Molecular; Multiple Myeloma; Mus; Musculoskeletal; Osteocytes; Osteogenesis; Osteolytic; Outcome; Paracrine Communication; Pathogenesis; Pathologic; Pathologic Neovascularization; Patient-Focused Outcomes; Patients; Phenotype; Plasma Cells; Play; Proliferating; Proteasome Inhibitor; Quality of life; Refractory; Refractory Disease; Regimen; Research; Resistance; Role; Serum; Signal Transduction; Source; Stromal Cells; TRANCE protein; Testing; VEGFA gene; Work; Xenograft procedure; absorption; angiogenesis; autocrine; bone; bone health; clinical database; data mining; design; effective therapy; efficacy evaluation; fibroblast growth factor 23; fracture risk; heparanase; improved; in silico; in vivo; inhibitor therapy; innovation; inorganic phosphate; lenalidomide; mouse model; novel; novel therapeutic intervention; paracrine; pharmacologic; receptor; relapse patients; repaired; response; stem; targeted treatment; therapy resistant; tool; treatment response; tumor; tumor growth; tumor microenvironment

Summary Multiple myeloma (MM) is characterized by the growth of malignant plasma cells in the bone marrow supported by increased angiogenesis. Despite significant advances in treatments, MM remains incurable due to frequent relapses originating from MM cells refractory to therapy. Further, MM induces a devastating bone disease, increasing fracture risk and decreasing quality of life. The long-term goal of this proposal is to improve clinical outcomes in MM by defining targetable mechanisms underlying MM growth, responses to therapy, and bone destruction. The rationale stems from work from the previous funding period demonstrating that osteocytes (Ots) are an abundant and long-lived source of signals in the MM tumor microenvironment (TME) that supports MM growth and promote bone destruction; and that targeting Ot-MM cell interactions decreases MM growth and improves bone health. In studies leading to this application, we found that MM cells upregulate the expression of Fibroblast growth factor (FGF) 23 in Ots and discovered that Ots support angiogenesis and promote resistance to Bortezomib-based therapies. The specific goal of this proposal is to evaluate the efficacy of targeting local FGF23 derived from Ots to decrease tumor growth, repair damaged bone, and improve responses to therapy in MM. The central hypothesis is that Ot-derived FGF23 promotes MM progression, bone destruction, and refractory disease via local TME autocrine and paracrine signals mediated by the FGF23 co-receptor α-Klotho (αKL). This hypothesis will be tested in three specific aims: (1) Determine the contribution of Ot-derived FGF23 to MM tumor growth and bone disease by interfering with paracrine and/or autocrine FGF23-αKL signaling; (2) Determine the impact of Ot-derived Vascular endothelial growth factor A (VEGFA), a downstream target of FGF23, and other osteocyte-derived pro-angeogenic factors on the pathological angiogenesis in the MM-TME; and (3) Determine the role of FGF23 and the FGF23 target gene Heparanase (HPSE) on TME-induced resistance to Bortezomib-based therapies in MM cells. These aims will be pursued using a combination of innovative in vitro, in vivo, and in silico approaches, including cell-specific genetic tools, pharmacological approaches, human MM xenograft and immunocompentent mouse models of MM, primary cells from MM patients, scRNAseq analysis, and mining of MM patient genetic/clinical databases.

总结

项目成果

Aplidin (plitidepsin) is a novel anti-myeloma agent with potent anti-resorptive activity mediated by direct effects on osteoclasts.

• DOI: 10.18632/oncotarget.26831
• 发表时间: 2019-04-12
• 期刊: Oncotarget
• 作者: Delgado-Calle, Jesus;Kurihara, Noriyoshi;Bellido, Teresita
• 通讯作者: Bellido, Teresita

Antagonistic interplay between mechanical forces and glucocorticoids in bone: a tale of kinases.

• DOI: 10.1002/jcb.22660
• 发表时间: 2010-09-01
• 期刊: Journal of cellular biochemistry
• 影响因子: 4

Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis.

• DOI: 10.1186/s13045-018-0666-5
• 发表时间: 2018-10-04
• 期刊: Journal of hematology & oncology
• 影响因子: 28.5
• 作者: Petrusca DN;Toscani D;Wang FM;Park C;Crean CD;Anderson JL;Marino S;Mohammad KS;Zhou D;Silbermann R;Sun Q;Kurihara N;Galson DL;Giuliani N;Roodman GD
• 通讯作者: Roodman GD

Engineering a Pro-Osteogenic Secretome through the Transient Silencing of the Gene Encoding Secreted Frizzled Related Protein 1.

• DOI: 10.3390/ijms241512399
• 发表时间: 2023-08-03
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Garcia-Sanchez, Daniel;Gonzalez-Gonzalez, Alberto;Alvarez-Iglesias, Itziar;del Dujo-Gutierrez, Monica;Bolado-Carrancio, Alfonso;Certo, Matilde;Perez-Nunez, Maria Isabel;Riancho, Jose A.;Rodriguez-Rey, Jose Carlos;Delgado-Calle, Jesus;Perez-Campo, Flor Maria
• 通讯作者: Perez-Campo, Flor Maria

Deciphering Cancer and Bone Interactions for Therapeutic Benefits.

破译癌症和骨骼的相互作用以获得治疗效果。

• DOI: 10.1002/jbm4.10137
• 发表时间: 2019
• 期刊: JBMR plus
• 影响因子: 3.8
• 作者: Roodman,GDavid