Role of SLAMF7 in Racial Disparities in Myeloma

SLAMF7 在骨髓瘤种族差异中的作用

• 批准号: 10648048
• 负责人: Yubin Kang
• 金额: $ 23.48万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648048
• 关键词: Affect; African American; African American population; Age; Antibodies; Archives; Automobile Driving; B lymphocyte-induced maturation protein 1; Binding; Biological Assay; Biological Markers; Biopsy Specimen; Blood; Bone Marrow Transplantation; Bone marrow biopsy; Caring; Cells; Characteristics; Chromosomal translocation; Chromosome abnormality; Clinical; Cytogenetics; Data Mart; Disease; Disparity; Effectiveness; Exhibits; FDA approved; Family member; Genetic Transcription; Genotype; Goals; Hematologic Neoplasms; Human; Incidence; Inferior; Knowledge; Length; Luciferases; Malignant Neoplasms; Mediating; Medical Records; Messenger RNA; Mission; Molecular Abnormality; Monoclonal Antibodies; Multiple Myeloma; Mutation; Outcome; Patient Care; Patient-Focused Outcomes; Patients; Persons; Plasma Cells; Play; Population; Public Health; Race; Refractory; Regimen; Reporter; Research; Retrospective cohort study; Role; SLAM protein; Secondary to; Single Nucleotide Polymorphism; Site-Directed Mutagenesis; Stem cell transplant; System; Testing; Treatment Protocols; United States; United States National Institutes of Health; Up-Regulation; Work; cell growth; chromatin immunoprecipitation; comorbidity; crosslink; disability; economic determinant; effective therapy; experience; high risk; improved; innovation; new technology; promoter; protein expression; racial disparity; response; social; therapeutic target; translational impact; tumorigenesis

Project Summary Our long-term goal is to improve the care and outcomes of all patients with multiple myeloma (MM), particularly African American (AA) patients to reduce racial disparity. MM exhibits one of the most striking racial disparities between AA and White persons. MM has a 2-3 fold higher incidence and occurs at much earlier age in AA persons. We found that the outcomes of AA patients with translocation t(11;14) myeloma were inferior to White patients even after adjusted for comorbidities, disease stage, the length of treatment, and the use of blood and bone marrow transplantation, etc. The mechanism for this racial disparity is unclear. We recently found that MM cells from AA patients had a higher expression of the signaling lymphocyte activation molecule family member 7 (SLAMF7) and were more sensitive to the inhibition by SLAMF7 antibody crosslinking. The objective of this proposal is to determine the effects of elotuzumab (an FDA approved, humanized SLAMF7 monoclonal antibody) in AA and White patients with t(11;14) MM and the mechanism underlying the differences in SLAMF7 expression between AA and White patients with t(11;14) MM. Our central hypothesis is that elotuzumab is particularly effective in AA patients with t(11;14) MM because of the higher expression of SLAMF7. Additionally, we hypothesized that A>G single nucleotide polymorphism (SNP) at -742 of SLAMF7 promoter affects Blimp- 1- mediated SLAMF7 gene transcription and results in the differences in SLAMF7 expression between AA patients and White patients with t(11;14) MM. The rationale for the proposed study is that with greater understanding of the effectiveness of elotuzumab in AA patients with t(11;14) MM and the impact of this SNP, we will be able to develop a more effective treatment regimen and biomarkers to reduce racial disparities. We have two specific aims. Aim 1 is to determine the clinical outcomes of AA patients with t(11;14) myeloma and White patients with t(11;14) myeloma in response to elotuzumab-based treatment. A retrospective cohort study incorporating patient characteristics and social economic determinants will be performed to examine the response and outcomes between AA patients with t(11;14) myeloma and White patients with t(11;14) myeloma treated with elotuzumab-based regimens. STAR PCORnet datamart will be used and medical records from a total of 257 patients with t(11;14) MM will be extracted and analyzed. Aim 2 is to determine the mechanism underlying the differences in SLAMF7 expression between AA patients with t(11;14) MM and White patients with t(11;14) MM. Chromatin immunoprecipitation assay, pGL-3 luciferase reporter system, site directed mutagenesis, and tetra primer-amplification refractory mutation system-PCR will be performed. Our research is innovative, because it incorporates novel technology and represents a new and substantive departure and significant advance from the status quo. Our study will not only fundamentally advance our knowledge of racial disparitie, but also have a positive translational impact on the care and outcomes of patients with MM, a disease that affects AA population disproportionally.

项目总结