Targeting centrosome‐mitotic kinases as a novel therapeutic approach against breast cancers in Hispanic/Latinas.

靶向中心体有丝分裂激酶作为治疗西班牙裔/拉丁裔乳腺癌的新方法。

基本信息

批准号：
10705160
负责人：
William Douglas Cress
金额：
$ 48.74万
依托单位：
PONCE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705160
关键词：
Address African African ancestry Age Aggressive behavior Aneuploidy Automobile Driving Biological Markers Biological Response Modifier Therapy Black Populations Black race Breast Cancer Patient Cancer Center Caribbean Hispanic Caribbean region Cell Line Cell Survival Cells Centrosome Cessation of life Chromosomal Instability Chromosomes Clinical Copy Number Polymorphism Cuban DNA sequencing Data Diagnosis Disparity Dominican E-Cadherin Estrogens Ethnic Origin European European ancestry Functional disorder Gene Expression Profile Generations Genetic Transcription Genome Genomics Goals Growth Hispanic Incidence Individual Invaded Laboratories Latina Population Latino Link Malignant Neoplasms Mammary Neoplasms Measures Mesenchymal Messenger RNA Mitotic Molecular Nature Neoplasm Metastasis Not Hispanic or Latino Organoids Outcome Pathology Pathway interactions Patient-derived xenograft models of breast cancer Patients Phosphorylation Phosphotransferases Prevalence Principal Investigator Probability Progesterone Prognosis Proliferating Publishing Puerto Rican Puerto Rico Race Relapse Research Personnel Risk Factors Sampling Signal Pathway Socioeconomic Status Survival Rate TBK1 gene Testing The Cancer Genome Atlas Tissue Microarray Treatment outcome Tumor Markers Tumor stage United States Vimentin Woman aurora kinase biobank black women breast cancer survival cancer cell cancer health disparity combinatorial epithelial to mesenchymal transition ethnic disparity experimental study high risk improved inhibitor malignant breast neoplasm migration mortality risk novel novel therapeutic intervention overexpression patient derived xenograft model prevent racial disparity racial diversity receptor recruit response slug stemness survival outcome transcription factor transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor growth tumor heterogeneity tumor initiation whole genome

项目摘要

Non-Hispanic black (NHB) and Hispanic/Latino (H/L) women in the United States (US) have higher probabilities of breast cancer-related death than non-Hispanic white (NHW) women. H/L women from the Caribbean (C-H/L, Puerto Rican, Cuban and Dominican) and black H/L are at an even higher risk of death than H/L from other regions and white H/L. This higher risk is in part due to NHB and C-H/L with breast cancers being more likely to be detected at younger ages, with tumors of higher stages and grades, and with triple-negative breast cancers (ER-PR- and Her2- or TNBC). African ancestry combined with less of the protective European genome greatly influences these risk factors in NHB and C-H/L women (on average having 79% and 27% African genomic contribution, respectively). Centrosome amplification-driven mitotic dysfunction leading to chromosome instability (CIN) and aneuploidy may also contribute to metastasis and poor clinical outcomes of these TNBC patients. The Co-PIs published that the centrosome/mitotic kinases TTK, NEK2, and TBK1 generate CA/CIN and that TTK and NEK2 drive the epithelial to mesenchymal transition (EMT). Preliminary data indicates that TTK, NEK2, and TBK1 mRNAs are dysregulated in NHB and TNBCs, and are overexpressed in breast tumors from C-H/L. Also, by using a novel NCI-BMAP3 region breast cancer tissue microarray (TMA) containing samples from NHW, NHB, and C-H/L women, the Co-PIs found that TTK and pTBK1 are overexpressed in TNBC and TTK correlates with EMT in TNBC. Inactivating TTK or TBK1 restored Rb in TNBC cells, suggesting it can restore Palbociclib responses. Co-inactivating TTK and TBK1 in TNBC cells reduced the levels of centrosome/mitotic regulators and EMT markers, and co-inactivating TTK/TBK1 or TTK/NEK2 significantly reduced the migration and invasion of TNBC. The study team hypothesizes that TTK, NEK2, and TBK1 dysregulation in C-H/L and NHB women with breast cancer (BC) is dictated by African ancestry and contributes to their poor survival outcomes by driving cancer cell survival and early metastasis. To test this hypothesis, the team proposes the following Specific Aims: (1) Investigating signaling pathways linking mitotic kinases to early metastasis and poor prognosis of non-Hispanic black (NHB), Caribbean Hispanic/Latino (C-H/L), and Hispanic/Latino (H/L) women with breast cancer. The team will determine if RNA expression signatures and copy number variations correlate with the expression of mitotic kinases with EMT markers, and survival outcomes, using RNA and DNA seq done by the ORIEN consortium and a novel TMA developed by the Puerto Rico Biobank. (2) To address how co-inactivation of mitotic kinases suppresses the mesenchymal state, metastasis, and restores Palbociclib responses in TNBC cells. This will be addressed by single and combinatorial inhibition of TTK, NEK2, and TBK1 in primary cell lines and PDX models of TNBC from NHB and H/L women with breast cancer. Results from the proposed experiments will help reduce ethnic/racial breast cancer disparities by identifying actionable targets (TTK, NEK2, TBK1, and other novel kinases found in Aim 1) against the aggressive growth and early metastatic progression in NHB and H/L women with TNBC.

美国 (US) 的非西班牙裔黑人 (NHB) 和西班牙裔/拉丁裔 (H/L) 女性的概率较高乳腺癌相关死亡的比例高于非西班牙裔白人 (NHW) 女性。来自加勒比地区的 H/L 女性（C-H/L，波多黎各人、古巴人和多米尼加人) 和黑人 H/L 的死亡风险甚至高于来自其他国家的 H/L 区域和白色 H/L。这种较高的风险部分是由于 NHB 和 C-H/L 乳腺癌更有可能发生在较年轻的年龄、较高阶段和级别的肿瘤以及三阴性乳腺癌中被发现（ER-PR- 和 Her2- 或 TNBC）。非洲血统与欧洲基因组的保护性较少相结合影响 NHB 和 C-H/L 女性的这些危险因素（平均有 79% 和 27% 的非洲基因组分别贡献）。中心体扩增驱动的有丝分裂功能障碍导致染色体不稳定性 (CIN) 和非整倍性也可能导致这些 TNBC 的转移和不良临床结果患者。 Co-PI 发表中心体/有丝分裂激酶 TTK、NEK2 和 TBK1 生成 CA/CIN TTK 和 NEK2 驱动上皮间质转化 (EMT)。初步数据表明 TTK、NEK2 和 TBK1 mRNA 在 NHB 和 TNBC 中失调，并在乳腺肿瘤中过度表达从C-H/L。此外，通过使用新型 NCI-BMAP3 区域乳腺癌组织微阵列 (TMA)，其中包含来自 NHW、NHB 和 C-H/L 女性的样本，Co-PI 发现 TTK 和 pTBK1 在 TNBC 中过度表达 TTK 与 TNBC 中的 EMT 相关。灭活 TTK 或 TBK1 可恢复 TNBC 细胞中的 Rb，这表明它可以恢复 Palbociclib 反应。在 TNBC 细胞中共同灭活 TTK 和 TBK1 可降低中心体/有丝分裂调节剂和 EMT 标记物，并显着共灭活 TTK/TBK1 或 TTK/NEK2 减少TNBC的迁移和侵袭。研究小组假设 TTK、NEK2 和 TBK1 患有乳腺癌 (BC) 的 C-H/L 和 NHB 女性的失调是由非洲血统决定的，并导致通过促进癌细胞存活和早期转移来导致其不良的生存结果。为了检验这个假设，团队提出以下具体目标：（1）研究有丝分裂激酶与早期细胞分裂之间的信号通路非西班牙裔黑人 (NHB)、加勒比西班牙裔/拉丁裔 (C-H/L) 和的转移和预后不良患有乳腺癌的西班牙裔/拉丁裔 (H/L) 女性。该团队将确定 RNA 表达特征和复制是否数量变化与具有 EMT 标记的有丝分裂激酶的表达以及生存结果相关，使用 ORIEN 联盟完成的 RNA 和 DNA 测序以及波多黎各开发的新型 TMA 生物样本库。 (2) 解决有丝分裂激酶的共失活如何抑制间充质状态、转移、并恢复 TNBC 细胞中的 Palbociclib 反应。这将通过单一和组合抑制来解决 TTK、NEK2 和 TBK1 在 NHB 和 H/L 乳腺癌女性 TNBC 的原代细胞系和 PDX 模型中的表达癌症。拟议实验的结果将有助于减少种族/种族乳腺癌差异识别可操作的靶点（TTK、NEK2、TBK1 和目标 1 中发现的其他新型激酶）患有 TNBC 的 NHB 和 H/L 女性的生长和早期转移进展。