MSK SPORE in Genomic Instability in Breast Cancer

MSK SPORE 在乳腺癌基因组不稳定性中的作用

• 批准号: 10704063
• 负责人: Simon N. Powell
• 金额: $ 227.48万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-13 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704063
• 关键词: Address; Area; Biological; Biological Models; Biology; Breast Cancer Risk Factor; Cell Line; Cell Survival; Cell Transplantation; Cell model; Cessation of life; Characteristics; Chromosomal Instability; Clinical; Clinical Trials; Clinical Trials Design; Clustered Regularly Interspaced Short Palindromic Repeats; Core Facility; Correlative Study; DNA; DNA sequencing; Development; Diagnosis; Disease; Disease Outcome; Enzymes; Estrogen receptor positive; Evaluation; Genes; Genetic; Genetic Screening; Genome; Genomic Instability; Genomics; Goals; Grouping; Growth; Heterogeneity; Immune response; Immune signaling; Incidence; Institution; Knowledge; Link; Malignant Neoplasms; Memorial Sloan-Kettering Cancer Center; Minnesota; Modeling; Mutagenesis; Mutation; Neoplasm Metastasis; Neoplasm Transplantation; Pathogenesis; Pathologic; Patient-Focused Outcomes; Patients; Pattern; Phenotype; Poly(ADP-ribose) Polymerase Inhibitor; Process; Prognosis; Proteins; Recurrence; Reproduction spores; Research; Research Project Grants; Resistance development; Resolution; Risk Taking; Role; Sampling; Structure; Testing; Therapeutic; Time; Translational Research; Universities; acquired drug resistance; biomarker development; cancer type; career; cell behavior; cell free DNA; cell growth; cellular engineering; clinical application; clinical biomarkers; clinical development; design; diagnostic tool; disorder subtype; genetically modified cells; genome sequencing; genomic profiles; high risk; homologous recombination; improved; improved outcome; innovation; insight; malignant breast neoplasm; medical schools; mouse model; novel; novel strategies; novel therapeutics; patient derived xenograft model; programs; protein expression; response; success; targeted treatment; therapeutic target; translational goal; tumor; tumor behavior; whole genome

ABSTRACT The research projects proposed in this SPORE address genomic instability in breast cancer. Three areas are the focus of study: homologous recombination deficiency, chromosomal instability and APOBEC mutagenesis. Our ultimate plan is to exploit tumor specific vulnerabilities by virtue of their underlying genomic instability. These profiles of genomic instability have offered novel insights about the drivers breast cancer development and progression. There are opportunities for therapeutic advances in breast cancer, which have emerged based on the initial successes, for example, in utilizing homologous recombination deficiency by treatment with a PARP inhibitor. The plan is to determine the optimal use of these agents and develop novel agents for these tumors. Chromosomal instability, which does not necessarily have a unique pattern of mutations, is associated with a poor prognosis, but no specific therapeutic strategy at present. The link between chromosomal instability and innate immune signaling has been made, and the goal is to exploit this connection for therapy. For APOBEC, we know that a characteristic pattern of SNVs are observed, but in this application, we are highlighting the role of APOBEC in the acquisition of drug resistance, and introducing novel approaches for reliably identifying and therapeutically targeting breast cancers with an active APOBEC mutagenesis process. In summary, the goals are to take the risks of genomic instability (poor prognosis, rapid development of resistance) and turn genomic instability into an advantage for therapeutic targeting, thereby improving the prognosis for high risk breast cancers.

抽象的 该孢子中提出的研究项目针对乳腺癌的基因组不稳定性。三个领域 研究重点：同源重组缺乏，染色体不稳定性和APOBEC诱变。 我们的最终计划是通过其潜在的基因组不稳定性来利用特定的肿瘤。 这些基因组不稳定性的特征提供了有关驱动因素乳腺癌发展的新见解 和进展。在乳腺癌中有治疗进展的机会，已经出现了 例如，基于最初的成功，例如，通过与 PARP抑制剂。该计划是确定这些试剂的最佳用途，并为这些代理开发新颖的代理 肿瘤。染色体不稳定性不一定具有独特的突变模式，与 预后较差，但目前尚无具体的治疗策略。染色体之间的联系 已经进行了不稳定性和先天的免疫信号传导，目的是利用这种联系进行治疗。 对于Apobec，我们知道观察到SNV的特征模式，但是在此应用中，我们是 强调Apobec在获取耐药性中的作用，并引入新的方法 可靠地识别和治疗靶向乳腺癌，并具有活性的APOBEC诱变过程。 总而言之，目标是承担基因组不稳定性的风险（预后不良，快速发展 抗性）并将基因组不稳定性变成治疗靶向的优势，从而改善了 高风险乳腺癌的预后。

项目成果

Genomic characterization of small cell carcinomas of the uterine cervix.

• DOI: 10.1002/1878-0261.12962
• 发表时间: 2022-03
• 期刊: Molecular oncology
• 影响因子: 6.6
• 作者: Schultheis AM;de Bruijn I;Selenica P;Macedo GS;da Silva EM;Piscuoglio S;Jungbluth AA;Park KJ;Klimstra DS;Wardelmann E;Hartmann W;Gerharz CD;von Petersdorff M;Buettner R;Reis-Filho JS;Weigelt B
• 通讯作者: Weigelt B

Mutational impact of APOBEC3A and APOBEC3B in a human cell line and comparisons to breast cancer.

• DOI: 10.1371/journal.pgen.1011043
• 发表时间: 2023-11
• 期刊: PLoS genetics
• 影响因子: 4.5

Intratumor genetic heterogeneity and clonal evolution to decode endometrial cancer progression.

• DOI: 10.1038/s41388-022-02221-0
• 发表时间: 2022-03
• 期刊: Oncogene
• 影响因子: 8
• 作者: Mota A;Oltra SS;Selenica P;Moiola CP;Casas-Arozamena C;López-Gil C;Diaz E;Gatius S;Ruiz-Miro M;Calvo A;Rojo-Sebastián A;Hurtado P;Piñeiro R;Colas E;Gil-Moreno A;Reis-Filho JS;Muinelo-Romay L;Abal M;Matias-Guiu X;Weigelt B;Moreno-Bueno G
• 通讯作者: Moreno-Bueno G

Implications of Selection Bias Due to Delayed Study Entry in Clinical Genomic Studies.

• DOI: 10.1001/jamaoncol.2021.5153
• 发表时间: 2022-02-01
• 期刊: JAMA ONCOLOGY
• 影响因子: 28.4
• 作者: Brown, Samantha;Lavery, Jessica A.;Shen, Ronglai;Martin, Axel S.;Kehl, Kenneth L.;Sweeney, Shawn M.;Lepisto, Eva M.;Rizvi, Hira;McCarthy, Caroline G.;Schultz, Nikolaus;Warner, Jeremy L.;Park, Ben Ho;Bedard, Philippe L.;Riely, Gregory J.;Schrag, Deborah;Panageas, Katherine S.
• 通讯作者: Panageas, Katherine S.

Genomic Profiling Reveals Germline Predisposition and Homologous Recombination Deficiency in Pancreatic Acinar Cell Carcinoma.

基因组分析揭示胰腺腺泡细胞癌的种系易感性和同源重组缺陷。

• DOI: 10.1200/jco.23.00561
• 发表时间: 2023
• 期刊: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
• 作者: Mandelker,Diana;Marra,Antonio;Zheng-Lin,Binbin;Selenica,Pier;Blanco-Heredia,Juan;Zhu,Yingjie;Gazzo,Andrea;Wong,Donna;Yelskaya,Zarina;Rai,Vikas;Somar,Joshua;Ostafi,Silvana;Mehta,Nikita;Yang,Ciyu;Li,Yirong;Brown,DavidN;daSi
• 通讯作者: daSi