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.

摘要

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

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.

The Evolution of STING Signaling and Its Involvement in Cancer.

• DOI: 10.1016/j.tibs.2020.12.010
• 发表时间: 2021-06
• 期刊: Trends in biochemical sciences
• 影响因子: 13.8
• 作者: Vashi N;Bakhoum SF
• 通讯作者: Bakhoum SF

Homologous recombination deficiency: how genomic signatures are generated.

• DOI: 10.1016/j.gde.2021.01.002
• 发表时间: 2021-03
• 期刊: Current opinion in genetics & development
• 影响因子: 4
• 作者: Setton J;Reis-Filho JS;Powell SN
• 通讯作者: Powell SN