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 本 SPORE 中提出的研究项目解决了乳腺癌的基因组不稳定性问题。三个区域是 研究重点：同源重组缺陷、染色体不稳定和APOBEC突变。 我们的最终计划是利用肿瘤潜在的基因组不稳定性的特定漏洞。 这些基因组不稳定性特征为乳腺癌发展的驱动因素提供了新的见解 和进展。乳腺癌治疗有机会取得进展，这些进展已经出现 基于最初的成功，例如，通过治疗利用同源重组缺陷 PARP 抑制剂。该计划是确定这些药物的最佳用途并为这些药物开发新药物 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，但目前尚无特效治疗策略。染色体之间的联系 不稳定和先天免疫信号传导已经建立，目标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，但在此应用中，我们是 强调 APOBEC 在获得耐药性中的作用，并介绍新的方法 通过主动 APOBEC 诱变过程可靠地识别乳腺癌并进行治疗。 总之，目标是承担基因组不稳定的风险（预后不良、疾病快速发展） 耐药性）并将基因组不稳定性转化为治疗靶向的优势，从而改善 高风险乳腺癌的预后。

项目成果

Re-awakening Innate Immune Signaling in Cancer: The Development of Highly Potent ENPP1 Inhibitors.

重新唤醒癌症中的先天免疫信号：高效 ENPP1 抑制剂的开发。

• 发表时间: 2020-11-19
• 影响因子: 8.6
• 作者: Cogan, Derek;Bakhoum, Samuel F
• 通讯作者: Bakhoum, Samuel F

Pancreatoblastomas and mixed and pure acinar cell carcinomas share epigenetic signatures distinct from other neoplasms of the pancreas.

胰母细胞瘤以及混合性和纯腺泡细胞癌具有与其他胰腺肿瘤不同的表观遗传特征。

• 发表时间: 2022-07
• 作者: Benhamida, Jamal K;Vyas, Monika;Tanaka, Atsushi;Wang, Lu;Bahrami, Armita;Ozcan, Kerem;Basturk, Olca;Villafania, Liliana;Mata, Douglas A;El Jabbour, Tony;Selenica, Pier;Roehrl, Michael H A;Weigelt, Britta;Reis;Scaltriti, Mauriz
• 通讯作者: Scaltriti, Mauriz

Biochemical, genomic, and epigenomic profiling of isolated cancer cell lines' micronuclei.

分离的癌细胞系微核的生化、基因组和表观基因组分析。

• 发表时间: 2022
• 作者: Agustinus, Albert S;Bakhoum, Samuel
• 通讯作者: Bakhoum, Samuel

Clinicopathologic and genomic features of lobular like invasive mammary carcinoma: is it a distinct entity?

小叶样浸润性乳腺癌的临床病理学和基因组特征：它是一个独特的实体吗？

• DOI: 10.1038/s41523-023-00566-7
• 发表时间: 2023-07-13
• 期刊: NPJ Breast Cancer
• 影响因子: 5.9
• 作者: Yu, Jing;da Silva, Edaise M.;La, Hae-Sun;Clark, Beth Z.;Fine, Jeffrey L.;Carter, Gloria J.;Villatoro, Tatiana M.;Soong, T. Rinda;Lee, Adrian V.;Oesterreich, Steffi;Basili, Thais;Blanco-Heredia, Juan;Selenica, Pier;Ye, Qiqi;Paula, Arnaud Da Cruz;Dopeso, Higinio;Gazzo, Andrea;Marra, Antonio;Pareja, Fresia;Reis-Filho, Jorge S.;Bhargava, Rohit
• 通讯作者: Bhargava, Rohit

Paired Tumor-Normal Sequencing Provides Insights Into the TP53-Related Cancer Spectrum in Patients With Li-Fraumeni Syndrome.

肿瘤-正常配对测序可深入了解 Li-Fraumeni 综合征患者的 TP53 相关癌症谱。

• 发表时间: 2021-11-29
• 作者: Ceyhan;Selenica, Pier;Chui, M Herman;Jayakumaran, Gowtham;Ptashkin, Ryan;Misyura, Maksym;Aypar, Umut;Jairam, Sowmya;Yang, Ciyu;Li, Yirong;Mehta, Nikita;Kemel, Yelena;Salo;Maio, Anna;Sheehan, Margaret;Zehir, Ahmet
• 通讯作者: Zehir, Ahmet