Proteogenomic studies aimed at understanding ovarian tumor responses to agents targeting the DNA damage response and translating this knowledge into clinical benefit

蛋白质组学研究旨在了解卵巢肿瘤对针对 DNA 损伤反应的药物的反应，并将这些知识转化为临床益处

• 批准号: 10602812
• 负责人: Michael Birrer
• 金额: $ 95.13万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602812
• 关键词: Proteogenomic; studies; aimed; understanding; ovarian

Project Summary/Abstract Epithelial ovarian cancer (EOC), the most lethal gynecological malignancy, is diagnosed in more than 225,000 women worldwide each year, with most patients presenting with advanced-stage, high-grade serous ovarian cancers (HGSOC). Despite improvements in surgical and chemotherapeutic approaches, overall mor- tality has not changed significantly for decades. Standard of care involves surgical debulking plus adju- vant/neoadjuvant combination chemotherapy with platinum compounds and taxanes. Platinum compounds damage DNA by inducing intra- and inter-strand cross-links (ICL) between purine ba- ses. ICL repair depends on both Fanconi anemia and BRCA proteins, which are required for homologous re- combination. EOC is one of the most chemo-sensitive epithelial tumors, with initial response rates of ~75% to platinum-based chemotherapy. The striking platinum sensitivity of EOC tumors is thought to be related to their HRD. Unfortunately, 80-90% of patients suffer relapse and develop drug-resistant disease. Moreover, ~20% of patients have platinum-refractory disease at diagnosis. Thus, there are crucial unmet clinical needs for methods to predict platinum responsiveness of EOCs, and for treatments that can be used either alone or in combination with platinum compounds to overcome resistance. The goals of our PTRC are to enhance our ability to predict which EOCs will respond to DNA-damaging platinum therapy, to understand mechanisms of resistance, and to identify potential new drug targets in resistant disease to point to desperately-needed new therapeutic approaches for these patients. Our Proteogenomic Translational Research Center will perform proteo-genomic analyses of EOC preclini- cal models (patient-derived xenografts and cell lines) pre- and post-treatment with platinum to add to and help prioritize potential predictive protein targets of platinum response that have been implicated in the literature. In our Clinical Arm, we will use targeted multiple reaction monitoring (MRM) mass spectrometry-based assays to quantify potential predictive protein targets in tumor specimens obtained through NCI-funded trials, to test their association with response to therapy. In addition, there is an imperfect and incompletely understood overlap in tumor responses between platinum and PARP inhibitors (PARPi); thus, in an exploratory sub-aim, we will de- termine which proteogenomic correlates of platinum response are also associated with response to PARPi (e.g. based on underlying defects in homologous recombination (HR)-mediated DNA repair).

项目摘要/摘要 上皮卵巢癌（EOC）是最致命的妇科恶性肿瘤，被诊断出多于 每年全球225,000名女性，大多数患者出现高级，高级浆液 卵巢癌（HGSOC）。尽管手术和化学治疗方法有所改善，但 数十年来，泰尔斯没有发生重大变化。护理标准涉及外科手术剪裁加上辅助 VANT/NEOADJUVANT组合化疗与铂化合物和紫杉烷。 铂金通过诱导嘌呤BA-之间的链内和链间交联（ICL）来损害DNA SES。 ICL修复取决于fanconi贫血和BRCA蛋白，这是同源重复所必需的 组合。 EOC是最敏感的上皮肿瘤之一，初始反应率约为75％ 基于铂的化学疗法。 EOC肿瘤的引人注目的铂敏感性被认为与其 人力资源不幸的是，80-90％的患者患有复发并发展出耐药性疾病。此外，约有20％ 患者在诊断时患有铂 - 难治性疾病。因此，有关键的未满足的临床需求 预测EOC的铂反应性的方法，以及可以单独或中使用的治疗方法 结合铂化合物以克服抗性。我们的PTRC的目标是增强我们的 能够预测哪些EOC将对破坏DNA的铂疗法做出反应，以了解 抵抗，并确定抗性疾病中潜在的新药物靶标，以指向迫切需要的新药物 这些患者的治疗方法。 我们的蛋白质组学转化研究中心将对EOC Preclini-进行蛋白质基因组分析 CAL模型（患者衍生的异种移植物和细胞系）与铂二和治疗后进行添加和帮助 优先考虑与文献有关的铂反应的潜在预测蛋白靶标。在 我们的临床部门，我们将使用针对性的多个反应监测（MRM）基于质谱的测定法 量化通过NCI资助的试验获得的肿瘤标本中潜在的预测蛋白靶标，以测试其 与对治疗的反应有关。此外，在 铂和PARP抑制剂之间的肿瘤反应（PARPI）；因此，在一个探索性子aim中，我们将 术语哪种蛋白质组学的铂反应的相关性也与对PARPI的反应有关 （例如，基于同源重组（HR）介导的DNA修复的潜在缺陷）。

项目成果

DAGBagM: learning directed acyclic graphs of mixed variables with an application to identify protein biomarkers for treatment response in ovarian cancer.

• DOI: 10.1186/s12859-022-04864-y
• 发表时间: 2022-08-05
• 期刊: BMC bioinformatics
• 影响因子: 3

Targeted Mass Spectrometry Enables Quantification of Novel Pharmacodynamic Biomarkers of ATM Kinase Inhibition.

• DOI: 10.3390/cancers13153843
• 发表时间: 2021-07-30
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Whiteaker JR;Wang T;Zhao L;Schoenherr RM;Kennedy JJ;Voytovich U;Ivey RG;Huang D;Lin C;Colantonio S;Caceres TW;Roberts RR;Knotts JG;Kaczmarczyk JA;Blonder J;Reading JJ;Richardson CW;Hewitt SM;Garcia-Buntley SS;Bocik W;Hiltke T;Rodriguez H;Harrington EA;Barrett JC;Lombardi B;Marco-Casanova P;Pierce AJ;Paulovich AG
• 通讯作者: Paulovich AG

Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function.

• DOI: 10.1126/scisignal.abe2606
• 发表时间: 2021-08-24
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Salter AI;Rajan A;Kennedy JJ;Ivey RG;Shelby SA;Leung I;Templeton ML;Muhunthan V;Voillet V;Sommermeyer D;Whiteaker JR;Gottardo R;Veatch SL;Paulovich AG;Riddell SR
• 通讯作者: Riddell SR

A highly annotated database of genes associated with platinum resistance in cancer.

• DOI: 10.1038/s41388-021-02055-2
• 发表时间: 2021-11
• 期刊: Oncogene
• 影响因子: 8
• 作者: Huang D;Savage SR;Calinawan AP;Lin C;Zhang B;Wang P;Starr TK;Birrer MJ;Paulovich AG
• 通讯作者: Paulovich AG

Targeted Mass Spectrometry Enables Multiplexed Quantification of Immunomodulatory Proteins in Clinical Biospecimens.

• DOI: 10.3389/fimmu.2021.765898
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Whiteaker JR;Lundeen RA;Zhao L;Schoenherr RM;Burian A;Huang D;Voytovich U;Wang T;Kennedy JJ;Ivey RG;Lin C;Murillo OD;Lorentzen TD;Thiagarajan M;Colantonio S;Caceres TW;Roberts RR;Knotts JG;Reading JJ;Kaczmarczyk JA;Richardson CW;Garcia-Buntley SS;Bocik W;Hewitt SM;Murray KE;Do N;Brophy M;Wilz SW;Yu H;Ajjarapu S;Boja E;Hiltke T;Rodriguez H;Paulovich AG
• 通讯作者: Paulovich AG