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).

项目总结/摘要 上皮性卵巢癌（EOC）是最致命的妇科恶性肿瘤， 全球每年有225，000名女性，大多数患者表现为晚期，高级别浆液性 卵巢癌（HGSOC）。尽管手术和化疗方法有所改进，但总体莫尔 几十年来，总体情况没有发生重大变化。标准治疗包括手术减积加调整- 用铂化合物和紫杉烷类进行vant/新辅助联合化疗。 铂化合物通过诱导嘌呤碱基之间的链内和链间交联（ICL）来损伤DNA。 ses。ICL的修复依赖于范可尼贫血和BRCA蛋白，这是同源重组所必需的。 组合.上皮性卵巢癌是最敏感的上皮性肿瘤之一，对化疗的初始反应率约为75%。 含铂化疗EOC肿瘤的惊人铂敏感性被认为与它们的 人力资源开发部。不幸的是，80-90%的患者会复发并出现耐药性疾病。此外，约20%的 患者在诊断时患有铂难治性疾病。因此，存在关键的未满足的临床需求， 用于预测EOC的铂反应性的方法，以及用于可以单独使用或与 与铂化合物组合以克服耐药性。我们的PTRC的目标是提高我们的 能够预测哪些EOC将对DNA损伤性铂类药物治疗产生反应， 耐药性，并确定耐药疾病的潜在新药靶点，以指出迫切需要的新的 为这些患者提供治疗方法。 我们的蛋白基因组转化研究中心将进行EOC preclini的蛋白基因组分析， cal模型（患者来源的异种移植物和细胞系）治疗前和治疗后使用铂添加和帮助 优先考虑文献中涉及的铂反应的潜在预测蛋白质靶点。在 我们的临床部门，我们将使用靶向多反应监测（MRM）质谱分析， 量化通过国家癌症研究所资助的试验获得的肿瘤标本中潜在的预测蛋白质靶点，以测试其 与对治疗的反应有关。此外，还有一个不完善和不完全理解的重叠， 铂和PARP抑制剂（PARPi）之间的肿瘤反应;因此，在探索性子目标中，我们将 铂反应的蛋白基因组学相关性也与PARPi反应相关 (e.g.基于同源重组（HR）介导的DNA修复中的潜在缺陷）。

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

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

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

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

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