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

项目摘要/摘要 卵巢上皮癌(EOC)是最致命的妇科恶性肿瘤，被诊断出的病例超过 全球每年有225,000名女性，大多数患者表现为晚期、高级别浆膜腔积液 卵巢癌(HGSOC)。尽管手术和化疗方法有所改进，但总体而言， 几十年来，死亡率没有显著变化。护理的标准包括手术除杂和调整- 用铂类化合物和紫杉烷进行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。 塞斯。ICL的修复依赖于Fanconi贫血和BRCA蛋白，这是同源修复所必需的 组合。卵巢上皮性癌是对化疗最敏感的上皮性肿瘤之一，对 以铂为基础的化疗。上皮性卵巢癌对铂的显著敏感性被认为与其 人力资源部。不幸的是，80%-90%的患者复发并患上抗药性疾病。此外，约20%的 患者在确诊时患有铂类难治性疾病。因此，存在着严重的未得到满足的临床需求 预测EOCs的铂敏感性的方法，以及单独使用或联合应用的治疗方法 与铂化合物结合以克服耐药性。我们PTRC的目标是加强我们的 能够预测哪些EOCs对DNA损伤的铂治疗有反应，了解 耐药性，并在耐药疾病中确定潜在的新药靶点，以指出迫切需要的新药物 这些患者的治疗方法。 我们的蛋白质基因组翻译研究中心将对EoC前倾斜率进行蛋白质基因组分析- CAL模型(患者来源的异种移植物和细胞系)治疗前后用铂添加和帮助 优先考虑文献中所涉及的铂反应的潜在预测蛋白靶点。在……里面 我们的临床部门，我们将使用基于靶向多反应监测(MRM)的质谱学分析来 量化通过NCI资助的试验获得的肿瘤标本中的潜在预测蛋白靶点，以测试其 与治疗反应有关。此外，还有一个不完美和不完全理解的重叠 铂和PARP抑制剂之间的肿瘤反应(PARPI)；因此，在一个探索性的子目标中，我们将去 白金反应的蛋白质组相关末端也与PARPI的反应相关 (例如，基于同源重组(HR)介导的DNA修复中的潜在缺陷)。

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).