Project 4: Targeting Genomic Instability in Distinct Subclasses of Prostate Cancer

摘要：项目4 基因组不稳定是人类癌症的一个基本特征。某些癌症类型存在潜在缺陷 因此特别容易受到引入DNA损伤的治疗策略的影响(例如， BRCA1突变乳腺癌和卵巢癌)。在前列腺癌(PCA)中，结构性基因组重排， 包括易位和拷贝数异常，是肿瘤发生的常见机制。 然而，易发生染色体重排的前列腺癌的遗传改变在很大程度上仍未确定。 全基因组测序表明，PCa在SPOP(SPOPmut)中存在反复出现的点突变 与其他临床定位的PCAS相比，PCAS的基因组重排数量显著增加。 这些观察结果增加了SPOP突变的可能性，SPOP突变是前列腺癌发生的早期事件，导致 基因组的不稳定性。 初步研究表明，大约10%的前列腺癌是SPOPmut，这些突变代表着一种独特的 分子亚类。体外初步研究表明，表达SPOP突变的细胞 由于DNA修复过程的改变而积累DNA双链断裂(DSB)。与这个孢子有关 项目中，我们已经证明了SPOP突变导致对DNA损伤治疗的敏感性增加 例如电离辐射和聚(ADP-核糖)聚合酶(PARP)抑制剂。基于这些 观察到，我们假设SPOP突变促进了基因组重排的积累 通过受损的DSB修复和Pca的SPOPmut亚类可能选择性地对DNA- 破坏性治疗，提名替代治疗策略。我们将使用一个 新型体外平台(有机类)用于研究内源性SPOP突变，体内小鼠模型测试 SPOP突变对DNA损伤反应的影响和患者样本确定SPOP突变的反应 患者接受DNA损伤治疗。 这个高度协作的项目汇集了由PCF和SU2C支持的知名调查人员- PCF现在将研究SPOPmut PCA的翻译方面。使用有机化合物，最先进的鼠标 模型和尖端的患者分析，我们将影响使用DNA损伤剂的临床试验如何 合理设计和分析。

SUMMARY: PROJECT 4 Genomic instability is a fundamental feature of human cancer. Certain cancer types harbor underlying defects in DNA repair and thus are particularly susceptible to therapeutic strategies introducing DNA damage (e.g., BRCA1 mutant breast and ovarian cancers). In prostate cancer (PCa), structural genomic rearrangements, including translocations and copy number aberrations, are a common mechanism driving tumorigenesis. However, genetic alterations in PCa predisposing to chromosomal rearrangements remain largely undefined. Whole genome sequencing demonstrates that PCa harboring recurrent point mutations in SPOP (SPOPmut) display significantly higher numbers of genomic rearrangements compared with other clinically localized PCas. These observations raise the possibility that SPOP mutations, early events in PCa tumorigenesis, lead to genomic instability. Preliminary studies demonstrate that around 10% of PCa are SPOPmut, and these represent a distinct molecular subclass. Preliminary studies in vitro demonstrate that cells expressing SPOP mutations accumulate DNA double-strand breaks (DSBs) due to altered DNA repair processes. Relevant to this SPORE project, we have shown that SPOP mutation results in increased sensitivity to DNA-damaging therapeutic agents such as ionizing radiation and poly (ADP-ribose) polymerase (PARP) inhibitors. Based on these observations, we hypothesize that SPOP mutation promotes accumulation of genomic rearrangements through impaired DSB repair and the SPOPmut subclass of PCa may be selectively responsive to DNA- damaging therapeutics, nominating alternative treatment strategies. We will test this hypothesis using a novel in vitro platform (organoids) to study endogenous SPOP mutations, in vivo mouse models testing the effect SPOP mutation on DNA damage response, and patient samples to define the response of SPOPmut patients to DNA damaging therapies. This highly collaborative project brings together established investigators supported by the PCF and SU2C- PCF who will now study the translational aspects of SPOPmut PCa. Using organoids, state-of-the-art mouse models, and cutting edge patient analyses, we will impact how clinical trials using DNA-damaging agents are rationally designed and analyzed.