Novel DNA damage response therapeutics targeting replication protein A

针对复制蛋白 A 的新型 DNA 损伤反应疗法

基本信息

项目摘要

Novel DNA damage response therapeutics targeting replication protein A Abstract The DNA damage response (DDR) is now considered a tractable pathway to target for cancer therapy. The DDR and DNA repair pathways are also amenable to personalized therapies by exploiting synthetic lethal interactions as evidenced by the clinical success of PARP inhibitors in homologous recombination (HR) deficient cancers. The DDR is initiated by engagement of the PI3 kinase-related kinases ATM, ATR, and DNA- PK. These kinases and the downstream checkpoint kinases CHK1 and CHK2, are clinically validated targets being actively investigated in multiple clinical trials. A novel target in the DDR pathway is the human single stranded DNA binding protein, replication protein A (RPA) which plays a critical role in the DDR to detect replication stress (RS) and signal to the ATR kinase. RS is a common feature in cancer cells and provides the therapeutic window for the anticancer activity of DDR targeted drugs. RS coupled with a DDR blockade results in replication catastrophe (RC) and eventually cell death. RPA is a critical protector from RC and depletion of RPA or “RPA exhaustion” can elicit RC and cell death when there is insufficient single-strand DNA binding capacity to protect the genomic DNA. We have identified a potent and selective small molecule RPA inhibitor (RPAi), NERx 329, which possesses biochemical RPA inhibition and cellular engagement of RPA. NERx 329 also displays no overt toxicity in vivo and possesses anticancer activity alone and in combination with DNA damaging chemotherapeutics and certain DDR targeted agents. While the anticancer activity could be the result of inhibiting RPA’s role in individual repair or replication pathways, our published and preliminary data point to a more global mechanism of action. Our overarching hypothesis is that chemical inhibition of RPA can mimic RPA exhaustion to inhibit the DDR and provide selective anticancer activity via novel genetic interactions common in lung and ovarian cancer. To address this hypothesis, we will elucidate the mechanisms and determinants of the cellular anticancer activity of our novel RPAi. We will focus on two cancers types, high grade serous epithelial ovarian cancer (EOC) and non-small cell lung cancer (NSCLC), as our analysis of clinical survival data reveals an important role for RPA in these cancers. In Aim 1 we will interrogate how chemical exhaustion of RPA impacts RS and the DDR in lung and ovarian cancer. Aim 2 will focus on elucidating the genetic determinants of sensitivity to RPAi’s. We will identify novel chemical-genetic interactions in a DDR focused CRISPR screen assessing RPAi activity. Clinically relevant genetic interactions will be identified in a unique series of PD-EOC spheroid lines we have developed. Whole genome sequencing will identify genetic alterations and chromosomal rearrangements which may correlate with response to RPAi therapy. From these studies, specific genetic alterations that impact RPAi sensitivity will be validated with in vivo PDX models of lung and ovarian cancer and DDR targeted developmental therapeutic agents. Completion of these aims will define RPAi mechanism of action and the genetic interactions that dictate RPAi sensitivity. These data are crucial towards developing novel DDR targeted cancer therapeutics and identifying the relevant genetics characteristics to maximize patient response and efficacy.
针对复制蛋白 A 的新型 DNA 损伤反应疗法 抽象的 DNA 损伤反应 (DDR) 现在被认为是癌症治疗靶点的一种易于处理的途径。这 DDR 和 DNA 修复途径也适合通过利用合成致死剂进行个性化治疗 PARP 抑制剂在同源重组 (HR) 中的临床成功证明了相互作用 缺乏癌症。 DDR 是由 PI3 激酶相关激酶 ATM、ATR 和 DNA 的参与启动的 PK。这些激酶和下游检查点激酶 CHK1 和 CHK2 是经过临床验证的靶标 正在多项临床试验中积极研究。 DDR途径中的一个新靶标是人类单克隆抗体 链状 DNA 结合蛋白、复制蛋白 A (RPA) 在 DDR 检测中发挥着关键作用 复制应激 (RS) 和 ATR 激酶信号。 RS 是癌细胞的一个常见特征,并提供 DDR靶向药物抗癌活性的治疗窗口。 RS 与 DDR 封锁结果相结合 复制灾难(RC)并最终导致细胞死亡。 RPA 是防止 RC 和资源耗尽的重要保护者 当单链 DNA 结合不足时,RPA 或“RPA 耗尽”会引发 RC 和细胞死亡 保护基因组DNA的能力。我们已经鉴定出一种有效且选择性的小分子 RPA 抑制剂 (RPAi),NERx 329,具有生化 RPA 抑制作用和 RPA 的细胞参与作用。 NERx 329 在体内也没有表现出明显的毒性,并且单独和与 DNA 结合都具有抗癌活性 破坏性化疗药物和某些 DDR 靶向药物。虽然抗癌活性可能是 抑制 RPA 在个体修复或复制途径中的作用的结果,我们已发表的初步数据 指出一个更加全球性的行动机制。我们的总体假设是化学抑制 RPA 可以模仿 RPA 耗竭来抑制 DDR,并通过新颖的方法提供选择性抗癌活性 肺癌和卵巢癌中常见的遗传相互作用。为了解决这个假设,我们将阐明 我们的新型 RPAi 的细胞抗癌活性的机制和决定因素。我们将重点关注两个 癌症类型,高级别浆液性上皮性卵巢癌(EOC)和非小细胞肺癌(NSCLC),如 我们对临床生存数据的分析揭示了 RPA 在这些癌症中的重要作用。在目标 1 中,我们将 探究 RPA 的化学耗尽如何影响肺癌和卵巢癌中的 RS 和 DDR。目标2将 重点是阐明对 RPAi 敏感的遗传决定因素。我们将鉴定新的化学遗传 评估 RPAi 活性的 DDR 聚焦 CRISPR 筛选中的相互作用。临床相关的遗传相互作用 将在我们开发的一系列独特的 PD-EOC 球体系中被识别。全基因组测序 将识别可能与 RPAi 反应相关的基因改变和染色体重排 治疗。从这些研究中,将验证影响 RPAi 敏感性的特定基因改变 肺癌和卵巢癌的体内 PDX 模型和 DDR 靶向发育治疗药物。完成 这些目标将定义 RPAi 的作用机制以及决定 RPAi 敏感性的遗传相互作用。 这些数据对于开发新型 DDR 靶向癌症疗法和确定相关的治疗方法至关重要。 遗传特征,以最大限度地提高患者的反应和疗效。

项目成果

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JOHN J. TURCHI其他文献

JOHN J. TURCHI的其他文献

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{{ truncateString('JOHN J. TURCHI', 18)}}的其他基金

Novel DNA damage response therapeutics targeting replication protein A
针对复制蛋白 A 的新型 DNA 损伤反应疗法
  • 批准号:
    10317276
  • 财政年份:
    2021
  • 资助金额:
    $ 49.69万
  • 项目类别:
Novel DNA damage response therapeutics targeting replication protein A
针对复制蛋白 A 的新型 DNA 损伤反应疗法
  • 批准号:
    10653707
  • 财政年份:
    2021
  • 资助金额:
    $ 49.69万
  • 项目类别:
Targeting nucleotide excision repair in combination cancer therapy
联合癌症治疗中的靶向核苷酸切除修复
  • 批准号:
    8652165
  • 财政年份:
    2013
  • 资助金额:
    $ 49.69万
  • 项目类别:
Development of Novel Agents Targeting Genome Stability and Maintenance for Treati
针对治疗的基因组稳定性和维持的新型药物的开发
  • 批准号:
    8649744
  • 财政年份:
    2013
  • 资助金额:
    $ 49.69万
  • 项目类别:
Targeting nucleotide excision repair in combination cancer therapy
联合癌症治疗中的靶向核苷酸切除修复
  • 批准号:
    8898026
  • 财政年份:
    2013
  • 资助金额:
    $ 49.69万
  • 项目类别:
Targeting nucleotide excision repair in combination cancer therapy
联合癌症治疗中的靶向核苷酸切除修复
  • 批准号:
    8743197
  • 财政年份:
    2013
  • 资助金额:
    $ 49.69万
  • 项目类别:
Development of Novel Agents Targeting Genome Stability and Maintenance for Treati
针对治疗的基因组稳定性和维持的新型药物的开发
  • 批准号:
    8201446
  • 财政年份:
    2012
  • 资助金额:
    $ 49.69万
  • 项目类别:
Development of methodologies for the analysis of DNA repair capacity to predict t
开发分析 DNA 修复能力以预测 t 的方法
  • 批准号:
    7434231
  • 财政年份:
    2008
  • 资助金额:
    $ 49.69万
  • 项目类别:
Development of methodologies for the analysis of DNA repair capacity to predict t
开发分析 DNA 修复能力以预测 t 的方法
  • 批准号:
    7682236
  • 财政年份:
    2008
  • 资助金额:
    $ 49.69万
  • 项目类别:
RECOGNITION AND REPAIR OF CISPLATIN DNA DAMAGE
顺铂 DNA 损伤的识别和修复
  • 批准号:
    6633491
  • 财政年份:
    2000
  • 资助金额:
    $ 49.69万
  • 项目类别:

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