Development of Novel Agents Targeting Genome Stability and Maintenance for Treati

描述(由申请人提供)：一旦观察到铂类药物耐药，上皮性卵巢癌(EOC)都是致命的。在每年近22,000例卵巢癌病例中，约有25%观察到先天耐药，这些病例中的癌症对铂治疗本质上是无效的。其余75%的妇女患有铂敏感症，缓解时间最长可达5年。然而，这些妇女中的大多数最终会患上复发的铂耐药癌症，并死于这种疾病。这些病程进展导致总的5年存活率为46%。为了应对这一持续而重大的临床问题，我们将利用铂疗法的机制和EOC的生物学特性，以一种新的治疗策略来实现基因组的稳定和维持。顺铂和卡铂都是通过形成铂-DNA加合物来传递化疗效果的，这些加合物可以阻止DNA复制和转录，最终导致细胞凋亡。通过核苷酸切除修复(NER)或同源重组修复(HRR)修复铂-DNA加合物会降低铂治疗的有效性。无论是固有的还是获得性耐药的EOC，通常都表现出DNA修复或损伤耐受性的变化，因此抑制DNA修复途径有可能使这些细胞对铂处理敏感。我们预计，修复途径上的直接作用机制和合成致死相互作用都可以用于治疗。为此，我们将继续开发和分析人类单链DNA结合蛋白复制蛋白A(RPA)的小分子抑制剂(SMI)。我们的方法是以蛋白质-DNA相互作用为目标，这可能会产生重大影响，从而使一类全新的相互作用成为目标。除了在NER和HRR中的重要作用(这为铂敏化提供了理论基础)外，RPA对于S期的DNA复制也是必不可少的，为快速分裂EOC细胞提供了一个有效的靶点。我们的数据表明，在肺癌和卵巢癌的细胞培养模型中，用小的类药物分子抑制RPA可以诱导抗癌活性。初步数据还表明，在小鼠身上没有明显的毒性，在人类癌症移植瘤中具有很强的抗肿瘤活性。我们将追求两个特定的目标，利用我们最近发现的先导RPA SMIs NERX-505X和NERX-313E，并推动这些分子用于治疗卵巢癌。因此，我们将：1)确定铅RPA SMIs作为单药以及与顺铂联合应用在铂敏感和耐药卵巢癌细胞系以及正常卵巢表面卵巢上皮细胞中的疗效；2)确定铅RPA SMIs的体内药代动力学特性，并评估使用含铂化合物的联合方案进行的异种移植毒性和有效性研究。这些研究的成功完成将支持第二阶段STTR申请，以进行研究性新药(IND)使能研究，包括扩大的安全性、毒性和有效性研究。 公共卫生相关性：本申请中提出的研究与公共健康直接相关，因为我们正在开发治疗卵巢癌的新疗法。这项工作的成功完成有可能影响每年超过22,000名被诊断为上皮性卵巢癌(EOC)的妇女。提供更有效的治疗方案对于提高被诊断为EOC的患者的总体生存和生活质量至关重要。

DESCRIPTION (provided by applicant): Epithelial ovarian cancer (EOC) is uniformly fatal once resistance to platinum based therapy (Pt) is observed. Innate resistance is observed in approximately 25% of the nearly 22,000 annual cases of EOC, where the cancer is intrinsically refractory to Pt therapy. The remaining 75% of women have Pt sensitive disease and will respond with remission lasting up to 5 years. However, the majority of these women will ultimately develop a recurrent, Pt-resistant cancer and succumb to the disease. These courses of disease progression result in an overall 5 year survival rate of 46%. To impact this continuing and significant clinical problem, we will exploit both the mechanism of Pt-therapy and the biology of EOC in a novel treatment strategy targeting genome stability and maintenance. Cisplatin and carboplatin both impart their chemotherapeutic effect by the formation of Pt-DNA adducts which block DNA replication and transcription culminating in apoptosis. Repair of Pt-DNA adducts via nucleotide excision repair (NER) or homologous recombination repair (HRR) reduces the effectiveness of Pt therapy. Both intrinsically and acquired resistant EOC often display alterations in DNA repair or damage tolerance and thus inhibition of DNA repair pathways holds the potential to sensitize these cells to Pt treatment. We anticipate that both direct mechanisms of action on the repair pathways and synthetic lethal interactions can be exploited for therapeutic benefit. Towards this end we will pursue the development and analysis of small molecule inhibitors (SMIs) of the human single-strand DNA binding protein replication protein A (RPA). Our approach is to target the protein-DNA interaction which holds the potential for significant impact to allow an entire new class of interactions to be targeted. In addition to essential roles in NER and HRR which provides the rationale for Pt-sensitization, RPA is also essential for S-phase DNA replication providing a validated target for rapidly dividing EOC cells. Our data demonstrate that RPA inhibition with small drug-like molecules elicits anti-cancer activity in cell culture models of both lung and ovarian cancer. Preliminary data also demonstrate no overt toxicity in mice and potent anti-tumor activity in human cancer xenografts. We will pursue two specific aims that exploit our recently identified lead RPA SMIs NERX-505X and NERX-313E, and advance these molecules for the treatment of EOC. We will therefore; 1) Determine the efficacy of lead RPA SMIs as single agents and in conjunction with cisplatin in Pt- sensitive and resistant ovarian cancer cell lines and in normal human surface ovarian epithelial cells and 2) Determine the in vivo pharmacokinetic properties of lead RPA SMIs and assess toxicity and efficacy xenograft studies using combination regimens which include platinum compounds. Successful completion of these studies will support a phase II STTR application to pursue Investigational New Drug (IND)-enabling studies, including expanded safety, toxicity, and efficacy studies. PUBLIC HEALTH RELEVANCE: The research proposed in this application is directly relevant to public health in that we are developing novel therapies for the treatment of ovarian cancer. Successful completion of this work had the potential to impact the over 22,000 women diagnosed with epithelial ovarian cancer (EOC) each year. Providing a more effective treatment regimen is essential to increase overall survival and enhance quality of life for those diagnosed with EOC.