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
• 负责人: JOHN J. TURCHI
• 金额: $ 22.97万
• 依托单位: NERX BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201446
• 关键词: A-Form DNA; Advanced Development; Apoptosis; Biology; Cancer cell line; Carboplatin; Cell Culture Techniques; Cell Cycle Arrest; Cell Death; Cells; Cisplatin; Clinical; Clinical Data; DNA Adducts; DNA Damage; DNA Repair; DNA Repair Pathway; DNA biosynthesis; DNA lesion; DNA-Protein Interaction; Data; Databases; Defect; Development; Diagnosis; Disease; Disease Progression; Disease remission; Drug Kinetics; Effectiveness; Epithelial Cells; Epithelial ovarian cancer; Excision; Genetic Transcription; Genome; Genome Stability; Human; In Vitro; Individual; Investigational Drugs; Lead; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Modeling; Mus; Nucleotide Excision Repair; Ovarian; Pathway interactions; Pharmaceutical Preparations; Phase; Platinum; Platinum Compounds; Play; Property; Proteins; Public Health; Quality of life; Recurrence; Refractory; Regimen; Research; Resistance; Role; S Phase; SS DNA BP; Safety; Signal Transduction; Small Business Technology Transfer Research; Solid Neoplasm; Substrate Interaction; Surface; Survival Rate; Therapeutic; Toxic effect; Treatment Protocols; Woman; Work; Xenograft procedure; base; cancer cell; cellular targeting; effective therapy; enzyme substrate; homologous recombination; in vivo; inhibitor/antagonist; innovation; novel; novel strategies; protein protein interaction; recombinational repair; repaired; replication factor A; response; small molecule; therapy resistant; treatment strategy; tumor

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.

描述（由申请方提供）：一旦观察到对铂类药物治疗（Pt）的耐药，上皮性卵巢癌（EOC）是一致致命的。在每年近22，000例EOC病例中，约25%观察到先天性耐药，其中癌症本质上对铂治疗无效。其余75%的女性患有铂敏感性疾病，并将持续缓解长达5年。然而，这些妇女中的大多数最终会发展成复发性耐铂癌症并死于这种疾病。这些疾病进展过程导致总体5年生存率为46%。为了影响这一持续的和重要的临床问题，我们将利用Pt治疗的机制和EOC的生物学在一个新的治疗策略，靶向基因组的稳定性和维护。顺铂和卡铂都通过形成Pt-DNA加合物来赋予其化疗效果，Pt-DNA加合物阻断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Pt-DNA加合物降低了铂治疗的有效性。固有和获得性耐药EOC通常显示DNA修复或损伤耐受性的改变，因此DNA修复途径的抑制具有使这些细胞对Pt治疗敏感的潜力。我们预期修复途径的直接作用机制和合成致死相互作用都可以用于治疗益处。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）。我们的方法是靶向蛋白质-DNA相互作用，它具有重大影响的潜力，可以靶向一类全新的相互作用。除了在NER和HRR中的重要作用（这为Pt致敏提供了理论基础）之外，RPA对于S期DNA复制也是必不可少的，为快速分裂的EOC细胞提供了经验证的靶标。我们的数据表明，小药物样分子的RPA抑制在肺癌和卵巢癌的细胞培养模型中增强抗癌活性。初步数据还表明，在小鼠中没有明显的毒性，在人类癌症异种移植物中具有有效的抗肿瘤活性。我们将追求两个具体目标，利用我们最近发现的领先RPA SMI NERX-505 X和NERX-313 E，并推进这些分子用于治疗EOC。因此，我们将：1）确定铅RPA SMI作为单一药剂和与顺铂联合在Pt敏感性和抗性卵巢癌细胞系和正常人表面卵巢上皮细胞中的功效，和2）确定铅RPA SMI的体内药代动力学性质，并使用包括铂化合物的组合方案评估异种移植研究的毒性和功效。这些研究的成功完成将支持II期STTR申请，以进行研究性新药（IND）研究，包括扩展的安全性，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卫生直接相关，因为我们正在开发治疗卵巢癌的新型疗法。这项工作的成功完成有可能影响每年超过22，000名被诊断患有上皮性卵巢癌（EOC）的女性。提供更有效的治疗方案对于增加总生存率和提高诊断为EOC的患者的生活质量至关重要。