Development of Novel Agents Targeting Genome Stability and Maintenance for Treati

描述（由申请人提供）：一旦观察到对铂基治疗（Pt）的耐药性，上皮性卵巢癌（EOC）是一致致命的。在每年近22,000例EOC病例中，先天性耐药约占25%，其中癌症对铂治疗具有本质难治性。其余75%的女性患有铂敏感疾病，并将缓解长达5年。然而，这些女性中的大多数最终会发展成复发的、耐铂的癌症，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%。为了解决这一持续而重要的临床问题，我们将利用pt治疗的机制和EOC的生物学，在一种针对基因组稳定和维持的新治疗策略中进行研究。顺铂和卡铂都通过形成Pt-DNA加合物来发挥其化疗作用，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加合物会降低Pt治疗的有效性。内在和获得性耐药EOC通常在DNA修复或损伤耐受性方面表现出改变，因此抑制DNA修复途径具有使这些细胞对Pt治疗敏感的潜力。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（SMIs）。我们的方法是瞄准蛋白质- dna相互作用，这可能会产生重大影响，从而使一种全新的相互作用成为目标。除了在NER和HRR中发挥重要作用（为pt致敏提供了基本原理）外，RPA对s期DNA复制也至关重要，为快速分裂的EOC细胞提供了有效的靶标。我们的数据表明，小药物样分子抑制RPA在肺癌和卵巢癌细胞培养模型中都具有抗癌活性。初步数据还表明，在小鼠中没有明显的毒性，而在人类癌症异种移植物中有很强的抗肿瘤活性。我们将追求两个具体目标，利用我们最近确定的先导RPA SMIs NERX-505X和NERX-313E，并推进这些分子用于EOC的治疗。因此，我们将；1)确定铅RPA SMIs作为单一药物和与顺铂联合使用对铂敏感和耐药的卵巢癌细胞系以及正常人卵巢表面上皮细胞的疗效；2)确定铅RPA SMIs的体内药代动力学特性，并评估包括铂化合物在内的联合方案的异种移植研究的毒性和疗效。这些研究的成功完成将支持II期STTR申请，以进行新药研究（IND），包括扩展的安全性、毒性和有效性研究。

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.