A Nanotechnology Platform for Suicide Gene Therapy of Recurring Ovarian Cancer

用于复发性卵巢癌自杀基因治疗的纳米技术平台

• 批准号: 8815552
• 负责人: Arash Hatefi
• 金额: $ 35.46万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815552
• 关键词: Address; Affect; Antineoplastic Agents; Applications Grants; Biodistribution; Blood capillaries; Cancer Patient; Cancer Relapse; Cancer cell line; Cell Density; Cells; Cisplatin; Clinic; Clinical; Complex; Data; Development; Disease; Disease remission; Drug Delivery Systems; Drug resistance; Effectiveness; Enzymes; Extracellular Protein; Functional disorder; Gene-Directed Enzyme Prodrug Therapy; Goals; Growth; Guidelines; Gynecologic; Heterogeneity; Life; Luciferases; Malignant Neoplasms; Malignant neoplasm of ovary; Medical; Multi-Drug Resistance; Nanotechnology; Normal tissue morphology; Nude Mice; Operative Surgical Procedures; Organ; Outcomes Research; Ovarian; Patients; Pharmaceutical Preparations; Platinum; Play; Primary Neoplasm; Prodrugs; Production; Property; Publishing; Recurrence; Relapse; Reporter Genes; Research; Role; Safety; Site; Solid Neoplasm; Staging; Suicide Gene Therapy; Survival Rate; System; Testing; Therapeutic; Tissues; Toxic effect; Translations; Treatment Efficacy; Woman; Xenograft procedure; animal imaging; anticancer activity; base; cancer cell; cancer stem cell; cancer type; capillary; cell killing; chemotherapy; cytotoxicity; design; enzyme activity; in vivo; killings; meetings; mortality; nanomedicine; neoplastic cell; novel; ovarian neoplasm; pre-clinical; public health relevance; response; screening; standard care; success; suicide gene; targeted treatment; text searching; theories; therapeutic target; treatment strategy; tumor; tumor xenograft; vector

DESCRIPTION (provided by applicant): Ovarian cancer is associated with the highest mortality rate of all gynecologic malignancies in US and with an overall 5 years survival rate of 30-40%. Although the majority of tumors initially respond to standard treatments combining surgery and chemotherapy with platinum-based drugs such as cisplatin, but the majority of treated patients acquire multidrug resistance and succumb to their disease due to relapse. It is believed that cancer initiating cells (CICs) also known as cancer stem cells play a major role in tumor recurrence and metastatic spread. Therefore, to inhibit relapse and increase patients' survival rate, it is crucial to design a treatment strategy that during the early stage treatment eradicates both differentiating ovarian cancer cells and CICs. Based on this premise, the primary objective of this research is to develop a targeted therapeutic system that can effectively kill both differentiating cancer cells and CICs and demonstrate not only eradication of the primary tumors but also inhibition of relapse. Solid tumors have complex pathophysiology and factors such as degree of capillary leakiness, extracellular proteins, tumor heterogeneity and tumor cell density significantly limit distribution and efficacy of therapeutic molecules. As a result, a subpopulation of differentiating cancer cells and/or CICs may survive the treatment. To overcome these obstacles and achieve the objective, we have developed a novel highly efficient targeted-shielded nanotechnology platform (vector) that utilizes passive, active and transcriptional targeting mechanisms in order to achieve high anticancer activity at the tumor site with minimal impact on normal tissues. Our live animal imaging and tumor regression studies illustrate that the developed system passively accumulates in tumors, is actively picked up by tumor cells, efficiently transfects and expresses reporter genes specifically in tumors but not other tissues and after gene directed enzyme/prodrug therapy completely eradicates two different types of aggressive xenograft drug resistant ovarian tumors. Furthermore, after careful screening through a panel of suicide genes, we have identified one enzyme/prodrug system that has the potential to inhibit relapse. It is our hypothesis that the novel targeted vector can effectively deliver suicide genes into a panel of xenograft and syngeneic ovarian tumors without affecting normal organs and result in eradication of the primary tumors and inhibition of relapse. We believe that this research is of high significance because it addresses an important problem; i.e., cancer relapse. Once developed, this nanotechnology-based system can be used as a platform for therapy of other types of cancer. The proposed studies in this grant application are designed to first isolate CICs and validate the ability to target and kill these cells followed by n extensive in vivo biodistribution, therapy response and toxicity studies to demonstrate the effectiveness of the system in treating various ovarian tumors. The outcome of this research could ultimately have a significant impact on cancer patients' survival rate because it will be the first nanomedicine that could effectively inhibit ovarian cancer relapse.

描述（由申请人提供）：卵巢癌是美国所有妇科恶性肿瘤中死亡率最高的癌症，总体 5 年生存率为 30-40%。尽管大多数肿瘤最初对手术和化疗与顺铂等铂类药物相结合的标准治疗有反应，但大多数接受治疗的患者会获得多药耐药性并因复发而死于疾病。据信，癌症起始细胞（CIC）也称为癌症干细胞，在肿瘤复发和转移扩散中发挥着重要作用。因此，为了抑制复发并提高患者的生存率，设计一种在早期治疗期间根除分化的卵巢癌细胞和CIC的治疗策略至关重要。基于这个前提，本研究的主要目标是开发一种靶向治疗系统，能够有效杀死分化的癌细胞和CIC，并证明不仅能根除癌细胞 对原发肿瘤还能抑制复发。实体瘤具有复杂的病理生理学特征，毛细血管渗漏程度、细胞外蛋白、肿瘤异质性和肿瘤细胞密度等因素显着限制了治疗分子的分布和功效。作为一个 结果，分化的癌细胞和/或 CIC 的亚群可能在治疗后存活下来。为了克服这些障碍并实现这一目标，我们开发了一种新型高效靶向屏蔽纳米技术平台（载体），利用被动、主动和转录靶向机制，在肿瘤部位实现高抗癌活性，同时对正常组织的影响最小。我们的活体动物成像和肿瘤消退研究表明，所开发的系统在肿瘤中被动积累，被肿瘤细胞主动拾取，有效转染并特异地在肿瘤而非其他组织中表达报告基因，并且在基因定向酶/前药治疗后完全根除两种报告基因。不同类型的侵袭性异种移植耐药卵巢肿瘤。此外，在仔细筛选一组自杀基因后，我们发现了一种具有抑制复发潜力的酶/前药系统。我们的假设是，新型靶向载体可以有效地将自杀基因传递到一组异种移植和同基因卵巢肿瘤中，而不影响正常器官，从而根除原发肿瘤并抑制复发。我们认为这项研究具有重要意义，因为它解决了一个重要问题；即癌症复发。一旦开发出来，这种基于纳米技术的系统可以用作治疗其他类型癌症的平台。本拨款申请中拟议的研究旨在首先分离 CIC 并验证靶向和杀死这些细胞的能力，然后进行广泛的体内生物分布、治疗反应和毒性研究，以证明该系统治疗各种卵巢肿瘤的有效性。这项研究的结果最终可能会对癌症患者的生存率产生重大影响，因为它将是 第一个可以有效抑制卵巢癌复发的纳米药物。