Stem Cell-based Platform for Targeted Enzyme/Prodrug Therapy of Recurrent Ovarian Cancer

基于干细胞的复发性卵巢癌靶向酶/前药治疗平台

• 批准号: 10380155
• 负责人: Arash Hatefi
• 金额: $ 38.22万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380155
• 关键词: ABCB1 gene; ABCG2 gene; Adipose tissue; Adverse effects; Antineoplastic Agents; Ascites; Biodistribution; Cancer Patient; Cancer Relapse; Cell Cycle Progression; Cells; Cisplatin; Clinic; Clinical Research; Clone Cells; Complement; Cytosine deaminase; DNA biosynthesis; Data; Diagnosis; Disease; Disease Resistance; Drug Delivery Systems; Drug Efflux; Drug Targeting; Drug resistance; Effectiveness; Engineering; Enzymes; Epithelial ovarian cancer; Excision; Flucytosine; Fluorouracil; Genetic Engineering; Genomics; Goals; Greater sac of peritoneum; Hematology; Histocytochemistry; Histopathology; Human; Hypoxia; Immunocompromised Host; Immunohistochemistry; In complete remission; Inflammatory Response; Magnetic Resonance Imaging; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Measures; Mesenchymal Stem Cells; Metastatic/Recurrent; Modality; Molecular; Mus; Names; Necrosis; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; Outcome; Ovarian; Ovary; Paclitaxel; Patient Care; Patients; Pharmaceutical Preparations; Platinum; Population; Prodrugs; Prognosis; Property; Public Health; Publishing; Recording of previous events; Recurrence; Recurrent tumor; Regimen; Relapse; Research; Resistance; SN-38; Statistical Data Interpretation; Supporting Cell; Survival Rate; System; Technology; Therapeutic; Therapy Evaluation; Tissues; Toxic effect; Treatment Side Effects; Treatment-related toxicity; Tropism; Tumor Burden; Tumor Debulking; Tumor Tissue; Type I DNA Topoisomerases; United States; Unresectable; Yeasts; advanced disease; aldehyde dehydrogenases; anti-cancer; base; bioluminescence imaging; cancer cell; cancer therapy; carboxylesterase; cell type; chemotherapy; clinically translatable; cytokine; disorder later incidence prevention; efflux pump; enzyme activity; esterase; experience; extracellular; humanized mouse; intraperitoneal; irinotecan; mortality; nanoluciferase; ovarian neoplasm; overexpression; preclinical study; prevent; resistance mechanism; response; standard of care; stem cells; stem-like cell; success; targeted treatment; treatment response; tumor; tumor xenograft

Project Summary: Ovarian cancer (OC) is associated with the highest mortality rate of all gynecologic malignancies in the United States. The low rate of survival is mainly due to two factors: 1) the advanced stage of the disease at diagnosis, and 2) the inadequate efficacy of available therapeutic options, especially for recurrent metastatic disease. The standard-of-care for patients with primary OC includes debulking surgery (removal of ovaries and visible intraperitoneal tumors) followed by chemotherapy with platinum-based drugs (e.g., cisplatin) and paclitaxel (PTX). However, approximately 90% of patients after suboptimal resection and 70% of patients after optimal cytoreduction will experience relapse within 18-24 months. Unfortunately, there is no effective standard-of-care for recurrent patients who return to the clinic with drug-resistant metastatic disease. As a result, their survival rate is very low. The objective of this research is “to develop a non-surgical, targeted, and clinically translatable stem cell-based platform that can overcome drug resistance in recurrent and metastatic ovarian cancer”. The success of the developed stem cell-based platform will be measured by not only demonstrating the eradication of metastasis and inhibition of relapse, but also providing long-term survival benefits. To achieve this objective, we genetically engineered and isolated a unique adipose-derived stem cell (ASC) clone that overexpresses secretory human carboxylesterase 2 for targeted enzyme/prodrug therapy of cancer, and nanoluciferase for quantification of response to therapy and evaluation of cancer relapse. Using bioluminescent imaging (BLI) complemented with magnetic resonance imaging (MRI) and immunohistochemistry, we demonstrated that the engineered ASCs migrate and localize at both ovarian tumor stroma and necrotic regions. Our published data also show that the engineered ASCs are able to target and kill the drug-resistant OC cells that are rich in cancer stem-like cells (CSCs), overexpress MDR-1/ABCG2 drug efflux pumps, and have high ALDH enzyme activity. Statistical analyses of tumor burden and survival rates showed that administration of the engineered ASCs in combination with the prodrug irinotecan provided complete tumor response and survival benefits in 80% of treated mice. To transform this ASC-based technology into a platform with a broad application in targeted therapy of recurrent OC, we will use epithelial OC cells that are obtained from patients who have received various treatment modalities but have returned to the clinic with drug-resistant disease. The biodistribution and tumor tropism of the engineered ASCs will be determined by BLI, MRI, and immunohistochemistry. The tumor response to therapy, inhibition of cancer relapse, and long-term survival benefits will be determined in immunocompromised mice. Tumor tissues from non-responsive groups will be collected and characterized at molecular, cellular and genomic levels to understand the mechanisms underlying their escape and to help develop corrective measures. Adverse effects during treatment and toxicity to healthy tissues will be studied by histopathology & hematology.

项目概述：卵巢癌（OC）是所有妇科疾病中死亡率最高的一种。 恶性肿瘤在美国。生存率低主要是由于两个因素：1）晚期 2）现有治疗方案的疗效不足，特别是对于 复发性转移性疾病。原发性OC患者的标准治疗包括减瘤手术 （切除卵巢和可见的腹膜内肿瘤），然后用铂类药物化疗 (e.g.,顺铂）和紫杉醇（PTX）。然而，大约90%的患者在次优切除后， 70%的患者在最佳细胞减灭术后将在18-24个月内复发。不幸的是 对于因耐药转移性肿瘤而返回诊所的复发患者，没有有效的标准治疗 疾病因此，它们的存活率非常低。这项研究的目的是“开发一种非手术， 靶向的，临床上可转移的基于干细胞的平台，可以克服复发性肿瘤的耐药性， 和转移性卵巢癌”。开发的基于干细胞的平台的成功将通过以下方式来衡量： 不仅证实了转移的根除和复发的抑制，而且还提供了长期的 生存福利。为了实现这一目标，我们基因工程和分离出一种独特的脂肪来源的 过表达分泌型人羧酸酯酶2用于靶向酶/前药干细胞（ASC）克隆 癌症治疗和用于定量对治疗的反应和评估癌症的纳米荧光素酶 复发使用生物发光成像（BLI），辅以磁共振成像（MRI）， 通过免疫组化，我们证明了工程化的ASCs迁移并定位于两个卵巢肿瘤， 间质和坏死区域。我们发表的数据还表明，工程化的ASC能够靶向并杀死 富含癌症干细胞样细胞（CSCs）的耐药OC细胞过度表达MDR-1/ABCG 2药物， 外排泵，并具有高ALDH酶活性。肿瘤负荷和生存率的统计分析 显示与前药伊立替康组合施用工程化ASC提供了 在80%的治疗小鼠中完全肿瘤反应和存活益处。要将此基于ASC的 技术转化为一个平台，在复发性OC的靶向治疗中具有广泛的应用，我们将使用上皮 OC细胞是从接受过各种治疗方式但已恢复正常的患者中获得的。 临床上的抗药性疾病。工程化的ASC的生物分布和肿瘤向性将是 通过BLI、MRI和免疫组织化学确定。肿瘤对治疗的反应，癌症的抑制 复发和长期存活益处将在免疫受损小鼠中确定。肿瘤组织 将收集无反应群体并在分子、细胞和基因组水平上进行表征， 了解他们逃跑的机制，并帮助制定纠正措施。不利影响 在治疗期间，将通过组织病理学和血液学研究对健康组织的毒性。