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.

项目摘要：卵巢癌 (OC) 是所有妇科癌症中死亡率最高的癌症 美国的恶性肿瘤生存率低主要是由于两个因素：1）晚期。 诊断时疾病的情况，以及 2) 现有治疗方案的疗效不足，尤其是对于 原发性 OC 患者的标准治疗包括肿瘤减灭手术。 （切除卵巢和可见的腹膜内肿瘤），然后用铂类药物进行化疗 （例如，顺铂）和紫杉醇（PTX）然而，约 90% 的患者在次优切除后出现这种情况。 不幸的是，70% 的患者在最佳细胞减灭术后会在 18-24 个月内出现复发。 对于因耐药转移而返回诊所的复发患者，没有有效的护理标准 因此，他们的存活率非常低，这项研究的目标是“开发一种非手术的、 基于干细胞的靶向且可临床转化的平台，可以克服复发性耐药性 所开发的基于干细胞的平台的成功将通过以下指标来衡量。 不仅证明了根除转移和抑制复发，而且提供了长期的治疗效果 为了实现这一目标，我们对一种独特的脂肪来源进行了基因改造和分离。 过表达分泌性人羧酸酯酶 2 的干细胞 (ASC) 克隆，用于靶向酶/前药 癌症治疗，以及用于量化治疗反应和评估癌症的纳米荧光素酶 使用生物发光成像（BLI）辅以磁共振成像（MRI）和 免疫组织化学，我们证明工程化的 ASC 能够迁移并定位于两个卵巢肿瘤 我们发表的数据还表明，工程化的 ASC 能够靶向并杀死基质。 富含癌症干细胞样细胞 (CSC) 的耐药 OC 细胞过度表达 MDR-1/ABCG2 药物 外排泵，并具有高 ALDH 酶活性，对肿瘤负荷和存活率进行统计分析。 结果表明，将工程化 ASC 与前药伊立替康联合给药可提供 80% 的治疗小鼠获得完全肿瘤缓解和生存获益 技术成为在复发性 OC 靶向治疗中具有广泛应用的平台，我们将使用上皮细胞 OC 细胞取自接受过各种治疗方式但已恢复健康的患者 工程化 ASC 的生物分布和肿瘤趋向性将受到耐药性疾病的影响。 通过 BLI、MRI 和免疫组织化学测定肿瘤对治疗、抑制癌症的反应。 将在免疫受损小鼠的肿瘤组织中确定复发和长期生存的益处。 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，以 了解其逃逸的机制并帮助制定纠正措施。 将通过组织病理学和血液学研究治疗期间对健康组织的毒性。