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: 10571917
• 负责人: Arash Hatefi
• 金额: $ 38.22万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 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 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571917
• 关键词: ABCB1 gene; ABCG2 gene; 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; Evaluation; 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; Penetration; 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; Tissues; Topoisomerase I inhibition; Toxic effect; Treatment Side Effects; Tropism; Tumor Burden; Tumor Debulking; Tumor Tissue; United States; Unresectable; Yeasts; adipose derived stem cell; advanced disease; aldehyde dehydrogenases; anti-cancer; bioluminescence imaging; cancer cell; cancer therapy; carboxylesterase; cell type; cellular targeting; chemotherapy; clinical translation; cytokine; efflux pump; enzyme activity; esterase; experience; extracellular; humanized mouse; intraperitoneal; irinotecan; migration; mortality; nanoluciferase; ovarian neoplasm; overexpression; preclinical study; prevent; relapse prevention; resistance mechanism; response; standard of care; stem cell migration; 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)是所有妇科疾病中死亡率最高的 美国的恶性肿瘤。存活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充分，特别是对 复发转移性疾病。对原发OC患者的标准护理包括去髓核手术 (摘除卵巢和可见的腹膜内肿瘤)，然后用铂类药物进行化疗 (如顺铂)和紫杉醇(PTX)。然而，大约90%的患者在次优切除和 70%的患者在最佳细胞减灭术后18-24个月内复发。不幸的是，有 对复发的耐药转移患者没有有效的标准护理 疾病。因此，它们的存活率很低。这项研究的目标是“开发一种非手术的， 靶向、临床可翻译的干细胞平台，可克服复发时的耐药性 和转移性卵巢癌“。开发的干细胞平台的成功将通过以下方式衡量 不仅显示了根除转移和抑制复发的作用，而且还提供了长期 生存福利。为了实现这一目标，我们通过基因工程技术分离出了一种独特的脂肪来源 靶向酶/前药高表达分泌型人羧酸酯酶2的干细胞克隆 癌症的治疗，以及用于量化治疗反应和癌症评估的纳米荧光素酶 旧病复发。使用与磁共振成像(MRI)互补的生物发光成像(BLI)和 免疫组织化学，我们证明了工程化的ASCs在卵巢肿瘤中迁移和定位 间质和坏死区。我们公布的数据还表明，经过改造的ASCs能够瞄准并杀死 富含肿瘤干细胞的耐药OC细胞高表达MDR-1/ABCG2药物 外排泵，并具有较高的ALDH酶活性。肿瘤负担与生存率的统计分析 显示工程ASCs与前药伊立替康的联合给药提供了 在80%的治疗小鼠中，完全的肿瘤反应和生存受益。要转变基于ASC的 将技术转化为一个在复发性OC靶向治疗中应用广泛的平台，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到 患有抗药性疾病的诊所。基因工程血管干细胞的生物分布和肿瘤趋向性将是 通过BLI、MRI和免疫组织化学检测。肿瘤对治疗的反应，对癌症的抑制 复发，免疫受损小鼠的长期生存益处将被确定。肿瘤组织来自 将收集无反应组，并在分子、细胞和基因组水平上进行表征，以 了解他们逃脱的机制，并帮助制定纠正措施。不良反应 在治疗过程中，对健康组织的毒性将通过组织病理学和血液学进行研究。