Nanotechnology-based personalized treatment of metastatic ovarian cancer

基于纳米技术的转移性卵巢癌个体化治疗

基本信息

批准号：
10634555
负责人：
Tamara Minko
金额：
$ 60.55万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-03 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634555
关键词：
Address Antineoplastic Agents Biological Markers Cancer Model Cell Culture Techniques Cell Death Induction Cell Proliferation Cell Separation Cervical Clinical Clinical Trials Complex Mixtures Cytotoxic agent Data Development Diagnosis Dosage Forms Drug Delivery Systems Drug resistance Effectiveness Endometrial Future Genes Genetic Genotype Goals Human Genetics Individual Investigation Lipids Liposomes Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant Vaginal Neoplasm Malignant neoplasm of ovary Malignant neoplasm of vulva Mammalian Oviducts Messenger RNA Modeling Molecular Profiling Molecular Target Mus Nanostructures Nanotechnology National Cancer Institute Neoplasm Metastasis Nucleic Acids Operative Surgical Procedures Organ Outcome Ovarian Carcinoma Patients Peptides Pharmaceutical Preparations Phenotype Primary Neoplasm Proliferating Proteins Public Health Radiation therapy Recommendation Research Resistance Sampling Small Interfering RNA Standardization System Testing Tissue Sample Tissues Translational Research Translations Treatment Effectiveness Treatment Efficacy Treatment Protocols Tumor Debulking Tumor Tissue United States Uterus Variant Woman Xenograft Model anticancer activity cancer cell cancer type chemotherapy clinically relevant design dosage drug metabolism drug sensitivity genetic information genetic makeup genetic profiling human model in vitro testing in vivo individual patient individualized medicine lipophilicity malignant ascites nanocarrier novel strategies novel therapeutics overexpression personalized approach personalized chemotherapy personalized medicine prevent profiles in patients protein expression response side effect structured lipid subcutaneous targeted delivery treatment planning tumor tumor growth

项目摘要

This is an application for an interdisciplinary project to develop a novel approach for personalized chemotherapy of gynecologic cancers. Estimates from the National Cancer Institute indicate that more than 116,000 women in the United States will be diagnosed with a gynecologic cancer and about 34,000 die from these types of cancer in 2021. Despite advances in surgical and radiation treatments, chemotherapy continues to be an important treatment option for gynecologic malignancies, especially for locally advanced and metastatic tumors. However, the efficacy of chemotherapy is substantially limited by the intrinsic and acquired resistance of cancer cells to cytotoxic drugs. We are proposing to develop and validate a nanotechnology-based approach of personalized treatment of ovarian carcinoma (most lethal type of gynecological cancers) constructed on the individual genetic profile of the patient’s tumor. Based on the results of the present translational research the following treatment protocol will be proposed for future clinical trials after the completion of the present project. Samples of a patient’s tumor and normal surrounding tissues will be obtained during the tumor debulking surgery and tumor profile data (the expression of predefined genes and proteins) will be obtained and analyzed. Based on this analysis, several molecular targets and the most effective anticancer drug(s) will be selected. Finally, a mixture of complex nanocarrier-based targeted delivery systems (TDS) containing drug(s)/siRNA(s)/targeted peptide will be selected from the pre-synthesized bank and the patient will be treated with the chosen cocktail of TDS designed specifically for their individual tumor. The selected systems will include the lipid-based carrier, the tumor targeting moiety, the most effective drug(s) and siRNA(s) selected for each individual patient based on a genetic profile of the patient’s tumor. It is expected that such personalized therapy will effectively suppress drug resistance and tumor growth, inhibit the development of metastases and limit adverse side effects of therapy in the particular patient. The main goals of the proposed research are to identify profiles of gene/protein expression in tissue samples isolated from patients with ovarian cancer that predict tumor response and resistance to anticancer drugs with different mechanisms of action. We also will develop a set of TDSs containing anticancer drug(s) or siRNA(s) targeted to different mRNAs overexpressed in the tumor of the patient. Finally, a genetic profile and protein expression phenotype will be performed on samples of tumor tissues and malignant ascites from patients with ovarian carcinoma. Cancer cells will be isolated from fresh samples obtained during surgery. Based on the results of the genetic profiling, a mixture of TDS will be created and tested in vitro (on cell culture model) and in vivo (on subcutaneous murine cancer model) using cancer cells isolated from each individual patient and recommendations for the personalized treatment of ovarian cancer will be developed.

这是一个跨学科项目的申请，旨在开发一种新的个性化化疗方法美国国家癌症研究所的估计显示，超过 116,000 名女性患有妇科癌症。美国将被诊断出患有妇科癌症，约 34,000 人死于此类癌症 2021 年。尽管手术和放射治疗取得了进展，但化疗仍然是重要的治疗方法妇科恶性肿瘤的治疗选择，特别是局部晚期和转移性肿瘤。化疗的功效在很大程度上受到癌细胞固有的和获得性的耐药性的限制我们建议开发和验证基于纳米技术的个性化方法。基于个体遗传的卵巢癌（最致命的妇科癌症类型）的治疗根据患者肿瘤的概况，进行以下治疗。本项目完成后，将针对未来的临床试验提出方案。肿瘤减灭手术期间将获得肿瘤和正常周围组织以及肿瘤概况数据（预定义基因和蛋白质的表达）将根据此分析获得并分析。最后，将选择分子靶点和最有效的抗癌药物。含有药物/siRNA/靶向肽的基于纳米载体的靶向递送系统（TDS）将被从预先合成的库中选择，患者将接受设计的 TDS 鸡尾酒的治疗专门针对其个体肿瘤而选择的系统将包括基于脂质的载体、肿瘤靶向。部分，根据遗传图谱为每个患者选择最有效的药物和 siRNA 预计这种个性化治疗将有效抑制患者的肿瘤耐药性。肿瘤生长，抑制转移的发展，并限制特定治疗的不良副作用拟议研究的主要目标是确定组织中基因/蛋白质表达的概况。从卵巢癌患者中分离出的样本可预测肿瘤反应和抗癌耐药性我们还将开发一套包含抗癌药物或不同作用机制的TDS。针对患者肿瘤中过度表达的不同 mRNA 的 siRNA 最后是遗传图谱和基因图谱。将对患者的肿瘤组织和恶性腹水样本进行蛋白质表达表型分析卵巢癌的癌细胞将从手术期间获得的新鲜样本中分离出来。根据基因分析结果，将创建 TDS 混合物并在体外（细胞培养模型）和环境中进行测试体内（皮下小鼠癌症模型）使用从每个患者身上分离的癌细胞将制定卵巢癌个性化治疗的建议。