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应用程序，用于开发一种新颖的个性化化学疗法妇科癌。国家癌症研究所的估计表明，有116,000多名女性美国将被诊断出患有妇科癌，大约有34,000种因这类癌症死亡在2021年。尽管手术和放射治疗方面取得了进步，但化学疗法仍然是重要的妇科恶性肿瘤的治疗选择，尤其是对于局部晚期和转移性肿瘤。然而，化学疗法的效率受到癌细胞对细胞毒性药物。我们建议开发和验证基于纳米技术的个性化方法卵巢癌（最致命类型的妇科癌症）的治疗患者肿瘤的轮廓。基于本翻译研究的结果本项目完成后，将提出协议以供将来的临床试验。病人的样本肿瘤和周围组织正常的组织将在肿瘤缓解手术和肿瘤轮廓数据中获得（预定义的基因和蛋白质的表达）将得到并分析。基于此分析，几个将选择分子靶标和最有效的抗癌药物。最后，复合物的混合物基于纳米载体的靶向输送系统（TDS），含有药物/siRNA/靶向肽从预先合成的银行中选出，患者将通过设计的TDS鸡尾酒进行治疗选定的系统将包括基于脂质的载体，肿瘤靶向部分是根据基于每个患者选择的最有效的药物和siRNA（s）患者的肿瘤。预计这种个性化疗法将有效抑制耐药性和肿瘤生长，抑制转移的发展并限制治疗的不良副作用病人。拟议研究的主要目标是鉴定组织中基因/蛋白质表达的谱图从卵巢癌患者中分离出的样品，这些样品预测肿瘤反应和抗抗癌的耐药性具有不同作用机理的药物。我们还将开发一组含有抗癌药物的TDS或 siRNA（s）针对患者肿瘤中过表达的不同mRNA。最后，遗传特征和蛋白质表达表型将在患者的肿瘤组织和恶性腹水的样品上进行与卵巢癌。将从手术期间获得的新鲜样品中分离出癌细胞。基于基因分析的结果，TD的混合物将在体外（在细胞培养模型上）以及在体外进行测试使用从每个患者分离的癌细胞和将开发有关个性化治疗卵巢癌的建议。