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

• 批准号: 10417379
• 负责人: Tamara Minko
• 金额: $ 61.8万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-03 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417379
• 关键词: Address; Antineoplastic Agents; Biological Markers; Cancer Model; Cations; Cell Culture Techniques; Cell Death Induction; Cell Proliferation; Cervical; Chemotherapy-Oncologic Procedure; Clinical; Clinical Trials; Complex Mixtures; Cytotoxic agent; Data; Development; Diagnosis; Dosage Forms; Drug Delivery Systems; Drug resistance; Effectiveness; Endometrial; Future; Gene Proteins; Genetic; Genotype; Goals; Human Genetics; In Vitro; Individual; Investigation; Lead; 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; 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; base; cancer cell; cancer type; chemotherapy; clinically relevant; design; dosage; drug metabolism; drug sensitivity; genetic information; genetic makeup; genetic profiling; human model; 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; subcutaneous; targeted delivery; treatment planning; tumor; tumor growth

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，以开发个性化化疗的新方法 妇科癌症美国国家癌症研究所的估计表明， 美国将被诊断出患有妇科癌症，大约34，000人死于这些类型的癌症， 2021年尽管手术和放射治疗取得了进展，但化疗仍然是一种重要的治疗方法。 妇科恶性肿瘤的治疗选择，特别是局部晚期和转移性肿瘤。然而，在这方面， 化疗的功效基本上受到癌细胞的内在和获得性抗性的限制 细胞毒性药物我们建议开发和验证一种基于纳米技术的个性化方法， 卵巢癌（最致命的妇科癌症类型）的治疗建立在个体遗传基础上， 病人肿瘤的轮廓根据目前翻译研究的结果， 在本项目完成后，将为未来的临床试验提出方案。病人的样本 在肿瘤减积手术期间将获得肿瘤和正常周围组织， (the预定义基因和蛋白质的表达）将被获得和分析。根据这一分析， 将选择分子靶点和最有效的抗癌药物。最后，一个复杂的混合物 含有药物/siRNA/靶向肽的基于纳米载体的靶向递送系统（TDS）将是 从预合成的库中选择，并且患者将用设计的TDS的所选混合物治疗 特别是针对他们的肿瘤。选定的系统将包括基于脂质的载体，肿瘤靶向 基于基因组的遗传谱，为每个个体患者选择最有效的药物和siRNA。 病人的肿瘤。预计这种个性化治疗将有效抑制耐药性， 肿瘤生长，抑制转移的发展，并限制治疗的不良副作用，特别是 病人拟议研究的主要目标是确定组织中基因/蛋白质表达谱 从卵巢癌患者中分离的样本，可预测肿瘤对抗癌药物的反应和抗性 具有不同作用机制的药物。我们还将开发一套含有抗癌药物或 靶向患者肿瘤中过表达的不同mRNA的siRNA。最后，基因图谱和 将对来自患者的肿瘤组织和恶性腹水样品进行蛋白表达表型分析 卵巢癌将从手术期间获得的新鲜样品中分离癌细胞。基于 根据遗传分析的结果，将产生TDS的混合物并在体外（在细胞培养模型上）和 使用从每个个体患者分离的癌细胞进行体内（在皮下鼠癌症模型上）， 将制定卵巢癌个性化治疗的建议。