Nanotechnology-based personalized treatment of metastatic ovarian cancer

点击翻译按钮获取中文摘要

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.