Ovarian cancer, the most lethal of all gynecologic neoplasms, is often associated with drug resistance, which becomes the major challenge in the clinical treatment. Maytansine (MTS), an exceptionally potent anticancer agent, shows excellent cytotoxicity to a range of drug-resistant cancer cell lines, including ovarian cancer. However, it could not distinguish cancer cells from normal cells and induces severe systemic toxicity, which restrains its further application in clinical treatment. Accordingly, antibody-drug conjugates of MTS derivatives have been developed for the increase of tumor targeting and the reduction of toxicity. Several successful antibody-MTS derivative conjugates have entered clinical trials, such as mirvetuximab soravtansine (IMGN853) for treating platinum-resistant ovarian cancer patients. However, there are still disadvantages of antibody-MTS conjugates. In comparison with antibodies, nucleic acid aptamers have limited immunogenicity, excellent tissue penetration and are unlikely to develop resistance, thus, have been widely used as tumor recognition elements. For example, an anti-nucleolin aptamer (NucA) AS1411, had shown good tumor targeting property with an acceptable safety profile in patients. This aptamer interacts with nucleolin protein, which is found expressing on the surface of ovarian cancer cells and many other cancer cells.
Our group designed and synthesized a nucleolin aptamer-MTS conjugate (NucA-MTS) with a non-cleavable thioether linker for the treatment of drug-resistant ovarian cancer. The NucA conferred NucA-MTS with high water solubility and the stability of NucA-MTS in human serum was verified by high performance liquid chromatograph. In addition, the MTS conjugation did not considerably affect the binding affinity between NucA and its target protein nucleolin, which was supported by both molecular dynamic simulation and isothermal titration calorimetry (ITC). The NucA modification was shown to facilitate the uptake of NucA-MTS in drug-resistant ovarian cancer cell lines (platinum-resistant A2780 and paclitaxel-resistant HEY-T30). The uptake of the conjugate is mainly by macropinocytosis in a nucleolin expression-dependent manner. Moreover, the NucA increased the in vitro cytotoxicity and mitosis inhibition of NucA-MTS in platinum/paclitaxel- resistant ovarian cancer cells, while the activity of the conjugate was better than that of a non-specific aptamer-MTS conjugate. Based on the above findings, we hypothesis that the NucA could facilitate the selective distribution of NucA-MTS in chemo-resistant ovarian cancer tissues/cells, and thus improving the anti-ovarian tumor activity and decreasing the toxicities of NucA-MTS.
The following specific aims will be achieved to test the above hypothesis in xenograft mouse models of human platinum-resistant ovarian cancer and human paclitaxel-resistant ovarian cancer treated with NucA-MTS:
This proposal would not only provide the next generation personalized MTS derivatives for multidrug-resistant ovarian cancer therapy, but also establish an innovative technology platform to develop smart compounds by modifying natural products with aptamers for cell targeted therapy.
This project is supported by the Research Grants Council (RGC), Hong Kong SAR, China (Project 12100719).
For further information on this research topic, please contact Prof. Aiping LU.