Because its symptoms are relatively silent, ovarian cancer is most often detected in the highly advanced stages of disease, when tumors have advanced to more aggressive forms, leading to a lowered clinical response to chemotherapy. When traditional chemotherapy drugs are introduced -- often a combination of platinum such as cisplatin, and paclitaxel or similar small molecule chemotoxins -- an aggressive schedule is needed. Unfortunately, a significant number of cells can survive this cascade of drugs by engaging genes that help prevent cell death or by suppressing genes that would normally facilitate cell death in the presence of the drug. High drug resistance is found in the majority of patients who experience recurrence, a particular trademark of ovarian cancer that leads to greatly lowered chances of long term survival.
One of the most promising means of addressing cancer is the use of siRNA (short interfering RNA) as a form of targeted therapy, which offers the ability to turn off specific genes or block genetic pathways connected to cancer cell survival and chemotherapy resistance. The ability to deliver siRNA to patients is limited by current methods. RNA degrades easily in the bloodstream, so it must be protected inside a carrier. The carriers that have been studied thus far include the use of viruses, which are effective at transmitting siRNA to cells, but are not specific to tumor cells, and can cause dangerous side effects or unintended infection or immune response that is harmful to the patient. Other methods involve chemicals that are toxic at higher doses, and greatly limit the amount of siRNA that can be delivered without causing harm to the patient. For this reason, despite its great promise, siRNA is not a clinically approved therapeutic for ovarian cancer at this time.
We have developed and examine in this work new methods for the delivery of siRNA that allow it to be packaged into nanometer-sized particles that can be easily adapted to delivery through the bloodstream and targeted to tumors without the use of viruses, and without toxic levels of synthetic materials. These approaches include the generation of longer chain structures that contain multiple sequences of siRNA that can assemble into their own delivery vehicles. It is also possible to layer the siRNA around nanoparticles that are already charged with chemotherapy drugs, so that, first, the siRNA in the layers is released to tumor cells to block their ability to resist cancer drugs, followed by the release of the chemotherapy drug to the resistance-disabled tumor cells to effectively kill tumor cells without the potential for recurrence. Once the nanoparticle is configured with its cargo, it is possible to modify the surfaces of the nanoparticle so that it binds specifically to the ovarian cancer cells, and avoids interacting with healthy cells in the body. This challenge of addressing selectivity and specific targeting of cancer cells is key to avoiding or eliminating many of the negative side effects of chemotherapy treatments, in which healthy tissue is inadvertently attacked.
The key goal of this work is to develop a system for siRNA delivery that can be translated to the clinic. The focus of our work will be on advanced serous ovarian cancer, which is the cancer type that leads to the largest number of cancer deaths and the greatest probability of recurrence among women. We will work with collaborators at the Massachusetts General Hospital and the Dana-Farber Cancer Center to identify the best genetic targets for siRNA and combination siRNA/chemotherapy treatments, and to use realistic models of ovarian cancer and evaluate the efficacy of our siRNA nanoparticle delivery platform. The nanoparticle platform that we develop will be adaptable to other forms of ovarian cancer, and successful completion of the project could lead to clinical translational efforts for which these systems may be developed for pre-clinical and/or clinical trials within 4 to 5 years following completion of this grant. The net impact on patients will be the opportunity for advanced personalized treatments in ovarian cancer that eliminate tumor recurrence and chemotherapy resistance, thus providing much more positive outcomes and significantly extended lifetime expectancies for advanced stage ovarian cancer patients.