Normalizing Cancer
Cells in normal tissues are programmed to divide on a regular schedule and also to die at the appropriate time. The balance of cell life and cell death is exquisitely maintained so that tissues neither shrink nor expand beyond their normal size.
Cancer is often caused when cells turn on cancer-promoting genes (oncogenes) and also when cells lose genes that keep cells behaving normally (tumor-suppressing genes). Loss of tumor-suppressor genes allows cancer cells to grow divide more, die less often, and to form the unconstrained masses that we call tumors.
Therapeutic approaches to cancer, and to most other diseases, usually focus on blocking, inhibiting or antagonizing some molecule associated with the disease. We rarely try to restore normal genes that might revert the cancer cells to their original, normal form. Ways to normalize cancer cells in this way are just emerging.
Questions being pursued in our laboratory:
Working with Drs. Jinjun Shi and Omid Farokhzad, we have been able to restore normal properties to tumor cells in mice. To do this, we load ultra-small nanoparticles that can be injected into the bloodstream and travel to tumors. When injected i.v., these particles travel to the tumor sites and deliver tumor suppressor messenger RNA to the tumor. This restores tumor suppressor activity in the tumor cells and causes them to act as normal cells, resulting in less tumor growth.
We expect that this approach can be combined with conventional chemotherapy or with molecules that block oncogene production such as SiRNA to provide a double hit to the tumor cells. In this treatment, tumor cells will simultaneously lose oncogene function and gain tumor suppressor activity, becoming more like normal cells. This novel approach should be useful in the great majority of tumors that have activated oncogenes along with tumor suppressor loss.
Front image: Delivery of mRNA to tumor via nanoparticles. Image by Kristin Johnson, Boston Children's Hospital, 2018