In a study published in Science Translational Medicine, researchers at Sylvester, along with colleagues at the University of Modena and Reggio Emilia, and Verona University Hospital in Italy, have demonstrated that a relatively new class of RNA molecules, called aptamers, can successfully guide chemotherapy into tumors. This research, conducted in animal models, could lead to advanced therapeutics that specifically target cancers while leaving healthy tissues alone.
The research article, “Aptamers against mouse and human tumor-infiltrating myeloid cells as reagents for targeted chemotherapy,” was released online on June 17.
“Chemotherapies are the first line of treatment for most cancers,” said Paolo Serafini, Ph.D., research assistant professor in the Department of Microbiology and senior author on the paper. “While they are effective treatments, they can also cause both short- and long-term damage to the body. Our goal was to make chemotherapy more intelligent, more effective and less toxic.”
Cancer researchers have been investigating targeted treatments for decades, often conjugating antibodies with therapeutic molecules to attack tumors. Unfortunately, these targeting antibodies are challenging to make, and cancer cells can evolve mechanisms to elude them.
To overcome these faults, the Serafini lab adapted RNA aptamers, instead of antibodies, to target rogue immune cells, called myeloid-derived suppressor cells (MDSCs). Tumors recruit these cells to suppress the immune response, making them cancer’s best friend. Because MDSCs have unique molecular features, do not evolve resistance and are ubiquitous inside tumors, they could also be handy therapeutic targets.
“Unlike tumor cells, which are quite heterogeneous, MDSCs are similar to each other within a patient, across patients and across cancer types.” Dr. Serafini said. “At the tumor sites, these cells acquire a unique phenotype that makes them different from all other cells in the body. As a result, they can mark where the tumor and metastases are located.”
Taking advantage of these traits, the Serafini lab investigated whether RNA aptamers, which can fold into different shapes and bind to diverse cell surface molecules, can effectively target MDSCs. Using a relatively simple chemical process, the lab synthesized 1015 aptamers. From these they isolated several that could be used to target MDSCs.
“We identified four RNA aptamers that specifically recognized MDSCs in the primary tumor and metastases but not the ones in healthy organs,” Dr. Serafini said.
They then conjugated chemotherapy (doxorubicin) molecules to the aptamers and tested them in animal models for breast cancer. This new formulation outperformed standard doxorubicin and showed little toxicity.
Developing RNA aptamers to direct therapeutic molecules to tumors could be a major breakthrough, as they are easier to manufacture than antibodies and may be more effective.
“They work like antibodies, but you don’t need cells to produce them,” Dr. Serafini said. “You don’t need big incubators; you can just do it chemically with an oligo synthesizer (an instrument that manufactures genetic material). They are tiny, so they can go deep into tissues, and we don’t need to humanize them, because they are not recognized by the immune system and are not immunogenic.”