Yale Daily News

Researchers at the Yale Cancer Center have developed a novel strategy to offer diagnosed cancer patients with a genomically amplified, drug-resistant cancer type. 

A Yale research team at the Yale Cancer Center led by Faye Rogers, associate professor of therapeutic radiology at the Yale School of Medicine, and William Saltzman, professor of biomedical and chemical engineering at the Yale School of Engineering, published the study on Oct. 28 in the journal Nature Biotechnology. The experiment demonstrated that triplex forming oligonucleotides (TFOs) can be weaponized to hijack a cell’s genetic infrastructure, generate excessive DNA damage and induce cell death of targeted cancerous cells. 

“This can be added to the current arsenal of therapeutics targeting genomically amplified cancer,” said Elias Quijano ’12 YSM ’23, a contributing researcher on the study. 

Current precision medicine being used for such purposes include Trastuzumab, a drug that targets specific, overexpressed proteins in tumor cells. The drug then blocks those proteins in order to stop tumor cell proliferation. However, some cancers have no protein to target or are resistant to Trastuzumab, rendering the therapy ineffective. 

“We are really excited about this technology,” Rogers said. “I really envision it making a difference as a new platform for so many cancers that don’t have effective therapeutic strategies right now.” 

The technology developed by Rogers’ team addresses both problems with drug-based therapies, and its applications are pertinent to cancers exhibiting drug resistance and those with gene amplification or that are lacking a protein site to target.

Researchers used both a drug-resistant model and a model using HER-2, a widely-studied protein that acts as an oncogenic driver for breast and ovarian cancer. This research is critical for the development of treatment plans for genomically amplified cancers which have insufficient therapeutic strategies. Fourteen distinct cancer subtypes are associated with gene amplification. 

“Not all proteins are considered druggable … this gives us the opportunity to target on the genomic level … [and provides a] method to specifically reach the cancer and … prevent having non-specific toxicity,” Rogers said. 

This treatment platform is as efficacious as precision medicines currently used, and is also proven to be efficacious in drug-resistant models. As a result, researchers are excited to see this technology translate into other therapies for cancer types with a similar mechanism of action.

Not only do TFOs mediate cell death in tumor tissues, they inflict minimal damage to normal cell tissue. Researchers also demonstrated that the use of biodegradable nanoparticles as part of the TFO delivery system has been proven to increase the efficacy of this novel platform. 

“TFO delivery to the tumor was achieved using nanoparticles, so successfully being implemented currently in the COVID-19 vaccines,” said Adam Krysztofiak, a contributing researcher and postdoctoral associate in the department of therapeutic radiology. “Our studies not only proved mechanistically, on a cell and molecular biology level, a novel strategy for targeted cancer therapy but also provided a promising outlook on the delivery of targeted anti-cancer compounds with nanoparticles.”

The results of this manuscript also show that this platform is effective in vivo. The study’s results demonstrated that this triplex formation technology led to a 52 percent reduction in tumor growth. Results also confirm that p53-independent apoptosis occurred via TFO treatment, an enthusiastic finding for those looking to treat cancers associated with p53 mutations, some of which are resistant to current therapies. 

“You can’t just use one strategy,” Rogers said in regards to fighting genomically amplified, drug-resistant cancers such as breast and ovarian cancer.

This new platform offers another tool in cancer care coordinators’ toolkits. The team’s collaborators all hope that this manuscript will catapult future research and development of precision medicine therapies that can work in conjunction with current cancer treatment options.  

According to Quijano, the next challenge for this development is to apply it to cancer health care administration in real human patients, ensuring that the cutting-edge technology is swiftly yet safely delivered to cancer patients. 

The study was a collaboration between labs at the Yale School of Engineering and the Yale School of Medicine.