The war on pediatric cancer hasn’t been going so well in the past couple of decades, says Timothy Triche, MD, PhD, a cancer researcher at Children’s Hospital Los Angeles. The existing intensive chemotherapy regimens carry a lot of “unfortunate baggage” for children in terms of lifelong morbidity, and haven’t brought about a tremendous change in outcomes, he says.
“We really don’t have a lot of new drugs, if any, and we really don’t have new targets,” he said at Boston Children’s Hospital’s Global Pediatric Innovation Summit + Awards last month. “Underlying this is the fundamental problem that we don’t understand a lot more about childhood cancer than we did before.”
In a Discovery Roundup highlighting four big ideas in pediatric care, Triche made the case for targeting the genome’s “dark matter” — the vast number of RNAs made from the genome that do not code for proteins.
Originally thought to be “random noise” in the genome, noncoding RNAs track with and play a central role in many cancers. Triche and colleagues have developed one noncoding RNA, FEZF1-AS, into a diagnostic test for Ewing sarcoma that’s now being commercialized. They have shown that this RNA promotes tumor metastasis and growth, and that it can be down-regulated with antisense oligonucleotides (ASOs), complementary nucleic acids that bind to and inactivate it.
Since ASOs have a short half-life, it’s hard to get to maintain them into tissues in high enough concentrations. That challenge led to the idea of bundling ASOs into targeted nanoparticles that carry them directly to the tumor, so none go to waste. NanoValent Pharmaceuticals, of which Triche is medical director, is partnering with CHLA to do just that, using monoclonal antibodies to guide the nanoparticles to their target.
In vitro studies of this approach in Ewing sarcoma have shown a dramatic reduction in tumor growth. There’s also a benefit for conventional chemotherapy, allowing smaller doses to be used: Nano-drugs that target delivery of agents such as doxorubicin have dramatically reduced toxicity in preclinical studies and are approaching Phase 1 trials.