“Junk” genome may actually unlock future cancer treatment

In 2016, Belgian cancer biologist Eleonora Leucci published the first of several papers on a particular RNA molecule called SAMMSON, which was particularly active in melanoma tumors.

Over the past eight years, Leucci and others have repeatedly shown that SAMMSON is crucial for the survival of melanoma cells, making it one of the most compelling new drug targets for the treatment of primary and metastatic melanomas. For Australian molecular biologist John Mattick, who has spent much of his career trying to assign functions to parts of the genome once described as ‘junk’, SAMSSON represents what so-called RNAs can be long non-coding – usually shortened to lncRNA. used as new drug targets for a whole range of disorders, from cancer to neurological disorders to obesity.

“The pen is starting to drop that if you want to treat these complex diseases, then you have to look at these things,” Mattick said.

In many ways, lncRNAs represent a paradigm shift that has occurred over the past two decades of my career. Initially, drug development focused entirely on the less than two percent of the human genome that codes for proteins. However, it has become increasingly clear that treating many chronic diseases that arise from interactions between our genes and our environment requires modifying key segments of the remaining 98% of the genome, sometimes referred to as the dark genome. While the importance of the dark genome was initially underestimated because it does not directly code for proteins, it is now known to contain many regions, including lncRNAs, which can directly affect the activity of various genes and critical cellular processes.

LncRNAs are defined by their length—they contain more than 500 nucleotides, the basic building blocks of DNA and RNA—but their most defining quality is their ability to alter our basic biology by interacting with so-called RNA-binding proteins (RBPs). However, their presence within our genetic code is not intended to cause disease. In fact, they control many processes that are essential to human development, guiding the trillions of cellular decisions required for us to go from an embryo to a fully grown adult, from the architecture of our bones to the wiring of the brain and core. nervous system.

However, subtle variations in the nucleotide structure of different lncRNAs, either inherited from our parents or by chance, are thought to make different people more or less susceptible to various environmental risk factors, ranging from exposure to to UV to infections. This has been seen in a large number of genome-wide association studies (GWAS) over the past 10 years, which have consistently implicated various lncRNAs with disease. For example, Mattick’s lab has shown that most GWAS regions, including those implicated in neurological disorders, express lncRNAs.

“Whether a genetic predisposition is realized usually depends on an environmental factor,” says Mattick. “For example, typically in the case of autoimmune disorders like multiple sclerosis or type 1 diabetes, the environmental trigger is likely to be a viral infection.”

The general theory is that in susceptible people, exposure to an environmental risk factor causes pathways controlled by lncRNAs to become dysregulated, meaning they interact with RBPs in a way that drives pathogenic processes, such as tumor formation, metastasis or transition to an autoimmune state. As we understand more about the mechanisms linking lncRNAs and complex diseases, small molecule drugs or RNA modulators can be designed to disrupt this process, opening the way to an entirely new class of treatments for many previously unknown diseases. unsolvable.

Some of the world’s largest pharmaceutical companies are now beginning to realize the great potential of this emerging field. Earlier this year, Eli Lilly struck a deal worth up to $1 billion with a biotech called Haya Therapeutics to develop therapies targeting various lncRNAs for obesity and metabolic diseases. My team at Bayer has also formed a partnership with NextRNA Therapeutics to develop new small molecules that can target lncRNAs for oncology applications.

According to Dominique Verhelle, co-founder and CEO of NextRNA Therapeutics, the company has been working on multiple lncRNAs associated with multiple cancers where there is a significant unmet need, such as breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma and glioblastoma. There is also an ongoing program investigating three lncRNAs that have been associated with the neurodegenerative disease amyotrophic lateral sclerosis.

While GWAS studies can help identify lncRNAs of interest, Verhelle explains that computational biology plays a critical role in narrowing down the most promising targets for drug development. She says the company’s approach uses a proprietary platform to identify and prioritize disease-driving lncRNAs based on their level of expression in disease versus normal tissue and association with disease progression, before developing small molecules capable of disrupting lncRNA and RBP interaction.

“Using our platform and unique capabilities, we have achieved success in oncology and neuroscience in identifying and, importantly, validating lncRNA-RBP interactions that drive disease,” she says.

While small molecules are currently at the forefront of efforts to modulate the activity of lncRNAs, in the future, other tools such as CRISPR and RNA interference have also been described as potential therapeutic strategies.

Mattick describes himself as optimistic, predicting that oncology will likely be the first sector where these new therapies begin to emerge, followed by autoimmune diseases and finally neurological disorders. However, he says there is still much work to be done in finding ways to identify the lncRNAs most critical for various diseases, compared to the thousands of potential targets emerging from GWAS or transcriptomic studies.

“There are thousands of publications reporting lncRNAs in some context,” he says. “But we’re just beginning to scratch the surface when it comes to mechanistic links between a particular lncRNA and disease processes. So in terms of where the field is, I’d say we’re getting out of the fog, there’s still a lot of fog, but it’s starting to clear up. Here we are now. And companies are starting to wake up to the opportunity and place some bets.”

Some of these bets could lead to lifesaving treatments for patients in need. I am eager to see where the next chapter of this story will lead in the years to come.

Thanks to David Cox for additional research and reporting on this article.