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Cancer Surfaceome Atlas IDs Genes Encoding Cell Surface Proteins With Drug Target Potential

NEW YORK — Researchers have developed a so-called Cancer Surfaceome Atlas that characterizes genes encoding cell surface proteins found in tumors. Because of their location and function, these proteins could represent potential druggable targets.

In an analysis appearing in Nature Cancer on Monday, a team led by researchers at the University of Pennsylvania found that nearly 65 percent of anticancer immune and targeted therapies approved by the US Food and Drug Administration target genes encoding cell surface proteins, or GESPs. But they also discovered that most of these drugs target only a small percentage of the surfaceome.

For their atlas, the researchers combined data from nine resources to identify more than 3,500 GESPs and further homed in on a set of about 400 that are expressed within cancers. By characterizing GESPs, they identified more than 1,400 potential drug targets that are recurrently altered in at least one cancer type.

"In the present study, we combined multiple computational approaches and systematically characterized the human surfaceome across 33 adult cancers," UPenn's Lin Zhang and colleagues wrote in their paper. "A publicly accessible surfaceome database (TCSA) was developed to assist researchers to explore GESPs in cancer genomes."

These different approaches included experimental evidence, computational predictions, and database annotations that predicted GESPs. By weighing the supporting evidence, the researchers developed a list of 3,567 high-confidence GESPs, of which more than half belonged to druggable gene families.

Using RNA sequencing data from the Genotype-Tissue Expression project and The Cancer Genome Atlas, the researchers also examined the expression of these GESPs in both normal and cancer tissue samples. Slightly more than 22 percent of GESPs were ubiquitously expressed across all cancer types, but more GESPs exhibited cancer-type specificity.

The researchers zeroed in on a set of 409 unique GESPs that were specifically expressed in at least one cancer type. Of these, 13 percent are known to be in advanced development as targets of cancer immune therapies.

Overall, they identified 1,433 potential treatment targets that are recurrently altered in at least one cancer type — spanning 33 cancer types. Also, 36 percent of the GESPs are considered druggable genes, based on their protein structures and other pharmaceutical properties.

However, the researchers noted that the top five proteins are currently targeted by more than 30 percent of approved drugs and 23 percent of drugs in clinical development, suggesting that there are still challenges in identifying and prioritizing cell surface protein-encoding gene targets for the development of anticancer drugs.

The researchers also developed a publicly accessible data resource, The Cancer Surface Atlas, through the Functional Cancer Genome data portal. This database, they wrote, "was developed to assist researchers to explore GESPs in cancer genomes."

They added that further functional analysis is needed to better understand the role of GESPs in cancer. "[Most] current functional studies are largely based on in vitro two-dimensional cell culture assays," the authors wrote. "High-throughput in vivo functional screening is still urgently needed for further characterization of GESP functions in cancer."