The Open Targets Platform brings together biomedical data from a range of sources to prioritize potential targets for drug development. The OT Platform integrates existing databases and datasets to obtain insight into links between diseases and genes for the purpose of finding druggable target genes. The strength of the OT Platform lies in the combination of these different data sources that jointly identify new targets.
One of the main data sources in the Open Targets Platform is genetic associations from GWAS studies, but there are many other data sources. The variability of the data sources allows for more targets to be identified for further study and validation; adding new and extra data sources therefore determines which targets can be identified. In this article, we examine the effect of adding a new data source to Open Targets Platform.
For the purpose of identifying oncological targets, Open Targets Platform contains information on somatic mutations, including these four sources:
While these sources contain much data, a well-known resource is currently not included, namely cBioPortal [5]. As one of the most comprehensive cancer genomics databases available, cBioPortal provides real-world patient data on a wide range of genetic alterations, including point mutations, structural variants (SVs), and copy number alterations (CNAs) [6]. By carefully processing this data source, cBioPortal has been added to the OT Platform as a data source (Figure 1, orange column on the right) that can be included like any other data source. The integration of read-world patient data from cBioPortal has contributed 49 diseases and 414 targets to Open Targets (v24.09) that were not present in the other four somatic data sources.
Spotlight on Esophageal Squamous Cell Carcinoma (ESCC)
To see the impact of cBioPortal on the associations that Open Targets reports, let's look at what impact this new data source has on the targets that are identified for Esophageal Squamous Cell Carcinoma (ESCC). ESCC is the most common type of esophageal cancer and a significant global health challenge due to its high mortality rate [7], [8]. Improving patient outcomes requires earlier diagnosis and more effective treatments.
Before the addition of cBioPortal as a data source, Open Targets (v25.06) identified 6,498 targets for ESCC. With the addition of cBioPortal's data, this number grew to 6,699, revealing 201 entirely new gene associations.
Among the top 10 new targets for ESCC identified by cBioPortal, four were completely novel to the somatic mutation evidence in Open Targets: CDKN2B, FGF19, FGF4, and FGF3. These genes are all critical in cancer biology, from regulating the cell cycle to signaling cell growth and survival [9], [10].
FGF19: A Previously Undetected Target for ESCC
The gene FGF19 stands out. Before cBioPortal's integration, it had no known association with ESCC or any other cancer in the Open Targets somatic mutation data. Let's explore why this discovery is so valuable for drug development.
FGF19 is known to be altered through gene amplification in several cancers, most frequently in breast, head, and neck cancers [11], [12]. It's located in a genomic region with other well-known oncogenes, making it challenging to pinpoint the primary driver of cancer growth [13]. However, studies have shown that overexpressing FGF19 can trigger tumor formation in various cancer types [14], [15], [16].
A pivotal study on Japanese patients with stage I ESCC further supports FGF19's role [17]. In this study, alterations in FGF19 were strongly linked to poorer progression-free survival. Notably, all the detected FGF19 alterations were copy number alterations (CNAs).
This highlights the unique strength of cBioPortal. CNAs make up 56.2% of the somatic mutation evidence it adds to Open Targets (Figure 2), a type of alteration often missed by other databases. This capability is crucial for identifying targets like FGF19.
Hypothesis: Targeting the FGF19-FGFR4 Pathway in ESCC
FGF19 is part of the fibroblast growth factor (FGF) family. While initially studied for its metabolic functions, its cancer-causing potential is now clear [15], [16], [18], [19], [20]. Research increasingly points to the FGF19-FGFR4 signaling pathway as a key driver in cancer development and progression [21], [22].
Here's why this pathway is a promising target:
- Evidence in Other Cancers: Amplification of the FGF19 gene has been found in liver, breast, lung, and bladder cancers [21].
- Preclinical Success: A neutralizing antibody targeting FGF19 has been shown to prevent liver cancer in mice and reduce tumor growth in liver and colon cancer models [25], [26].
- FGFR4 Inhibitors: Drugs that inhibit FGFR4 have also demonstrated tumor reduction in various cancer models [26].
- Relevance to ESCC: The genomic data from ESCC patients, showing a link between FGF19 amplifications and poorer outcomes, strongly suggests that targeting this pathway could be a viable treatment strategy [17].
Conclusion: adding data sources leads to more (Open) Targets
The discovery of FGF19 as a potential drug target for ESCC powerfully demonstrates the value of integrating cBioPortal into the Open Targets Platform. By incorporating real-world genomic data, particularly on CNAs, a novel link between this gene and ESCC was uncovered. Such new associations can lead to the identification of targets that are essentially overlooked therapeutic opportunities. FGF19's role in cancer progression, its link to poor patient outcomes, and the supporting preclinical evidence all point to its potential as a drug target for ESCC.
In conclusion, this article describes the effects of adding a novel dataset to Open Targets Platform. It highlights how integrating diverse, comprehensive data sources can accelerate drug discovery by uncovering new associations, and ultimately guide the development of new therapies for patients in need.
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