US Food & Drug Administration Pediatric Molecular Target Lists (FDA PMTL)

In 2018, the United States Food & Drug Administration (FDA) published the Pediatric Molecular Target Lists (PMTL). Briefly, these lists contain targets that are important for studies of pediatric cancer; one list defines molecular targets that are relevant to the growth of pediatric cancer, while the other defines molecular targets that are explicitly not relevant. The targets in these lists have special legal requirements associated with drug development.

While the FDA publicationsoutbounnd web site icon remain the authoritative source for these targets, a computable interpretation of the lists is integrated into the Molecular Targets Platform.

Browse the FDA Pediatric Molecular Target Lists to identify pediatric molecular targets within the Molecular Targets Platform.

Designations

In the Molecular Targets Platform, all targets fall into one of three FDA PMTL designations:

R

Relevant Molecular Target: These targets have evidence indicating their relevance in the growth or progression of pediatric cancers. Any new drugs developed for these targets in adult cancers must also be studied for use in pediatric cancers. These targets are from the FDA’s published list of Relevant Molecular Targets.

NR

Non-Relevant Molecular Target: These targets have evidence indicating that they are not relevant in the growth or progression of pediatric cancers, or that studies of them would be ineffective or impractical for therapeutic pediatric use. Any new drugs developed for these targets in adult cancers will receive an automatic waiver from also studying them in pediatric cancers. These targets are from the FDA’s list of Non-Relevant Molecular Targets (Automatic Waivers).

?

Unspecified Target: These targets are not mentioned in the FDA PMTL. Most targets within the Molecular Targets Platform fall into this category by default.

Molecular Targets Platform Compatibility

The PMTL as published by the FDA is optimized for human-readability. This presents several computational challenges for integration into the Molecular Targets Platform. To overcome these challenges and make the PMTL compatible with the Molecular Targets Platform, significant reformatting and interpretation was required.

In the Molecular Targets Platform, every Target is identified with gene-level resolution by a unique (Ensembl stable IDoutbounnd web site icon), and then mapped to other information (e.g. gene name and symbol). As published, the FDA PMTL does not use a standardized, computable naming system. In addition, many FDA PMTL targets are representations of complex proteins or pathways, each consisting of a multitude of genes (e.g. “Proteasome”, “Tubulins” or “Hippo Pathway”).

In order to implement the FDA PMTL into the Molecular Targets Platform, each target needs to be machine-readable and contain mappable IDs at gene-level resolution. Thus, the following standardization steps were taken to obtain our interpretation of the FDA PMTL:

1. Separated each list of genes, gene fusions, and gene abnormalities contained within a single target into separate targets

2. Identified and separated pathways, gene groups, and other complex targets that required “unpacking” into component genes with manual many-to-one mapping

3. Using Human Genome Organization Gene Nomenclature Committee (HUGO HGNCoutbounnd web site icon) resources, manually standardized the names and symbols of all targets, which enabled mapping each target to Ensembl gene IDs. Original FDA-curated citations within the PMTL were used to guide this process.

Note that each FDA PMTL target appearing in our interpretation can be directly traced to one or more targets in the FDA’s published lists. No new targets were added that do not depend upon the FDA source.

Also note that many Target Symbols occur more than once in the FDA Pediatric Molecular Target Lists by design. Any target derived from multiple FDA Targets will appear once for each FDA Target. For example, BRAF is derived from three separate FDA Targets: “BRAF | Gene Abnormality: BRAF”, “ERK | Gene Abnormality: BRAF, MAP2K1”, and “MEK | Gene Abnormality: BRAF and BRAF gene fusions, MAP2K1, NF1”. Searching the Target Symbol column for “BRAF” on the FDA Pediatric Molecular Target Lists will show all of these derivations separately.

Version

The current version of the FDA PMTL used in the Molecular Targets Platform is version .

We intend to update the targets listed in our interpretation of the FDA PMTL as needed in response to publications from the FDA or feedback from the community. The first digit of the version identifier will increase upon a new FDA publication, and the second digit notes iterative interpretations upon that FDA publication.

FDA PMTL Columns

The table below contains examples and descriptions of each column within the searchable FDA Pediatric Molecular Target Lists.

Column Header Example Value Description
Target SymbolJAK1Gene-resolution HGNC approved symbol compatible with the Molecular Targets Platform
DesignationRelevant Molecular TargetFDA designation of “Relevant” or “Non-Relevant” in the growth of pediatric cancers
FDA ClassGene AbnormalityCategory of the target as listed in the FDA publication
FDA Target

JAK1, 2, and 3 | Gene Abnormality: JAK1, 2, and 3

Target as originally listed in the FDA publication. For targets in the Gene Abnormality FDA Class, the gene abnormality from the FDA publication is included here, separated from the target by “ | “
Mapping DescriptionSeparate ListBrief description of the action taken to map the target as listed in the FDA publication into one or more gene-level targets compatible with the Molecular Targets Platform

FDA PMTL Mapping Description

The table below contains a description of each potential value in the Mapping Description column. These describe the action(s) taken to map targets within the published FDA PMTL into the computable, gene-level targets used in the Molecular Targets Platform. Many FDA targets required more than one action to reach Molecular Targets Platform compatibility; these are all listed for each target when appropriate (e.g. “Separate list and standardize symbol”).

Mapping Description Example FDA Target Example Target Symbol(s) after reformatting Description
Unchanged from FDA listPTENPTENFDA Target appears exactly as in the FDA publication
Standardize symbolThymidylate synthaseTYMSFDA Target was mapped to a single HGNC approved symbol
Separate listJAK1, 2, and 3

JAK1

JAK2

JAK3

FDA Targets in a human-readable list were separated into unique targets
Separate gene fusionBRD3-NUTM1

BRD3

NUTM1

FDA Target gene fusions were separated into component genes as unique targets
Separate gene abnormalities

EZH2 | Gene

Abnormalities: SMARCB1, SMARCA4

EZH2

SMARCB1

SMARCA4

FDA Targets and their listed gene abnormalities were separated into unique targets
Unpack complex targetBET bromodomain family

BRD2

BRD3

BRD4

BRDT

FDA Targets consisting of multiple genes (such as gene families or complex proteins) were separated into unique, gene-level targets
Fix human error…IDH1 and IHD2

IDH1

IDH2

FDA Targets containing typos or mismatched citations were corrected. Details given for each instance
Cannot be mapped to gene-level targetGD2GD2 (Disialoganglioside)Feedback from the FDA indicated that the FDA Target should not be mapped to any gene. Though incompatible with the Molecular Targets Platform, it will remain in the table for reference