EPHB4 as a Radioligand Therapy Target
EPHB4, EPH receptor B4, is a cell-surface protein (membrane receptor). In Human Protein Atlas immunohistochemistry, EPHB4 staining is highest in colorectal cancer (92% of samples positive), neuroendocrine tumors (100% of samples positive) and endometrial cancer (73% of samples positive). Published literature reports that EPHB4 internalizes after ligand binding, which helps retain a radionuclide inside tumor cells. Clinical status: Clinical-stage (up to phase 3, any modality).
Is EPHB4 a good radioligand therapy target?
Scored against the six criteria that decide whether a protein can become a radioligand therapy:
- ✅ Cell-surface accessibility: Localized to the cell surface, so a radioligand can reach it from circulation.
- ✅ Tumor expression: High IHC staining in colorectal cancer, 92% of samples positive.
- ✅ Internalization: Reported to internalize, which favors radionuclide retention.
- ✅ Clinical precedent: Clinical-stage (up to phase 3, any modality)
- ❔ Shedding: Not yet assessed.
- ❔ Normal-tissue dosimetry: Check kidney, liver, bone marrow and salivary expression in the Human Protein Atlas tissue atlas.
EPHB4 expression in cancer
Protein expression of EPHB4 across 20 cancer types from Human Protein Atlas immunohistochemistry. The score is a weighted staining intensity from 0 to 1; "% positive" is the share of patient samples with detectable staining.
| Cancer type | IHC score | Level | % positive |
|---|---|---|---|
| Colorectal Cancer | 0.67 | High | 92% |
| Neuroendocrine Tumors | 0.58 | High | 100% |
| Endometrial Cancer | 0.48 | Medium | 73% |
| Testicular Cancer | 0.39 | Medium | 83% |
| Prostate Cancer | 0.39 | Medium | 75% |
| Gastric Cancer | 0.30 | Medium | 73% |
| Head and Neck Cancer | 0.25 | Medium | 50% |
| Cervical Cancer | 0.22 | Medium | 58% |
| Pancreatic Cancer | 0.20 | Medium | 50% |
| Ovarian Cancer | 0.19 | Low | 58% |
| Breast Cancer | 0.18 | Low | 46% |
| Thyroid Cancer | 0.17 | Low | 50% |
| Liver Cancer | 0.17 | Low | 33% |
| Bladder Cancer | 0.15 | Low | 36% |
| Melanoma | 0.14 | Low | 25% |
| Kidney Cancer | 0.11 | Low | 33% |
| Skin Cancer | 0.09 | Low | 27% |
| Glioma | 0.09 | Low | 27% |
| Lung Cancer | 0.03 | Low | 10% |
Not detected by IHC in: lymphoma.
Is EPHB4 internalized?
Yes. this biomimetic nanoparticle (NP) exploits the endogenous EphB4-EphrinB2 (EFNB2) signaling axis to achieve selective recognition and preferential uptake by EFNB2-expressing osteoclasts (OCs), displaying significantly higher internalization in OCs compared with mesenchymal stem cells (MSC), macrophages (Mφ), and OBs in vitro.
Sources: PMID 41957808 · PMID 39696437 · PMID 36208510 · PMID 36131205 · PMID 31949258. AI-extracted from abstracts, so verify before citing.
EPHB4 clinical trials
Clinical-stage (up to phase 3, any modality). Nuclens hasn't indexed trials for EPHB4 yet. Search ClinicalTrials.gov for EPHB4 trials.
EPHB4 normal tissue expression
Normal-tissue expression in dose-limiting organs (kidney, liver, bone marrow, salivary glands) drives radioligand dosimetry risk. Nuclens is re-validating its normal-tissue values, so they are not shown here yet. See EPHB4 in the Human Protein Atlas tissue atlas, and read how normal-tissue expression predicts radioligand dosimetry risk.
EPHB4 gene essentiality (DepMap)
CRISPR knockout effect across 1258 cancer cell lines: 0.04 (not essential). Radioligands kill by radiation, not by blocking the target, so essentiality matters less than for inhibitors. A non-essential target can still be an excellent radioligand target.
Related colorectal cancer radioligand targets
c-MET (MET) · HER3 (ERBB3) · FAP · EGFR · CEA (CEACAM5) · EPCAM · SSTR2 · STEAP2
See all radioligand therapy targets in colorectal cancer.
See how EPHB4 ranks against 15,000 targets for your indication.
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Subcellular localization: UniProt via Open Targets (CC BY 4.0 / CC0). Tumor immunohistochemistry: Human Protein Atlas (CC BY-SA 4.0). Clinical trials: ClinicalTrials.gov (public domain). Gene essentiality: DepMap (CC BY 4.0). Internalization and shedding: AI-extracted from PubMed abstracts, so verify against the cited papers before relying on them. Nuclens is a first-pass triage layer, not a substitute for wet-lab validation or clinical dosimetry. Derived expression data on this page is shared under CC BY-SA 4.0.