What is Radioligand Therapy?

When you browse the internet, you may see the term “Radioligand Therapy (RLT)” and wondered what it was.  There’s a simple explanation to what it is; and why you may be seeing more of it.  Firstly, you will all be aware of Peptide Receptor Radionuclide Therapy (PRRT), right?  Well that is just a type of RLT where the target is somatostatin receptors (SSTR). RLTs can have different targets.  You may be seeing the term Radioligand Therapy more because this technology is starting to be used on other cancers but almost always different target routes.  The obvious example is Prostate‑Specific Membrane Antigen (PSMA) which is now in service treating prostate cancer.  But can there be different targets for Neuroendocrine Neoplasms?  The answer is yes and that is what this post is about.

Breaking It Down

• • Ligand: The “homing device” — a molecule designed to recognize and attach to a specific receptor on a cell (for example, using somatostatin receptors on neuroendocrine tumour cells). Thus why a somatostatin analogue is part of the mix.
  • Radioisotope: The “payload” — a radioactive atom (such as Lutetium‑177, Yttrium‑90, Actinium‑225, or Lead‑212) that emits radiation.
  • Radioligand: When the ligand and isotope are chemically linked, the result is a radioligand — a targeted radiopharmaceutical. i.e. the ligand takes the radioactive payload to the receptor.

Theranostics

So, just as we have targeted imaging (e.g.) Ga68 Dotaxxx PET/CT for NETs (i.e. SSTR PET), there is also a Ga68 PSMA PET/CT for Prostate Cancer.  It’s the same for therapy, just as we have Lu177 Dotatate (e.g. Lutathera) to treat NETs, there is a version for Prostate e.g. Lu177 PSMA.  The principle is the same, just a different target. The combined use of imaging and therapy for the target is known as ‘Theranostics” (a truncation of therapy and diagnostics).  Get used to seeing the word Radioligand Therapy as big pharma has bought up lots of companies who are developing targeted radioligands for other cancers, they see this as a sound investment in the future of imaging and therapy for different targets needed in different cancers.  NETs led the way on this and we are still seeing other PRRT developments in clinical study e.g. alpha-emitter PRRT.   For now, we in the NET community can continue to use the term PRRT because that fits SSTR targeting – but it’s a type of RLT.

New Ligands for Neuroendocrine Neoplasms

But I also wanted to cover a very exciting development which does involve a new RLT for Neuroendocrine Neoplasms.  You will note I used the term RLT rather than PRRT.  Simple explanation – the target is not SSTRs!  The target is DLL3 i.e. Delta‑like ligand 3, something I started writing about earlier in 2025. Many NENs do not express SSTR and so PRRT is often not an efficient treatment for sections of the NEN community (mainly high grade) which is a capability gap.  DLL3 is an emerging target for Neuroendocrine Carcinomas but also expressed in a subset of well differentiated NETs (see my DLL-3 blog click here).

DLL3 is a protein involved in the Notch signalling pathway. Unlike other Notch ligands, DLL3 is usually found inside cells, but in certain cancers it is abnormally expressed on the cell surface. scientists have discovered that DLL3 is highly expressed in high‑grade neuroendocrine carcinomas, especially small cell lung cancer (SCLC) and extrapulmonary NECs (i.e. Situated or occurring outside the lungs). It is generally not expressed in normal adult tissues, making it an attractive therapeutic target. In fact there are several studies ongoing and I have already written about this new possibilities.  You can read more about DLL3 expression in NENs plus ongoing trials by clicking here.

DLL3 targeted Radioligand Therapy for Neuroendocrine Neoplasms 

The first trial for a DLL3 targeted RLT is forecast to begin by the end of this year (that’s pretty soon!)  The Phase 1 Investigational New Drug (IND) application for MP0712, a ²¹²Pb-based Radio-DARPin therapy (RDT) candidate targeting the Tumor-associated protein delta-like ligand 3 (DLL3), co-developed with Orano Med for the treatment of small cell lung cancer (SCLC) and other DLL3-expressing neuroendocrine cancers, has been filed. Dialogue with the FDA is ongoing and, pending regulatory clearance, the Phase 1 trial is expected to initiate before the end of 2025. The news item said “MP0712 is a first-in-class Radio-DARPin therapeutic targeting DLL3 with ²¹²Pb for small cell lung cancer (SCLC) and high-grade neuroendocrine tumours, now entering clinical development in 2025”.  I will update the clinical trial reference once I have it and add inclusion and exclusion criteria. It’s also known that a subset of well differentiated NETs may have some degree of DLL3 uptake and may be candidates for these trials (tbc). The DLL3 target work comprises two companies, Molecular Partners (DLL3) and Orano Med (the RLT).  The latter is already a leader in targeted alpha therapy (click here to see their ongoing alpha-emitter PRRT trial for NET).

For those who like technical detail behind the DLL3 RLT trial – click here.