Development of targeted radionuclide therapy for medullary thyroid cancer

Leading Opinions, 13.07.2017

Prof. Dr. Roger Schibli
Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen
Department of Chemistry and Applied Biosciences, ETH Zürich
Dr. Martin Behe
Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen
Dr. Michal Grzmil
Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen
E-Mail: michal.grzmil@psi.chmartin.behe@psi.ch

Onkologie | Diabetologie & Endokrinologie

Targeting overexpressed G-protein coupled receptors by radio­labeled receptor-binding ligands has proven clinical value for cancer diagnosis and treatment. The emerging advancements in nuclear medicine towards targeted radionuclide therapy enabled efficient and cancer-selective delivery of radioactive drugs. Development of gastrin analogues which bind cholecystokinin B receptor shows promise for effective internal radiotherapy in medullary thyroid cancer patients.


  • G-protein coupled receptors (GPCRs) represent the largest class of molecular targets for approved therapeutics.
  • Targeted radionuclide therapy (TRT) enables accurate and efficient delivery of radiation into the cancer sites.
  • Radiolabeled minigastrin analogues show favorable properties for targeting cholecystokinin B receptor (CCKBR) in medullar thyroid cancer.


Targeted radionuclide therapy

Currently, half of all diagnosed cancer patients as a part of standard medical care will receive radiotherapy either alone or in the combination with other treatment modalities. Conventional external beam radiation therapy (EBRT) represents major cancer radiotherapy. The response rates depend on the cancer type or stage and for many patients the survival rate is still very low. In order to improve the therapeutic ratio of the radiation treatment, previous technology advancements led to development of targeted radionuclide therapies (TRTs) by employing radiopharmaceuticals that specifically target cancer cells. These treatments have high potential to deliver high dose of radiation very accu­rately and without damaging of healthy tissues. Overexpression of G-protein coupled receptors (GPCR) such as somatostatin receptor (SSTR) that selectively binds small-peptide ligands allowed development of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors (NETs) including thyroid cancer.1 An example of routine diagnostic PET/CT scan with 68Ga-DOTATATE that binds SSTR in metastatic NET is presented in Figure 1. Targeted GPCRs bind ligand-based therapeutics and it results in rapid conforma­tional changes of the receptor if they act as agonists. These activated GPCRs undergo desensitization via arrestin-mediated internalization process, whereby GPCRs can be trafficked to lysosomes, where they are ultimately degraded, or to recycling endosomes for recycling back to the cell surface.2 Importantly, as a consequence of internalization, ligand conjugated radioactive nuclide is delivered into the cancer cells. Many recent TRT studies have been focused on optimizing radiolabeled ligand properties such as affinity, stability, emitter type and dosimetry aiming at increase in radiation and dose delivered into tumor cells and thus, treatment efficacy. Selec­tive and efficient tumor targeting also allows reducing radioactive dose and diminishes cytotoxic side effects on healthy organs especially on those responsible for drug excretion like kidneys or livers.

Targeting medullary thyroid cancer (MTC) with radiolabeled minigastrin analogues

MTC is a relatively rare cancer and it accounts for 3–5% of all thyroid cancers. However, the responses to standard-of-care therapy including surgical resection are only transient clearly indicating that better treatments warrant further devel­opment.3 Therapeutic response in clinical trials with chemotherapeutics was limited to only few patients with rapidly progressive metastatic disease. Use of doxorubicin alone or together with cisplatin produced only little benefit. Thus, radiotherapy improvement gives hope for the effective MTC treatment.
High level of cholecystokinin B receptor (CCKBR) was previously verified by radioligand binding analysis in a variety of cancers including medullary thyroid cancer (MTC), astrocytomas, small cell lung cancer and stromal ovarian cancers as well as in gastroenteropancreatic tumors, breast, endometrial, and ovarian adenocarcinomas.4 Minigastrin (MG), the shortest phys­iological form of gastrin, is a small peptide hormone that binds with a high affinity to CCKBR. Thus, many previous and recent studies have been focusing on development of various minigastrin peptide analogues for therapy and diagnostic (theranostic) applications.5 Conjugation of DOTA-like chelating agents to peptides enables labeling with various radioactive nuclides such as lutetium-177 (177Lu; β/γ emitter) for therapeutic applications or indium-111 (111In; γ-ray emitter) for tumor imaging. In order to improve favor­able pharmacokinetics, high stability and tumor uptake, recent study introduced ionic D-amino residues into MG analogues which led to development of PP-F11.6, 7 Furthermore, to overcome a possible Met oxidation and enzymatic hydrolysis at Met-Asp bond, methionine was replaced by non-oxidizable amino acid norleucine in PP-F11N without changing peptide bind­ing affinity and internalization rate.8 Currently, both radiopharmaceuticals are under evaluation in clinical trials with non-operative MTC patients. Multi-center clinical trial with 111In labeled DOTA-conjugated PP-F11 (CP04) in MTC patients has been initiated for safety, biodistribution and dosimetry assessment,7 whereas 177Lu labeled DOTA-functionalized PP-F11N has entered pilot and phase I study for receptor targeted therapy and imaging of metastatic medullary thyroid cancer in a cooperative project between Centre of Radiopharmaceutical Sciences PSI and Department of Nuclear Medicine University Hospital Basel (NCT02088645).9 An overview of TRT with radiolabeled minigastrin analogues is shown in Figure 2. Administrated 177Lu-DOTA-PP-F11N targets primary tumor as well as CCKBR-overexpressing metastatic lesions. Activated CCKBRs undergo internalization process, whereby ligand-conjugated 177Lu is delivered into the cancer cells. Reabsorption of circulating radiopeptides by kidneys can cause nephrotoxicity, limiting the maximum activity dose and the efficacy of TRT.


Current clinical trials with radiolabeled minigastrin analogues will validate their clinical potential for MTC treatment. Further development of radiopeptides towards increased tumor uptake and reduction in kidney to tumor activity ratio will undoubtedly improve their clinical use. Structural study of targeted CCKBR, especially in its active conformation, as well as receptor dimerization might lead to further compound development with highly favorable properties for targeting het­erogeneous cancer. In addition, as shown by a recent preclinical study, concomitant treatment with kinase inhibitors dimin­ished activation of survival pathways and consequently sensitized medullary thyroid cancer cells to radiolabeled peptides.10 Thus, understanding of the resistance mechanism to TRTs and appropriate application of combinatory treatments holds promise for more effective internal radiotherapy.

We thank Prof. Damian Wild (University Hospital Basel) for PET/CT images. Our research is supported by the Swiss Cancer League (KFS-3960-08-2016) and the SNF Sinergia grant (CRSII2_160805).