The Current Status and Future Potential of Theranostics to Diagnose and Treat Childhood Cancer

Abstract

In theranostics (i.e., therapy and diagnostics) radiopharmaceuticals are used for both therapeutic and diagnostic purposes by targeting one specific tumor receptor. Biologically relevant compounds, e.g., receptor ligands or drugs, are labeled with radionuclides to form radiopharmaceuticals. The possible applications are multifold: visualization of biological processes or tumor biology in vivo, diagnosis and tumor staging, therapy planning, and treatment of specific tumors. Theranostics research is multidisciplinary and allows for the rapid translation of potential tumor targets from preclinical research to “first-in-man” clinical studies. In the last decade, the use of theranostics has seen an unprecedented value for adult cancer patients. Several radiopharmaceuticals are routinely used in clinical practice (e.g., [⁶⁸Ga/¹⁷⁷Lu]DOTATATE), and dozens are under (pre)clinical development. In contrast to these successes in adult oncology, theranostics have scarcely been developed to diagnose and treat pediatric cancers. To date, [^123/131I]meta-iodobenzylguanidine ([^123/131I]mIBG) is the only available and approved theranostic in pediatric oncology. mIBG targets the norepinephrine transporter, expressed by neuroblastoma tumors. For most pediatric tumors, including neuroblastoma, there is a clear need for novel and improved radiopharmaceuticals for imaging and therapy. The strategy of theranostics for pediatric oncology can be divided in (1) the improvement of existing theranostics, (2) the translation of theranostics developed in adult oncology for pediatric purposes, and (3) the development of novel theranostics for pediatric tumor-specific targets. Here, we describe the recent advances in theranostics development in pediatric oncology and shed a light on how this methodology can affect diagnosis and provide additional treatment options for these patients.

Introduction

Theranostics in nuclear medicine includes the use and application of two identical or very closely related radiopharmaceuticals for therapy and diagnosis. In oncology, tumor-specific substrates, receptor ligands, or drugs can serve as lead for theranostic development when labeled with specific radionuclides for imaging or therapy (Figure 1A). As the molecular structure of both the diagnostic and therapeutic radiopharmaceuticals are identical, diagnostic images can become predictive for therapeutic response because the biological characteristics and binding potential of both are similar, irrespective of the radionuclide (2–4).

Figure 1

For diagnosis, positron emission tomography (PET) is a nuclear imaging technique that enables the visualization and quantification of molecules equipped with positron emitting radionuclides. The most used radionuclide for imaging is Fluorine-18 (¹⁸F) in the form of [¹⁸F]FDG. [¹⁸F]FDG PET visualizes increased carbohydrate uptake in tissue, e.g., tumor tissue, and is important for diagnosis, staging and treatment monitoring. For PET tracer development, any molecule that displays tumor-specific targeting can be used, including small molecules, peptides or biologicals. Radionuclides used for PET tracer development are, among others, Carbon-11 (¹¹C) and Fluorine-18 (¹⁸F) facilitating small molecule labeling, Gallium-68 (⁶⁸Ga) for peptide radiolabeling, and Copper-64 (⁶⁴Cu) or Zirconium-89 (⁸⁹Zr) for the labeling of monoclonal antibodies (mAbs) and other biologicals. PET imaging enables studying the distribution and kinetics of labeled molecules and the biochemical and physiological processes. Molecular imaging by means of PET can, thus, facilitate and guide cancer treatment in many ways (5, 6). Currently, PET is the most sensitive technique for nuclear imaging; it requires nanomolar amounts of the radiopharmaceutical for imaging. These nanomolar amounts will not induce pharmacological effects, hold minimal risks for toxicity, and are described as the micro-dosing concept. Micro-dosing allows for fast translation of novel PET tracers into clinical trials in small “first-in-man” or phase 0 studies, when produced under good manufacturing practice (GMP). Single photon emission computed tomography (SPECT) is an alternative nuclear imaging technique and enables the visualization of γ-emitting radionuclides and was the basis for early theranostics development, where, among others, the different radionuclides of iodine were used for imaging (e.g., Iodine-123 (¹²³I) and Iodine-131 (¹³¹I)).

Therapeutic radiopharmaceuticals for treatment of cancer are predominantly labeled with β-emitting radionuclides. The radionuclide ¹³¹I, Lutetium-177 (¹⁷⁷Lu) and Yttrium-90 (⁹⁰Y) are frequently used for this purpose. The emitted β-particles travel 1–12 mm through tissue upon decay while losing energy and causing cytotoxic damage to the cell to induce apoptosis. Alternatively and more recently, α-emitting radionuclides, e.g., Astatine-211 (²¹¹At) or Actinium-225 (²²⁵Ac) were explored for therapy (7–9). The high energy deposition and a limited range of the α-particles in tissue (0.005–0.11 mm) result in very strong cytotoxic and therapeutic effects. Nowadays, α-emitting radionuclides become more widely available, research toward the development of therapeutic radiopharmaceuticals with these radionuclides is emerging, and first-in-man studies are expected in the near future.

Successful theranostics have been developed for somatostatin receptor positive neuroendocrine tumors with [⁶⁸Ga/¹⁷⁷Lu]DOTATATE and prostate-specific membrane antigen (PSMA) positive prostate cancer patients as prime examples (10–13). Currently, for childhood cancers and more specifically norepinephrine transporter (NET) positive neuroblastoma tumors, [^123/131I]meta-iodobenzylguanidine ([^123/131I]mIBG) is the only available theranostic to date (14–16). Despite the proven value of theranostics in adult oncology, its potential was minimally explored for childhood cancer and is still at its infant stage. However, many opportunities and applications present themselves. In this review, we discuss different strategies for theranostics development for childhood cancer and divided these into (1) the existing theranostics and improvement thereof, (2) theranostics developed for adult oncology and translation thereof for childhood cancer, and (3) the development of novel theranostics for specific pediatric tumor targets. By describing the recent advances in theranostics research we discuss how it can affect diagnosis and therapy for childhood cancer in the future.

Current Theranostics in Pediatric Oncology

[^123/131I]mIBG is the only theranostic currently available for routine clinical use to image and treat neuroblastoma tumors that express the norepinephrine transporter (NET). mIBG is a structural analog of the neurotransmitter norepinephrine and is actively transported into the tumor by NET. Inside the cell, mIBG is stored in the cytoplasm, mitochondria, and in vesicular monoamine transporter (VMAT)-coated and neurosecretory vesicles (17–21). [¹²³I]mIBG SPECT imaging is currently the standard of care to diagnose primary tumors and distant metastases in neuroblastoma and for staging and disease response evaluation after treatment. In total, approximately 95% of neuroblastoma tumors are [¹²³I]MIBG avid. The remaining 5% of tumors are either well-differentiated ganglioblastoma or very undifferentiated neuroblastoma with little or no NET transporter expression. Although [¹²³I]mIBG SPECT has a high specificity and sensitivity, it also has disadvantages being poor image resolution, long scanning times, and iodine-driven thyroid toxicity. Accompanied by imaging, [¹³¹I]mIBG initially showed therapeutic effectiveness in bulky tumors (22). Subsequently, it was shown that [¹³¹I]mIBG was feasible and effective in the first treatment of high-risk neuroblastoma patients (23). However, two systematic reviews failed to show a survival advantage for [¹³¹I]mIBG treated patients (24, 25). In two studies [¹³¹I]mIBG was combined with busulfan and melphalan followed by autologous stem cell rescue. For both, acceptable toxicity in highly pretreated patients and encouraging responses were observed. This has led to the implementation of this combination for ultra-high-risk patients who failed to respond adequately during induction treatment for high-risk neuroblastoma. The current European SIOPEN VERITAS study explores the role of [¹³¹I]mIBG in combination with topotecan and stem cell rescue followed by another high-dose consolidation with Buslfan and Melphalan and a second stem cell rescue. The aim is to increase the survival of these ultra-high-risk patients. In conclusion, [¹³¹I]mIBG treatment is still under investigation and its definitive role has not been determined. In addition to the discussion on therapeutic response, patients receiving [¹³¹I]mIBG also suffer from iodine uptake in the thyroid and increased risk for long-term thyroid dysfunction or secundary thyroid cancer. Last, after [¹³¹I]mIBG administration, patients need to live in isolation for 5–7 days and strict precepts for 2–3 weeks. Despite the value of [^123/131I]mIBG as a theranostic, both imaging and therapy have serious disadvantages and limitations that steer the research toward novel approaches.

An ¹⁸F-labeled analog of [¹²³I]mIBG, [¹⁸F]meta-fluorobenzylguanidine ([¹⁸F]mFBG]) has long been proposed as a possible PET alternative for the imaging of NET-positive neuroblastoma tumors (26). The radionuclide ¹⁸F is a cyclotron produced β⁺-emitter with a short range in vivo, resulting in a high image quality. Furthermore, PET-CT (or PET-MRI) images can be analyzed quantitatively for tracer distribution. ¹⁸F-labeled radiopharmaceuticals are, therefore, ideal for high-resolution diagnosis, faster acquisition, and low radiation burden. Until recently, however, the production of [¹⁸F]mFBG has been challenging. It requires a nucleophilic aromatic substitution of an electron-rich molecule (27, 28). Recent advances and novel radiofluorination reactions now give access to the production and clinical translation of [¹⁸F]mFBG (1, 29).

Pandit-Taskar et al. reported the first clinical results with [¹⁸F]mFBG, described a biodistribution and dosimetry study in neuroblastoma patients, and compared the results with [¹²³I]mIBG. In all five neuroblastoma patients, [¹⁸F]mFBG scored better than [¹²³I]mIBG with respect to lesion counts, improved image quality, and the absence of any thyroid uptake (Figure 1B). These encouraging results gave rise to additional and more extensive clinical testing of [¹⁸F]mFBG as an alternative to [¹²³I]mIBG as the current gold standard (Table 1) (30, 31).

In addition to improved imaging, research is now focused on the development of an improved alternative for [¹³¹I]mIBG therapy. ¹³¹I is a β^–-emitter with a t_1/2 of 8.04 days. Furthermore, when [¹³¹I]mIBG is metabolized and ¹³¹I is released, it will accumulate in the thyroid. Therefore, the thyroid is blocked as a preventive action by administration of excess iodine to avoid undesired effects. As an alternative for ¹³¹I, ²¹¹At has been explored. ²¹¹At is an α-emitter with a t_1/2 of 7.2 h and a range of 0.005–0.11 mm in tissue. These physical properties cause very strong cytotoxic and therapeutic effects. Furthermore, ²¹¹At does not accumulate in the thyroid and potentially will not cause any undesired damage (32, 33), As ²¹¹At has benefits over ¹³¹I, [²¹¹At]meta-astatobenzylguanidine ([²¹¹At]mABG) was reported as an alternative for [¹³¹I]mIBG for the treatment of NET positive tumors. To date, [²¹¹At]mABG has only been evaluated in preclinical models on PC12 xenografted mice (Table 1). [²¹¹At]mABG showed a dose-dependent tumor regression and increased survival compared to the control animals. It should, however, be noted that a high dose of [²¹¹At]mABG caused the death of the animals. Therefore, the toxicity profile and maximum tolerated dose of [²¹¹At]mABG needs to be assessed and compared to [¹³¹I]mIBG. An important additional note is the availability of ²¹¹At to produce [²¹¹At]mABG, which may become a practical concern. ²¹¹At can only be produced by high-energy cyclotrons, of which a few are installed worldwide, and thereby the access is limited (34).

From Adult Oncology to Pediatric Oncology

Theranostics available in routine clinical care are a rich source of potential theranostic candidates in pediatric oncology.

The somatostatin receptor (SSTR) family is one of the first discovered and most successful targets identified for which theranostics were developed. To date, 5 subtypes of SSTR (i.e., SSTR-1, 2A, 3, 4, and 5) are characterized. In particular, SSTR-2A is important with high expression levels for neuroendocrine tumors. It is involved in secretion, proliferation, and the induction of apoptosis (35). For pediatric cancers, SSTR-2A expression was reported for neuroblastoma tumors by Alexander et al. as well as for neuro-oncological malignancies (e.g., glioblastomas and medulloblastomas) (36–38). Analogs of somatostatin, the natural ligand of SSTR-2A, have successfully been developed to inhibit neuroendocrine tumor growth. Radiolabeling of these compounds led to the development of [⁶⁸Ga]DOTATATE as a PET tracer and received FDA approval in 2016 (Table 1). In 2018, [¹⁷⁷Lu]DOTATATE (Lutathera, AAA/Novartis) was approved as a therapeutic agent to treat SSTR-2A positive tumors. As DOTATATE is an SSTR-2A agonist, it stimulates the receptors, potentially causing undesired tumor growth. To circumvent these agonistic effects, the theranostics pair [⁶⁸Ga]OPS202/[¹⁷⁷Lu]OPS201 (Ipsen) was developed as an SSTR-2A antagonist and is currently in Phase I/II trials (Table 1) (10, 11, 39, 40). Because SSTR-2A expression was also validated for neuroblastomas and neuro-oncological malignancies and with several theranostics available, a straightforward translation to pediatric oncology is feasible. Small-scale experimental pilot studies were reported for these pediatric cancers with [⁶⁸Ga]DOTATATE, and results are encouraging (41). This warrants further clinical studies on imaging and treating SSTR-2A positive pediatric cancers with these theranostics in the near future (Figure 1C) (42).

Another theranostic candidate target that was extensively explored in adult oncology is the C-X-C chemokine receptor 4 (CXCR4). The expression levels of CXCR4 and its natural ligand, CXCL12, are correlated to tumor development and metastasis and were validated for breast cancer, prostate cancer, lung cancer, colorectal cancer, and primary brain tumors (43). By immunohistochemical staining, CXCR4 expression was also demonstrated for neuroblastomas, rhabdomyosarcomas, glioblastomas, and hematological malignancies (44–47). To date, several CXCR4-targeting drugs are under (pre)clinical development, e.g., Ulocuplumab, PRX177561, AMD3100, and Plerixafor, which demonstrates that CXCR4 targeting is clinically feasible and relevant. For theranostic development, the PET tracer and cyclic-pentapeptide [⁶⁸Ga]Pentixafor (Scintomics) is currently the most advanced and under investigation in multiple Phase I clinical trials (Table 1) (48). Labeling of pentixafor with ¹⁷⁷Lu or ⁹⁰Y to obtain the therapeutic counterpart of the diagnostic led to a strongly decreased affinity for the target receptor. This affinity could be restored after small molecular adaptations to the pentixafor scaffold and resulted in the successful development of [¹⁷⁷Lu]Pentixather (Table 1) (43, 49, 50). [⁶⁸Ga]Pentixafor and [¹⁷⁷Lu]Pentixather are candidates for clinical trials in pediatric patients as well as CXCR4 is reported for these tumors.

A target that recently received much attention is the fibroblast activation protein α (FAP) (51). FAP is a serine protease that is selectively expressed in the stromal fibroblasts of the tumor, which is often observed for breast cancer, colon cancer, and pancreatic cancers (52). FAP expression is observed in glioblastomas and can be a valuable theranostic target for pediatric cancers. FAP-specific inhibitors (FAPI) have been developed based on quinoline scaffolds. For diagnostic purposes, promising results were obtain after radiolabeling with ⁶⁸Ga (53, 54). In particular, [⁶⁸Ga]FAPI-04, -21, and -46 resulted in high-contrast images, and as a proof-of-concept, 28 different tumor types were visualized with [⁶⁸Ga]FAPI-04 (55, 56). All FAPI compounds allow radiolabeling with ¹⁷⁷Lu too to obtain the corresponding therapeutic radiopharmaceutical. Preclinical studies with [¹⁷⁷Lu]FAPI-21 and -46 in tumor-bearing mice gave promising results (Table 1) (57). As FAP is also expressed by glioblastomas, these theranostics have potential for the diagnosis and treatment of pediatric cancers.

Monoclonal antibodies (mAbs) and mAb-fragments had unprecedented impact on the treatment of cancer patients. However, clinical benefit is usually only achieved in a percentage of the patient population. The application of ⁸⁹Zr-labeled mAbs as ImmunoPET tracers has become increasingly important to visualize these compounds in vivo and assess the distribution, kinetics, and the biochemical and physiological behaviour (4, 58). Nowadays, more than 75 clinical trials are ongoing with ⁸⁹Zr-labeled mAbs and the radiolabeling can be achieved via generic methods (59, 60). Despite the clinical impact of ImmunoPET with [⁸⁹Zr]mAbs for adult oncology and other indications, ImmunoPET with available [⁸⁹Zr]mAbs has barely been explored for pediatric cancers. The only reported application of ImmunoPET was [⁸⁹Zr]bevacizumab in diffuse intrinsic pontine glioma to study vascular endothelial growth factor (VEGF) excretion and the potential to treat these patients with bevacizumab (61). Though ImmunoPET in pediatric cancer patients is not common, it should be anticipated that this methodology can also have an impact for these patients in the future.

Specific Theranostic Targets in Pediatric Oncology

Pediatric cancers have a distinct biological profile with unique molecular targets that are not expressed in adult cancers. These targets embody unique opportunities for the diagnosis and treatment of pediatric cancers, but due to small patient populations, it remains a challenge to identify them and develop theranostics against these targets.

A target of interest for theranostic development is ganglioside D2 (GD2). GD2 is a glycosphingolipid and selective cellular marker that is expressed by neuroblastomas, osteosarcomas, and glioblastomas (62, 63). Though its exact function is still not fully understood, it is assumed that it plays a crucial role in cell adhesion, migration, and tumor metastasis. Dinutuximab (Unituxin^®, United Therapeutics) is FDA approved, and Dinutuximab beta (Qarziba^®, EUSA Pharma) is EMA approved for the treatment of GD2-positive neuroblastoma tumors (64, 65). Despite increased survival rates from 46% to 66%, for high-risk neuroblastoma patients, 30% of the patients will relapse independent of the GD2 expression levels (Table 1) (66). Several radiopharmaceuticals have been developed to image GD2-positive tumors. ⁶⁴Cu-labeled hu14.18K322A showed clear accumulation and retention in preclinical osteosarcoma models, and [⁸⁹Zr]dinutuximab was mentioned as a PET tracer in meeting abstracts (67–69). In addition to radiolabeled mAbs, Müller et al. reported on the development of [⁶⁸Ga]DOTA- WHWRLPS heptapeptide and demonstrated its accumulation in neuroblastoma xenografted mice (70). Though encouraging, clinical translation of these radiopharmaceuticals has yet to be achieved.

More recently, B7-H3 (CD276) has become a validated pediatric cancer target for immunotherapy in pontine gliomas and neuroblastomas (71, 72). To date, two mAbs were developed, Enoblituzumab (MacroGenics) and Omburtamab (Y-mAbs), to treat B7-H3 positive tumors (73, 74) Based on these immunotherapeutics, attempts at the development of theranostics are reported. Especially with 8H9 (i.e., Omburtamab) multiple clinical trials are ongoing. The theranostics pair [^124/131I]8H9 is investigated for B7-H3 positive pontine glioma tumors and a modest survival benefit was reported (Table 1) (75, 76). As specific brain tumors (e.g., gliomas) express B7-H3, it is important that passage and delivery of the radiopharmaceutical across the blood–brain barrier is achieved. As such, radiolabeled [^124/131I]Omburtamab is ideal to investigate drug targeting in these patients. As B7-H3 is acknowledged as a pan-tumor target, theranostics targeting B7-H3 might become of general importance for childhood cancer.

Considerations and Requirements for Nuclear Medicine in Childhood Cancer

The application of theranostics for the diagnosis and treatment of childhood cancers is in its infancy. With the availability of radiopharmaceuticals and theranostics for the various adult cancers, there is a lot of potential to translate and directly apply these for childhood cancers. Clinically available SPECT/PET tracers and therapeutic radiopharmaceuticals can directly be applied for pediatric cancers when the target is present and validated for the respective tumor type. Examples include SSTR-2A, CXCR4, and FAP-positive tumors. As childhood cancers have unique target expression profiles, with GD2 and B7-H3 as examples, novel theranostics can be developed for these yet unexplored targets. Unique target-finding programs are in place to unveil novel childhood cancer-specific biological features for which theranostics can be developed. A critical note and challenge is that target expression of cancers in general cannot always be directly correlated to positive imaging and treatment results. Preclinical research programs are, therefore, required to validate target expression and the potential of the target against which to developed theranostics.

A successfully developed theranostic that shows potential in preclinical studies warrants clinical translation. To achieve that, the theranostic needs to be produced under GMP to guarantee product quality and patient safety (77). Clinical translation of developed theranostics is relatively straightforward as procedures and GMP production facilities are widely available.

Conclusion

Theranostics have unprecedented value to diagnose and treat cancers. Many novel theranostics are under development and expected to enter clinical trials and care in the near future. For the diagnosis and treatment of childhood cancers, theranostics research is still in its infancy, but following the path of adult oncology, its value is promising. They are expected to become additional and valuable tools to diagnose and treat childhood cancers.

Funding

Sponsored by UMC Utrecht and Princess Máxima Center for Pediatric Oncology, Netherlands.

References

• 1

  RotsteinBWangLLiuRPattesonJKwanEEVasdevNet al. Mechanistic Studies and Radiofluorination of Structurally Diverse Pharmaceuticals with Spirocyclic Iodonium(III) Ylides. Chem Sci (2016) 7:4407–17. doi: 10.1039/C6SC00197A

  • CrossRef
  • Google Scholar

• 2

  LangbeinTWeberWEiberM. Future of Theranostics: An Outlook on Precision Oncology in Nuclear Medicine. J Nucl Med (2019) 60:13S–9S. doi: 10.2967/jnumed.118.220566

  • CrossRef
  • Google Scholar

• 3

  TurnerJH. Recent advances in theranostics and challenges for the future. Br J Radiol (2018) 91:1091. doi: 10.1259/bjr.20170893

  • CrossRef
  • Google Scholar

• 4

  RöschFHerzogHQaimSM. The Beginning and Development of the Theranostic Approach in Nuclear Medicine, as Exemplified by the Radionuclide Pair ⁸⁶Y and ⁹⁰Y. Pharmaceuticals (Basel) (2017) 10:56. doi: 10.3390/ph10020056

  • CrossRef
  • Google Scholar

• 5

  Van DongenGAMSPootAJVugtsDJ. PET imaging with radiolabeled antibodies and tyrosine kinase inhibitors: immuno-PET and TKI-PET. Tumour Biol (2012) 33:607–15. doi: 10.1007/s13277-012-0316-4

  • CrossRef
  • Google Scholar

• 6

  SlobbePPootAJWindhorstADVan DongenGAMS. PET imaging with small-molecule tyrosine kinase inhibitors: TKI-PET. Drug Discovery Today (2012) 17:1175–87. doi: 10.1016/j.drudis.2012.06.016

  • CrossRef
  • Google Scholar

• 7

  NavalkissoorSGrossmanA. Targeted Alpha Particle Therapy for Neuroendocrine Tumours: The Next Generation of Peptide Receptor Radionuclide Therapy. Neuroendocrinology (2019) 108:256–64. doi: 10.1159/000494760

  • CrossRef
  • Google Scholar

• 8

  GuérardFGestinJ-FBrechbielMW. Production of [²¹¹At]-Astatinated Radiopharmaceuticals and Applications in Targeted α-Particle Therapy. Cancer Biother Radiopharm (2013) 28:1–20. doi: 10.1089/cbr.2012.1292

  • CrossRef
  • Google Scholar

• 9

  MorgensternAApostolidisCKratochwilCSathekgeMKrolickiLBruchertseiferF. An Overview of Targeted Alpha Therapy with ²²⁵Actinium and ²¹³Bismuth. Curr Radiopharm (2018) 11:200–8. doi: 10.2174/1874471011666180502104524

  • CrossRef
  • Google Scholar

• 10

  SanliYGargIKandathilAKendiTBaladron ZanettiMJKuyumcuSet al. Neuroendocrine Tumor Diagnosis and Management: ⁶⁸Ga-DOTATATE PET/CT. Am J Roentgenol (2018) 2:267–77. doi: 10.2214/AJR.18.19881

  • CrossRef
  • Google Scholar

• 11

  MittraES. Neuroendocrine Tumor Therapy: ¹⁷⁷Lu-DOTATATE. Am J Roentgenol (2018) 2:278–85. doi: 10.2214/AJR.18.19953

  • CrossRef
  • Google Scholar

• 12

  RahbarKAfshar-OromiehAJadvarHAhmadzadehfarH. PSMA Theranostics: Current Status and Future Directions. Mol Imaging (2018) 17. doi: 10.1177/1536012118776068

  • CrossRef
  • Google Scholar

• 13

  AhmadzadehfarHRahbarKEsslerMBiersackHJ. PSMA-Based Theranostics: A Step-by-Step Practical Approach to Diagnosis and Therapy for mCRPC Patients. Semin Nucl Med (2019) 50:98–109. doi: 10.1053/j.semnuclmed.2019.07.003

  • CrossRef
  • Google Scholar

• 14

  MatthayKKShulkinBLadersteinRMichonJGiammarileFLewingtonVet al. Criteria for evaluation of disease extent by ¹²³I-metaiodobenzylguanidine scans in neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task Force. Br J Cancer (2010) 102:1319–26. doi: 10.1038/sj.bjc.6605621

  • CrossRef
  • Google Scholar

• 15

  MatthayKKPaninaCHubertyJPriceDGliddenDVTangHRet al. Correlation of tumor and whole-body dosimetry with tumor response and toxicity in refractory neuroblastoma treated with ¹³¹I-MIBG. J Nucl Med (2001) 42:1713–21.

  • Google Scholar

• 16

  KraalKCJMTytgatGAMVan Eck-SmitBLFKamBCaronHNVan NoeselMM. Upfront treatment of high-risk neuroblastoma with a combination of ¹³¹I-MIBG and Topotecan. Pediatr Blood Cancer (2015) 62:1886–91. doi: 10.1002/pbc.25580

  • CrossRef
  • Google Scholar

• 17

  VaidyanathanG. Meta-iodobenzylguanidine and analogues: chemistry and biology. Q J Nucl Med Mol Imaging (2008) 52:351–68.

  • Google Scholar

• 18

  GlowniakJVKiltyJEAmaraSGHoffmanBJTurnerFE. Evaluation of metaiodobenzylguanidine uptake by the norepinephrine, dopamine and serotonin transporters. J Nucl Med (1993) 34:1140–6.

  • Google Scholar

• 19

  GazeMNHuxhamIMMairsRJBarrettA. Intracellular localization of metaiodobenzyl guanidine in human neuroblastoma cells by electron spectroscopic imaging. Int J Cancer (1991) 47:875–80. doi: 10.1002/ijc.2910470615

  • CrossRef
  • Google Scholar

• 20

  SmetsLAJanssenMMetwallyELoesbergC. Extragranular storage of the neuron blocking agent meta-iodobenzylguanidine (MIBG) in human neuroblastoma cells. Biochem Pharmacol (1990) 39:1959–64. doi: 10.1016/0006-2952(90)90615-R

  • CrossRef
  • Google Scholar

• 21

  SmetsLAJanssenMRutgersMRitzenKButtenhuisC. Pharmacokinetics and intracellular distribution of the tumor-targeted radiopharmaceutical m-iodo-benzylguanidine in SK-N-SH neuroblastoma and PC-12 pheochromocytoma cells. Int J Cancer (1991) 48:609–15. doi: 10.1002/ijc.2910480421

  • CrossRef
  • Google Scholar

• 22

  HoefnagelCADe KrakerJValdes OlmosRAVoûtePA. 131I-MIBG as a first-line treatment in high-risk neuroblastoma patients. Nucl Med Commun (1994) 9:712–7. doi: 10.1097/00006231-199409000-00008

  • CrossRef
  • Google Scholar

• 23

  KraalKCJMBleekerGMVan Eck-SmitBLFvan EijkelenburgNKABertholdFVan NoeselMMet al. Feasibility, toxicity and response of upfront metaiodobenzylguanidine therapy therapy followed by German Pediatric Oncology Group Neuroblastoma 2004 protocol in newly diagnosed stage 4 neuroblastoma patients. Eur J Cancer (2017) 76:188–96. doi: 10.1016/j.ejca.2016.12.013

  • CrossRef
  • Google Scholar

• 24

  KraalKCJMVan DalenECTytgatGAMVan Eck-SmitBLF. Iodine-131-meta-iodobenzylguanidine therapy for patients with newly diagnosed high-risk neuroblastoma. Cochrane Database Syst Rev (2017) 4:CD010349. doi: 10.1002/14651858.CD010349.pub2

  • CrossRef
  • Google Scholar

• 25

  WilsonJSGainsJEMorozVWheatleyKGazeMN. A systematic review of 131I-meta iodobenzylguanidine molecular radiotherapy for neuroblastoma. Eur J Cancer (2014) 50:801–5. doi: 10.1016/j.ejca.2013.11.016

  • CrossRef
  • Google Scholar

• 26

  GargPKGargSZalutskyMR. Synthesis and preliminary evaluation of para- and meta-[18F]fluorobenzylguanidine. Nucl Med Biol (1994) 21:97–103. doi: 10.1016/0969-8051(94)90135-x

  • CrossRef
  • Google Scholar

• 27

  ColeELStewartMNLittichRHoareauRScottPJ. Radiosyntheses using fluorine-18: the art and science of late stage fluorination. Curr Top Med Chem (2014) 14:875–900. doi: 10.2174/1568026614666140202205035

  • CrossRef
  • Google Scholar

• 28

  Van der BornDPeesAPootAJOrruRVAWindhorstADVugtsDJ. Fluorine-18 labelled building blocks for PET tracer synthesis. Chem Soc Rev (2017) 46:4709–73. doi: 10.1039/c6cs00492j

  • CrossRef
  • Google Scholar

• 29

  TredwellMPreshlockSMTaylorNJGruberSHuibanMPasschierJet al. A General Copper Mediated Nucleophilic ¹⁸F Fluorination of Arenes. Angew Chem Int Ed (2014) 53:7751–5. doi: 10.1002/anie.201404436

  • CrossRef
  • Google Scholar

• 30

  Pandit-TaskarNZanzonicoPStatonKDCarrasquilloJAReidy-LagunesDLyashchenkoSet al. Biodistribution and dosimetry of ¹⁸F-Meta Fluorobenzyl Guanidine (MFBG): A first-in-human PET-CT imaging study of patients with neuroendocrine malignancies. J Nucl Med (2018) 59:147–53. doi: 10.2967/jnumed.117.193169

  • CrossRef
  • Google Scholar

• 31

  ZhangHHuangRCheungN-KVGuoHZanzonicoPBThalerHTet al. Imaging the norepinephrine transporter in neuroblastoma: a comparison of [¹⁸F]-MFBG and ¹²³I-MIBG. Clin Cancer Res (2014) 20:2182–91. doi: 10.1158/1078-0432.CCR-13-1153

  • CrossRef
  • Google Scholar

• 32

  ZalutskyMRPruszynskiM. Astatine-211: Production and Availability. Curr Radiopharm (2011) 4:177–85. doi: 10.2174/1874471011104030177

  • CrossRef
  • Google Scholar

• 33

  VaidyanethanGZalutskyMR. Applications of ²¹¹At and ²²³Ra in Targeted Alpha-Particle Radiotherapy. Curr Radiopharm (2011) 4:283–94. doi: 10.2174/1874471011104040283

  • CrossRef
  • Google Scholar

• 34

  OhshimaYSudoHWatanabeSNagatsuKTsujiABSakashitaTet al. Antitumor effects of radionuclide treatment using α-emitting meta-²¹¹At-astato-benzylguanidine in a PC12 pheochromocytoma model. Eur J Nucl Med Mol Imaging (2018) 45:999–1010. doi: 10.1007/s00259-017-3919-6

  • CrossRef
  • Google Scholar

• 35

  MizutaniGNakahishiYWatanabeNHonmaTObanaYSekiTet al. Expression of Somatostatin Receptor (SSTR) Subtypes (SSTR-1, 2A, 3, 4 and 5) in Neuroendocrine Tumors Using Real-time RT-PCR Method and Immunohistochemistry. Acta Histochem Cytomchem (2012) l45:167–76. doi: 10.1267/ahc.12006

  • CrossRef
  • Google Scholar

• 36

  AlexanderNMarranoPThornerPNaranjoAVan RynCMartinezDet al. Prevalence and clinical correlations of somatostatin receptor-2 (SSTR2) expression in neuroblastoma. J Pediatr Hematol Oncol (2019) 41:222–7. doi: 10.1097/MPH.0000000000001326

  • CrossRef
  • Google Scholar

• 37

  KiviniemiAGardbergMKivinenKPostiJPVourinenVSipiläJet al. Somatostatin receptor 2A in gliomas: Association with oligodendrogliomas and favourable outcome. Oncotarget (2017) 8:49123–32. doi: 10.18632/oncotarget.17097

  • CrossRef
  • Google Scholar

• 38

  GuyotatJChampierJPierreGSJouvetABretPBrissonCet al. Differential Expression of Somatostatin Receptors in Medulloblastoma. J Neuro-Oncol (2001) 51:93–103. doi: 10.1023/a:1010624702443

  • CrossRef
  • Google Scholar

• 39

  ChenSCheungWLeungYLChengKWongKNWongYHet al. ¹⁷⁷Lu-DOTATATE radionuclide therapy for pediatric patients with relapsed high-risk neuroblastoma negative on ¹³¹I-MIBG imaging - a pilot study. J Nucl Med (2018) 59:Suppl 1–307.

  • Google Scholar

• 40

  NicolasGPBeykanSBouterfaHKaufmannJBaumanALassmannMet al. Safety, Biodistribution, and Radiation Dosimetry of ⁶⁸Ga-OPS202 in Patients with Gastroenteropancreatic Neuroendocrine Tumors: A Prospective Phase I Imaging Study. J Nucl Med (2018) 59:909–14. doi: 10.2967/jnumed.117.199737

  • CrossRef
  • Google Scholar

• 41

  NicolasGPMansiRMcDougallLKaufmanJBouterfaHWildDet al. Biodistribution, Pharmacokinetics, and Dosimetry of ¹⁷⁷Lu-, ⁹⁰Y-, and ¹¹¹In-Labeled Somatostatin Receptor Antagonist OPS201 in Comparison to the Agonist ¹⁷⁷Lu-DOTATATE: The Mass Effect. J Nucl Med (2017) 58:1435–41. doi: 10.2967/jnumed.117.191684

  • CrossRef
  • Google Scholar

• 42

  search term: Neuroblastoma, SSTR2, DOTATATE (2020). Available at: www.clinicaltrials.gov (Accessed May 25, 2020).

  • Google Scholar

• 43

  KircherMHerhausPSchotteliusMBuckAKWernerRAWesterH-Jet al. CXCR4-directed theranostics in oncology and inflammation. Ann Nucl Med (2018) 32:503–11. doi: 10.1007/s12149-018-1290-8

  • CrossRef
  • Google Scholar

• 44

  RussellHVHicksJOkcuMFNuchternJG. CXCR4 expression in neuroblastoma primary tumors is associated with clinical presentation of bone and bone marrow metastases. J Pediatr Surg (2004) 39:1506–11. doi: 10.1016/j.jpedsurg.2004.06.019

  • CrossRef
  • Google Scholar

• 45

  MiyoshiKKohashiKFushimiFYamamotoHKishimotoJTaguchiTet al. Close correlation between CXCR4 and VEGF expression and frequent CXCR7 expression in rhabdomyosarcoma. Hum Pathol (2014) 45:1900–9. doi: 10.1016/j.humpath.2014.05.012

  • CrossRef
  • Google Scholar

• 46

  EckertFSchilbachKKlumppLBardosciaLSezginECSchwabMet al. Potential Role of CXCR4 Targeting in the Context of Radiotherapy and Immunotherapy of Cancer. Front Immunol (2018) 9:3018:3018. doi: 10.3389/fimmu.2018.03018

  • CrossRef
  • Google Scholar

• 47

  PeledAKleinSBeiderKBurgerJAAbrahamM. Role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies. Cytokine (2018) 109:11–6. doi: 10.1016/j.cyto.2018.02.020

  • CrossRef
  • Google Scholar

• 48

  search term: Pentixafor, CXCR4 (2020). Available at: www.clinicaltrials.gov (Accessed June 8, 2020).

  • Google Scholar

• 49

  CooperTMSisonEARBakerSDLiLAhmedATrippettTet al. A phase 1 study of the CXCR4 antagonist plerixafor in combination with high-dose cytarabine and etoposide in children with relapsed or refractory acute leukemias or myelodysplastic syndrome: A Pediatric Oncology Experimental Therapeutics Investigators’ Consortium study (POE 10-03). Pediatr Blood Cancer (2017) 64. doi: 10.1002/pbc.26414

  • CrossRef
  • Google Scholar

• 50

  HerrmannKSchotteliusMLapaCOslTPoschenriederAHänscheidHet al. First-in-Human Experience of CXCR4-Directed Endoradiotherapy with ¹⁷⁷Lu- and ⁹⁰Y-Labeled Pentixather in Advanced-Stage Multiple Myeloma with Extensive Intra- and Extramedullary Disease. J Nucl Med (2016) 57:248–51. doi: 10.2967/jnumed.115.167361

  • CrossRef
  • Google Scholar

• 51

  BusekPMateuRZubalMKotackovaLSedoA. Targeting Fibroblast Activation Protein in Cancer - Prospects and Caveats. Front Biosci (Landmark Ed) (2018) 23:1933–68. doi: 10.2741/4682

  • CrossRef
  • Google Scholar

• 52

  PuréEBlombergR. Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics. Oncogene (2018) 37:4343–57. doi: 10.1038/s41388-018-0275-3

  • CrossRef
  • Google Scholar

• 53

  BusekPBalaziovaEMatrasovaIHilserMTomasRSyrucekMet al. Fibroblast Activation Protein Alpha Is Expressed by Transformed and Stromal Cells and Is Associated With Mesenchymal Features in Glioblastoma. Tumour Biol (2016) 37:13961–71. doi: 10.1007/s13277-016-5274-9

  • CrossRef
  • Google Scholar

• 54

  JansenKHeirbaurLChengJDJoossensJRyabtsovaOCosPet al. Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold. ACS Med Chem Lett (2013) 4:491–6. doi: 10.1021/ml300410d

  • CrossRef
  • Google Scholar

• 55

  LindnerTLoktevAAltmannAGieselFKratochwilCDebusJet al. Development of Quinoline-Based Theranostic Ligands for the Targeting of Fibroblast Activation Protein. J Nucl Med (2018) 59:1415–22. doi: 10.2967/jnumed.118.210443

  • CrossRef
  • Google Scholar

• 56

  GieselFLKratochwilCLindnerTMarschalekMMLehnertWDebusJet al. ⁶⁸Ga-FAPI PET/CT: Biodistribution and Preliminary Dosimetry Estimate of 2 DOTA-Containing FAP-Targeting Agents in Patients with Various Cancers. J Nucl Med (2018) 60:386–92. doi: 10.2967/jnumed.118.215913

  • CrossRef
  • Google Scholar

• 57

  KratochwilCFlechsigPLindnerTAbderrahimLAltmannAMierWet al. ⁶⁸Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer. J Nucl Med (2019) 60:801–5. doi: 10.2967/jnumed.119.227967

  • CrossRef
  • Google Scholar

• 58

  LoktevALindnerTBurgerA-MAltmannAGieselFKratochwilCet al. Development of Fibroblast Activation Protein-Targeted Radiotracers With Improved Tumor Retention. J Nucl Med (2019) 60:1421–9. doi: 10.2967/jnumed.118.224469

  • CrossRef
  • Google Scholar

• 59

  JauwYWSMenke-van der Houven van OordtCWHoekstraOSHendrikseNHVugtsDJZijlstraJMet al. Immuno-Positron Emission Tomography with Zirconium-89-Labeled Monoclonal Antibodies in Oncology: What Can We Learn from Initial Clinical Trials? Front Pharmacol (2016) 7:131. doi: 10.3389/fphar.2016.00131

  • CrossRef
  • Google Scholar

• 60

  HeskampSRaavéRBoermanORijpkemaMGoncalvesVDenatF. ⁸⁹Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art ⁸⁹Zr Radiochemistry. Bioconjug Chem (2017) 28:2211–23. doi: 10.1021/acs.bioconjchem.7b00325

  • CrossRef
  • Google Scholar

• 61

  89Zr, Zirconium-89 (2020). Available at: www.clinicaltrials.gov (Accessed June 8, 2020).

  • Google Scholar

• 62

  JansenMHVeldhuijzen van ZantenSEMVan VuurdenDGHuismanMCVugtsDJHoekstraOet al. Molecular Drug Imaging: ⁸⁹Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma. J Nucl Med (2017) 58:711–6. doi: 10.2967/jnumed.116.180216

  • CrossRef
  • Google Scholar

• 63

  SaitSModakS. Anti-GD2 immunotherapy for neuroblastoma. Expert Rev Anticanc (2017) 17:889–904. doi: 10.1080/14737140.2017.1364995

  • CrossRef
  • Google Scholar

• 64

  HungJ-TYuA. Chapter-4: GD2-targeted immunotherapy of neuroblastoma. In: Neuroblastoma, Molecular Mechanisms and Therapeutic Interventions. Cambridge, United States: Academic Press (2019). p. 63–78. doi: 10.1016/B978-0-12-812005-7.00004-7

  • CrossRef
  • Google Scholar

• 65

  HoyS. Dinutuximab, a review in high-risk neuroblastoma. Target Oncol (2016) 11:247–53. doi: 10.1007/s11523-016-0420-2

  • CrossRef
  • Google Scholar

• 66

  YuALGilmanALOzkaynakMFLondonWBKreissmanSGChenHXet al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med (2010) 363:1324–34. doi: 10.1056/NEJMoa0911123

  • CrossRef
  • Google Scholar

• 67

  TerzicTCordeauMHerblotSTeiraPCournoyerSBeaunoyerMet al. Expression of Disialoganglioside (GD2) in Neuroblastic Tumors: A Prognostic Value for Patients Treated With Anti-GD2 Immunotherapy. Ped Dev Path (2018) 21:355–62. doi: 10.1177/1093526617723972

  • CrossRef
  • Google Scholar

• 68

  ButchERMeadPEDiazVATillmanHStewartEMishraJKet al. Positron Emission Tomography Detects In Vivo Expression of Disialoganglioside GD2 in Mouse Models of Primary and Metastatic Osteosarcoma. Cancer Res (2019) 79:3112–24. doi: 10.1158/0008-5472.CAN-18-3340

  • CrossRef
  • Google Scholar

• 69

  ButchEMishraJDiazVAVavereASnyderS. Selective detection of GD2-positive pediatric solid tumors using ⁸⁹Zr-Dinutuximab PET to facilitate anti-GD2 immunotherapy. J Nucl Med (2018) 59:suppl 1–170.

  • Google Scholar

• 70

  MüllerJReichelRVogtSSauerweinWBrandauWEggertAet al. Identification and Tumour-Binding Properties of a Peptide with High Affinity to the Disialoganglioside GD2. PloS One (2016) 11:e0163648. doi: 10.1371/journal.pone.0163648

  • CrossRef
  • Google Scholar

• 71

  CastellanosJRPurvisIJLabakCMGudaMRTsungAJVelpulaKKet al. B7-H3 role in the immune landscape of cancer. Am J Clin Exp Immunol (2017) 6:66–75.

  • Google Scholar

• 72

  Flem-KarlsenKFodstadOTanMNunes-XavierCE. B7-H3 in Cancer – Beyond Immune Regulation. Trends Cancer (2018) 4:401–4. doi: 10.1016/j.trecan.2018.03.010

  • CrossRef
  • Google Scholar

• 73

  PowderlyJCoteGFlahertyKSzmulewitzRZRibasAWeberJet al. Interim results of an ongoing Phase I, dose escalation study of MGA271 (Fc-optimized humanized anti-B7-H3 monoclonal antibody) in patients with refractory B7-H3-expressing neoplasms or neoplasms whose vasculature expresses B7-H3. J Immunother Cancer (2015) 3:Suppl 2-O8. doi: 10.1186/2051-1426-3-S2-O8

  • CrossRef
  • Google Scholar

• 74

  ModakSKramerKGultekinSHGuoHFCheungN-KV. Monoclonal Antibody 8H9 Targets a Novel Cell Surface Antigen Expressed by a Wide Spectrum of Human Solid Tumors. Cancer Res (2001) 61:4048–54.

  • Google Scholar

• 75

  KramerKKushnerBHModakSPandit-TaskarNSmith-JonesPZanzonicoPet al. Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma. J Neurooncol (2010) 97:409–18. doi: 10.1007/s11060-009-0038-7

  • CrossRef
  • Google Scholar

• 76

  LutherNZhouZZanzonicoPCheungNKHummJEdgarMAet al. The potential of theragnostic ¹²³I-8H9 convection-enhanced delivery in diffuse intrinsic pontine glioma. Neuro Oncol (2014) 6:800–6. doi: 10.1093/neuonc/not298

  • CrossRef
  • Google Scholar

• 77

  European Pharmacopoea 10th edition (2020). Available at: https://www.edqm.eu/en/european-pharmacopoeia-ph-eur-10th-edition (Accessed June 8, 2020).

  • Google Scholar

• 78

  WeissBVoraAHubertyJHawkinsRAMatthayKK. Secondary myelodysplastic syndrome and leukemia following 131I-metaiodobenzylguanidine therapy for relapsed neuroblastoma. J Pediatr Hematol Oncol (2003) 7:543–7. doi: 10.1097/00043426-200307000-00009

  • CrossRef
  • Google Scholar