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Cancer Science Jun 2022Theranostics is a term coined by combining the words "therapeutics" and "diagnostics," referring to single chemical entities developed to deliver therapy and diagnosis... (Review)
Review
Theranostics is a term coined by combining the words "therapeutics" and "diagnostics," referring to single chemical entities developed to deliver therapy and diagnosis simultaneously. Neuroendocrine tumors are rare cancers that occur in various organs of the body, and they express neuroendocrine factors such as chromogranin A and somatostatin receptor. Somatostatin analogs bind to somatostatin receptor, and when combined with diagnostic radionuclides, such as gamma-emitters, are utilized for diagnosis of neuroendocrine tumor. Somatostatin receptor scintigraphy when combined with therapeutic radionuclides, such as beta-emitters, are effective in treating neuroendocrine tumor as peptide receptor radionuclide therapy. Somatostatin receptor scintigraphy and peptide receptor radionuclide therapy are some of the most frequently used and successful theranostics for neuroendocrine tumor. In Japan, radiopharmaceuticals are regulated under a complex law system, creating a significant drug lag, which is a major public concern. It took nearly 10 years to obtain the approval for somatostatin receptor scintigraphy and peptide receptor radionuclide therapy use by the Japanese government. In 2021, Lu-DOTATATE (Lutathera), a drug for peptide receptor radionuclide therapy, was covered by insurance in Japan. In this review, we summarize the history of the development of neuroendocrine tumor theranostics and theranostics in general, as therapeutic treatment for cancer in the future. Furthermore, we briefly address the Japanese point of view regarding the development of new radiopharmaceuticals.
Topics: Humans; Neuroendocrine Tumors; Positron-Emission Tomography; Precision Medicine; Radioisotopes; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin
PubMed: 35271754
DOI: 10.1111/cas.15327 -
European Journal of Nuclear Medicine... Jun 2023Fibroblast activation protein (FAP) is highly overexpressed in stromal tissue of various cancers. While FAP has been recognized as a potential diagnostic or therapeutic... (Review)
Review
INTRODUCTION
Fibroblast activation protein (FAP) is highly overexpressed in stromal tissue of various cancers. While FAP has been recognized as a potential diagnostic or therapeutic cancer target for decades, the surge of radiolabeled FAP-targeting molecules has the potential to revolutionize its perspective. It is presently hypothesized that FAP targeted radioligand therapy (TRT) may become a novel treatment for various types of cancer. To date, several preclinical and case series have been reported on FAP TRT using varying compounds and showing effective and tolerant results in advanced cancer patients. Here, we review the current (pre)clinical data on FAP TRT and discuss its perspective towards broader clinical implementation. METHODS: A PubMed search was performed to identify all FAP tracers used for TRT. Both preclinical and clinical studies were included if they reported on dosimetry, treatment response or adverse events. The last search was performed on July 22 2022. In addition, a database search was performed on clinical trial registries (date 15 of July 2022) to search for prospective trials on FAP TRT.
RESULTS
In total, 35 papers were identified that were related to FAP TRT. This resulted in the inclusion of the following tracers for review: FAPI-04, FAPI-46, FAP-2286, SA.FAP, ND-bisFAPI, PNT6555, TEFAPI-06/07, FAPI-C12/C16, and FSDD.
CONCLUSION
To date, data was reported on more than 100 patients that were treated with different FAP targeted radionuclide therapies such as [Lu]Lu-FAPI-04, [Y]Y-FAPI-46, [Lu]Lu-FAP-2286, [Lu]Lu-DOTA.SA.FAPI and [Lu]Lu-DOTAGA.(SA.FAPi). In these studies, FAP targeted radionuclide therapy has resulted in objective responses in difficult to treat end stage cancer patients with manageable adverse events. Although no prospective data is yet available, these early data encourages further research.
Topics: Humans; Cell Line, Tumor; Membrane Proteins; Protein Transport; Radioisotopes; Fibroblasts; Positron Emission Tomography Computed Tomography; Gallium Radioisotopes
PubMed: 36813980
DOI: 10.1007/s00259-023-06144-0 -
Current Radiopharmaceuticals 2018Recent reports of the remarkable therapeutic efficacy of 225Ac-labeled PSMA- 617 for therapy of metastatic castration-resistant prostate cancer have underlined the... (Review)
Review
BACKGROUND
Recent reports of the remarkable therapeutic efficacy of 225Ac-labeled PSMA- 617 for therapy of metastatic castration-resistant prostate cancer have underlined the clinical potential of targeted alpha therapy.
OBJECTIVE AND CONCLUSION
This review describes methods for the production of 225Ac and its daughter nuclide 213Bi and summarizes the current clinical experience with both alpha emitters with particular focus on recent studies of targeted alpha therapy of bladder cancer, brain tumors, neuroendocrine tumors and prostate cancer.
Topics: Actinium; Alpha Particles; Bismuth; Clinical Trials as Topic; Humans; Neoplasms; Radiochemistry; Radioimmunotherapy; Radioisotopes; Radiopharmaceuticals
PubMed: 29732998
DOI: 10.2174/1874471011666180502104524 -
Journal of Nuclear Medicine : Official... Mar 2022Fibroblast activation protein (FAP) is a promising target for diagnosis and therapy of numerous malignant tumors. FAP-2286 is the conjugate of a FAP-binding peptide,...
Fibroblast activation protein (FAP) is a promising target for diagnosis and therapy of numerous malignant tumors. FAP-2286 is the conjugate of a FAP-binding peptide, which can be labeled with radionuclides for theranostic applications. We present the first-in-humans results using Lu-FAP-2286 for peptide-targeted radionuclide therapy (PTRT). PTRT using Lu-FAP-2286 was performed on 11 patients with advanced adenocarcinomas of the pancreas, breast, rectum, or ovary after prior confirmation of uptake on Ga-FAP-2286 or Ga-FAPI-04 PET/CT. Administration of Lu-FAP-2286 (5.8 ± 2.0 GBq; range, 2.4-9.9 GBq) was well tolerated, with no adverse symptoms or clinically detectable pharmacologic effects being noticed or reported in any of the patients. The whole-body effective dose was 0.07 ± 0.02 Gy/GBq (range, 0.04-0.1 Gy/GBq). The mean absorbed doses for kidneys and red marrow were 1.0 ± 0.6 Gy/GBq (range, 0.4-2.0 Gy/GBq) and 0.05 ± 0.02 Gy/GBq (range, 0.03-0.09 Gy/GBq), respectively. Significant uptake and long tumor retention of Lu-FAP-2286 resulted in high absorbed tumor doses, such as 3.0 ± 2.7 Gy/GBq (range, 0.5-10.6 Gy/GBq) in bone metastases. No grade 4 adverse events were observed. Grade 3 events occurred in 3 patients-1 with pancytopenia, 1 with leukocytopenia, and 1 with pain flare-up; 3 patients reported a pain response. Lu-FAP-2286 PTRT, applied in a broad spectrum of cancers, was relatively well tolerated, with acceptable side effects, and demonstrated long retention of the radiopeptide. Prospective clinical studies are warranted.
Topics: Adenocarcinoma; Feasibility Studies; Female; Gallium Radioisotopes; Humans; Peptides; Positron Emission Tomography Computed Tomography; Prospective Studies; Radioisotopes; Tissue Distribution
PubMed: 34168013
DOI: 10.2967/jnumed.120.259192 -
Frontiers in Endocrinology 2022Lu-177 has been developed for the treatment of patients with peptide receptor radionuclide therapy (PRRT). A second generation pure no-carrier-added Lu-177 has a high... (Review)
Review
Lu-177 has been developed for the treatment of patients with peptide receptor radionuclide therapy (PRRT). A second generation pure no-carrier-added Lu-177 has a high specific activity and has waste disposal advantages over the first generation carrier-added Lu-177. PRRT has recently been developed for the treatment of neuroendocrine tumors (NETs). The majority of pancreatic and gastroenteric NETs (GEP-NETs) express the somatostatin receptors (SSTRs) 2 and 5. These receptors can be specifically targeted with a somatostatin peptide analogue (DOTATOC/DOTATATE) which can be chelated to a positron emission tomography (PET) emitting radioisotope such as Ga-68 for imaging or to a β-emitting radioisotope Lu-177 for therapy. A key advantage of this approach is that the receptor expression can be demonstrated by PET imaging before the patient is treated. Clinical studies in G1 and G2 GEP-NETS have demonstrated that PRRT is extremely effective in terms of progression free survival (PFS), symptom control and quality of life, with a well-established safety profile. A beneficial effect on outcome survival awaits to be confirmed. The first commercially available product Lu-177-DOTATATE was approved following the NETTER-1 trial in G1 and G2 GE-NETS. Lu-177-DOTATATE 7,4 GBq every 8 weeks for 4 cycles, together with octreotide LAR 30 mg monthly, demonstrated a median PFS of 28,4 months compared to 8,5 months for octreotide LAR 60 mg monthly. A second pivotal study COMPETE is currently in progress, comparing no carrier-added (n.c.a.) Lu-177-DOTATOC to the m-TOR inhibitor Everolimus in both GE-NETs and PNETs. Two studies, NETTER-2 and COMPOSE are currently underway in patients with high grade G2 and G3 NETs. Novel SSTR antagonists are being developed as next generation targeting molecules for SSTR2-expressing tumors. Antagonists have a higher tumor binding to receptors than agonists, opening up the potential indications for SSTR2 targeting to tumors which have a relatively lower expression of SSTR2 compared to NET such as small cell lung cancer, hepatocellular carcinoma and breast cancer. In addition to Lu-177, radioisotopes with different radiation properties such as Tb-161 and the α-emitter Ac-225 are being developed which have the potential to improve treatment efficacy across the range of G1 to G3 NETs.
Topics: Humans; Neuroendocrine Tumors; Octreotide; Gallium Radioisotopes; Actinium; Quality of Life; Radioisotopes; Radiopharmaceuticals
PubMed: 36387893
DOI: 10.3389/fendo.2022.941832 -
Radiology. Imaging Cancer Jul 2023Theranostics is the combination of two approaches-diagnostics and therapeutics-applied for decades in cancer imaging using radiopharmaceuticals or paired... (Review)
Review
Theranostics is the combination of two approaches-diagnostics and therapeutics-applied for decades in cancer imaging using radiopharmaceuticals or paired radiopharmaceuticals to image and selectively treat various cancers. The clinical use of theranostics has increased in recent years, with U.S. Food and Drug Administration (FDA) approval of lutetium 177 (Lu) tetraazacyclododecane tetraacetic acid octreotate (DOTATATE) and Lu-prostate-specific membrane antigen vector-based radionuclide therapies. The field of theranostics has imminent potential for emerging clinical applications. This article reviews critical areas of active clinical advancement in theranostics, including forthcoming clinical trials advancing FDA-approved and emerging radiopharmaceuticals, approaches to dosimetry calculations, imaging of different radionuclide therapies, expanded indications for currently used theranostic agents to treat a broader array of cancers, and emerging ideas in the field. Molecular Imaging, Molecular Imaging-Cancer, Molecular Imaging-Clinical Translation, Molecular Imaging-Target Development, PET/CT, SPECT/CT, Radionuclide Therapy, Dosimetry, Oncology, Radiobiology © RSNA, 2023.
Topics: United States; Male; Humans; Precision Medicine; Radiopharmaceuticals; Positron Emission Tomography Computed Tomography; Radioisotopes; Neoplasms
PubMed: 37477566
DOI: 10.1148/rycan.220157 -
International Journal of Molecular... May 2023Targeted radionuclide therapy (TRT) has been burgeoning worldwide, with several radiopharmaceuticals for the treatment of metastatic cancers being approved for clinical...
Targeted radionuclide therapy (TRT) has been burgeoning worldwide, with several radiopharmaceuticals for the treatment of metastatic cancers being approved for clinical use [...].
Topics: Humans; Neoplasms; Radiopharmaceuticals; Neoplasms, Second Primary; Radioisotopes
PubMed: 37240433
DOI: 10.3390/ijms24109081 -
Molecules (Basel, Switzerland) Apr 2021Theranostics is a precision medicine which integrates diagnostic nuclear medicine and radionuclide therapy for various cancers throughout body using suitable tracers and... (Review)
Review
Theranostics is a precision medicine which integrates diagnostic nuclear medicine and radionuclide therapy for various cancers throughout body using suitable tracers and treatment that target specific biological pathways or receptors. This review covers traditional theranostics for thyroid cancer and pheochromocytoma with radioiodine compounds. In addition, recent theranostics of radioimmunotherapy for non-Hodgkin lymphoma, and treatment of bone metastasis using bone seeking radiopharmaceuticals are described. Furthermore, new radiopharmaceuticals for prostatic cancer and pancreatic cancer have been added. Of particular, F-18 Fluoro-2-Deoxyglucose (FDG) Positron Emission Tomography (PET) is often used for treatment monitoring and estimating patient outcome. A recent clinical study highlighted the ability of alpha-radiotherapy with high linear energy transfer (LET) to overcome treatment resistance to beta--particle therapy. Theranostics will become an ever-increasing part of clinical nuclear medicine.
Topics: Animals; Fluorodeoxyglucose F18; Humans; Neoplasms; Positron Emission Tomography Computed Tomography; Radioisotopes; Therapeutics
PubMed: 33924345
DOI: 10.3390/molecules26082232 -
The Journal of Clinical Endocrinology... Nov 2022The concept of using a targeting molecule labeled with a diagnostic radionuclide for using positron emission tomography or single photon emission computed tomography...
The concept of using a targeting molecule labeled with a diagnostic radionuclide for using positron emission tomography or single photon emission computed tomography imaging with the potential to demonstrate that tumoricidal radiation can be delivered to tumoral sites by administration of the same or a similar targeting molecule labeled with a therapeutic radionuclide termed "theranostics." Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs (SSAs) is a well-established second/third-line theranostic treatment for somatostatin receptor-positive well-differentiated (neuro-)endocrine neoplasms (NENs). PRRT with 177Lu-DOTATATE was approved by the regulatory authorities in 2017 and 2018 for selected patients with low-grade well-differentiated gastroenteropancreatic (GEP) NENs. It improves progression-free survival as well as quality of life of GEP NEN patients. Favorable symptomatic and biochemical responses using PRRT with 177Lu-DOTATATE have also been reported in patients with functioning metastatic GEP NENs like metastatic insulinomas, Verner Morrison syndromes (VIPomas), glucagonomas, and gastrinomas and patients with carcinoid syndrome. This therapy might also become a valuable therapeutic option for inoperable low-grade bronchopulmonary NENs, inoperable or progressive pheochromocytomas and paragangliomas, and medullary thyroid carcinomas. First-line PRRT with 177Lu-DOTATATE and combinations of this therapy with cytotoxic drugs are currently under investigation. New radiolabeled somatostatin receptor ligands include SSAs coupled with alpha radiation emitting radionuclides and somatostatin receptor antagonists coupled with radionuclides.
Topics: Humans; Neuroendocrine Tumors; Receptors, Somatostatin; Quality of Life; Octreotide; Organometallic Compounds; Somatostatin; Radioisotopes; Radiopharmaceuticals
PubMed: 36198028
DOI: 10.1210/clinem/dgac574 -
Chimia Dec 2020The concept of targeted radionuclide therapy (TRT) is the accurate and efficient delivery of radiation to disseminated cancer lesions while minimizing damage to healthy... (Review)
Review
The concept of targeted radionuclide therapy (TRT) is the accurate and efficient delivery of radiation to disseminated cancer lesions while minimizing damage to healthy tissue and organs. Critical aspects for successful development of novel radiopharmaceuticals for TRT are: i) the identification and characterization of suitable targets expressed on cancer cells; ii) the selection of chemical or biological molecules which exhibit high affinity and selectivity for the cancer cell-associated target; iii) the selection of a radionuclide with decay properties that suit the properties of the targeting molecule and the clinical purpose. The Center for Radiopharmaceutical Sciences (CRS) at the Paul Scherrer Institute in Switzerland is privileged to be situated close to unique infrastructure for radionuclide production (high energy accelerators and a neutron source) and access to C/B-type laboratories including preclinical, nuclear imaging equipment and Swissmedic-certified laboratories for the preparation of drug samples for human use. These favorable circumstances allow production of non-standard radionuclides, exploring their biochemical and pharmacological features and effects for tumor therapy and diagnosis, while investigating and characterizing new targeting structures and optimizing these aspects for translational research on radiopharmaceuticals. In close collaboration with various clinical partners in Switzerland, the most promising candidates are translated to clinics for 'first-in-human' studies. This article gives an overview of the research activities at CRS in the field of TRT by the presentation of a few selected projects.
Topics: Humans; Neoplasms; Radioisotopes; Radiopharmaceuticals; Switzerland; Translational Research, Biomedical
PubMed: 33357286
DOI: 10.2533/chimia.2020.939