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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 -
Journal of Nuclear Medicine : Official... May 2021Treatment of advanced metastatic castration-resistant prostate cancer after failure of approved therapy options remains challenging. Prostate-specific membrane antigen...
Treatment of advanced metastatic castration-resistant prostate cancer after failure of approved therapy options remains challenging. Prostate-specific membrane antigen (PSMA)-targeting β- and α-emitters have been introduced, with promising response rates. Here, we present the first-to our knowledge-clinical data for PSMA-targeted α-therapy (TAT) using Ac-PSMA imaging and therapy (I&T). Fourteen patients receiving Ac-PSMA-I&T were included in this retrospective analysis. Eleven of the 14 had prior second-line antiandrogen treatment with abiraterone or enzalutamide, prior chemotherapy, and prior Lu-PSMA treatment. Patients were treated at bimonthly intervals until progression or intolerable side effects. Prostate-specific antigen (PSA) was measured for response assessment. Hematologic and nonhematologic side effects were recorded according to the Common Terminology Criteria for Adverse Events, version 5.0. Thirty-four cycles of Ac-PSMA-I&T were applied (median dose, 7.8 MBq; range, 6.0-8.5), with 1 cycle in 3 patients, 2 cycles in 7 patients, 4 cycles in 3 patients, and 5 cycles in 1 patient. No acute toxicity was observed during hospitalization. Baseline PSA was 112 ng/mL (range, 20.5-818 ng/mL). The best PSA response after TAT (a PSA decline ≥ 50%) was observed in 7 patients, and a PSA decline of any amount was observed in 11 patients. Three patients had no PSA decline at any time. A subgroup analysis of 11 patients with prior Lu-PSMA treatment showed any PSA decline in 8 patients and a decline of at least 50% in 5 patients. After TAT, grade 3 anemia was observed in 3 of the 14 patients, with 2 of them presenting with grade 2 anemia already at baseline. Grade 3 leukopenia was observed in 1 patient. Eight patients with preexisting xerostomia after Lu-PSMA showed no worsening after TAT. Newly diagnosed grade 1 or 2 xerostomia after TAT was observed in 5 patients. One patient reported no xerostomia at all. Our first clinical data for TAT using Ac-PSMA-I&T showed a promising antitumor effect in advanced metastatic castration-resistant prostate cancer. These results are highly comparable to data on Ac-PSMA-617 TAT.
Topics: Actinium; Antigens, Surface; Beta Particles; Glutamate Carboxypeptidase II; Humans; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome
PubMed: 33008928
DOI: 10.2967/jnumed.120.251017 -
Health Physics Feb 2019Radiopharmaceutical therapy involves the use of radionuclides that are either conjugated to tumor-targeting agents (e.g., nanoscale constructs, antibodies, peptides, and...
Radiopharmaceutical therapy involves the use of radionuclides that are either conjugated to tumor-targeting agents (e.g., nanoscale constructs, antibodies, peptides, and small molecules) or that concentrate in tumors through natural physiological mechanisms that occur predominantly in neoplastic cells. In the latter category, radioiodine therapy of thyroid cancer is the prototypical and most widely implemented radiopharmaceutical therapy. In the category of radionuclide-ligand conjugates, antibody and peptide conjugates have been studied extensively. The efficacy of radiopharmaceutical therapy relies on the ability to deliver cytotoxic radiation to tumor cells without causing prohibitive normal tissue toxicity. After some 30 y of preclinical and clinical research, a number of recent developments suggest that radiopharmaceutical therapy is poised to emerge as an important and widely recognized therapeutic modality. These developments include the substantial investment in antibodies by the pharmaceutical industry and the compelling rationale to build upon this already existing and widely tested platform. In addition, the growing recognition that the signaling pathways responsible for tumor cell survival and proliferation are less easily and durably inhibited than originally envisioned has also provided a rationale for identifying agents that are cytotoxic rather than inhibitory. A number of radiopharmaceutical agents are currently undergoing clinical trial investigation; these include beta-particle emitters, such as Lu, that are being used to label antisomatostatin receptor peptides for neuroendocrine cancers and also prostate-specific membrane antigen targeting small molecules for prostate cancer. Alpha-particle-emitting radionuclides have also been studied for radiopharmaceutical therapy; these include At for glioblastoma, Ac for leukemias and prostate cancer, Pb for breast cancer, and Ra for prostate cancer. The alpha emitters have tended to show particular promise, and there is substantial interest in further developing these agents for therapy of cancers that are particularly difficult to treat.
Topics: Humans; Neoplasms; Radiation Dosage; Radiopharmaceuticals
PubMed: 30585960
DOI: 10.1097/HP.0000000000001000 -
Journal of Nuclear Medicine : Official... Dec 2016Prostate-specific membrane antigen (PSMA) is a promising target in prostate cancer. Recently, we started the first-in-human treatment with an α-radionuclide-labeled...
UNLABELLED
Prostate-specific membrane antigen (PSMA) is a promising target in prostate cancer. Recently, we started the first-in-human treatment with an α-radionuclide-labeled PSMA ligand. Although the case series is still ongoing, we here report in advance about two patients in highly challenging clinical situations who showed a complete response to Ac-PSMA-617 therapy.
METHODS
Ga-PSMA-11 PET/CT validated the presence of the PSMA-positive tumor phenotype. A 100-kBq activity of Ac-PSMA-617 per kilogram of body weight was administered bimonthly. Prostate-specific antigen response and hematologic toxicity were measured at least every 4 wk. Restaging was performed with Ga-PSMA-11 PET/CT.
RESULTS
Both patients experienced a prostate-specific antigen decline to below the measurable level and showed a complete response on imaging. No relevant hematologic toxicity was observed. Xerostomia was the only mentionable clinical side effect.
CONCLUSION
Targeted α-therapy with Ac-PSMA-617, although still experimental, obviously has strong potential to significantly benefit advanced-stage prostate cancer patients.
Topics: Actinium; Alpha Particles; Antigens, Surface; Beta Particles; Dipeptides; Glutamate Carboxypeptidase II; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Neoplasm Metastasis; Positron Emission Tomography Computed Tomography; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Radioisotopes
PubMed: 27390158
DOI: 10.2967/jnumed.116.178673 -
Frontiers in Immunology 2020Phagocytic integrins are endowed with the ability to engulf and dispose of particles of different natures. Evolutionarily conserved from worms to humans, they are... (Review)
Review
Phagocytic integrins are endowed with the ability to engulf and dispose of particles of different natures. Evolutionarily conserved from worms to humans, they are involved in pathogen elimination and apoptotic and tumoral cell clearance. Research in the field of integrin-mediated phagocytosis has shed light on the molecular events controlling integrin activation and their effector functions. However, there are still some aspects of the regulation of the phagocytic process that need to be clarified. Here, we have revised the molecular events controlling phagocytic integrin activation and the downstream signaling driving particle engulfment, and we have focused particularly on αβ/CR3, αβ/CR4, and a brief mention of αβ/αβintegrins.
Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Humans; Integrin alphaXbeta2; Integrins; Macrophage-1 Antigen; Membrane Proteins; Phagocytosis; Protein-Tyrosine Kinases; Signal Transduction; Talin; rap1 GTP-Binding Proteins
PubMed: 32425937
DOI: 10.3389/fimmu.2020.00738 -
Seminars in Interventional Radiology Oct 2021Transarterial radioembolization with yttrium-90 ( Y) is a mainstay for the treatment of liver cancer. Imaging the distribution following delivery is a concept that... (Review)
Review
Transarterial radioembolization with yttrium-90 ( Y) is a mainstay for the treatment of liver cancer. Imaging the distribution following delivery is a concept that dates back to the 1960s. As β particles are created during Y decay, bremsstrahlung radiation is created as the particles interact with tissues, allowing for imaging with a gamma camera. Inherent qualities of bremsstrahlung radiation make its imaging difficult. SPECT and SPECT/CT can be used but suffer from limitations related to low signal-to-noise bremsstrahlung radiation. However, with optimized imaging protocols, clinically adequate images can still be obtained. A finite but detectable number of positrons are also emitted during Y decay, and many studies have demonstrated the ability of commercial PET/CT and PET/MR scanners to image these positrons to understand Y distribution and help quantify dose. PET imaging has been proven to be superior to SPECT for quantitative imaging, and therefore will play an important role going forward as we try and better understand dose/response and dose/toxicity relationships to optimize personalized dosimetry. The availability of PET imaging will likely remain the biggest barrier to its use in routine post- Y imaging; thus, SPECT/CT imaging with optimized protocols should be sufficient for most posttherapy subjective imaging.
PubMed: 34629714
DOI: 10.1055/s-0041-1735569 -
Seminars in Radiation Oncology Jan 2021In the current era of precision medicine, there is renewed interest in radiopharmaceutical therapy and theranostics. The approval of somatostatin receceptor directed... (Review)
Review
In the current era of precision medicine, there is renewed interest in radiopharmaceutical therapy and theranostics. The approval of somatostatin receceptor directed therapy and norepinephrine transporter targeted I-MIBG therapies by the FDA and the rapid progress of highly promising beta and alpha emitter tagged PSMA directed therapy of prostate cancer have stimulated clinically impactful changes in practice. Many novel strategies are being explored and novel radiopharmaceutical therapeutic agents including peptide based ligands as well as antibodies or antibody fragments are being developed preclinically or are in early phase clinical trials. While beta particle emitters have most commonly been used for targeted radiotherapy and radioimmunotargeting, there is an emerging interest in alpha emitters that cause greater density of ionization events leading to increased double-strand DNA damage and cluster breaks because of the high-energy particles within a shorter tissue range of penetration and thereby lower toxicity to adjacent normal tissues.
Topics: Humans; Male; Precision Medicine; Prostatic Neoplasms; Radiopharmaceuticals
PubMed: 33246639
DOI: 10.1016/j.semradonc.2020.07.010 -
Seminars in Radiation Oncology Jan 2021Radiation oncologists and nuclear medicine physicians have seen a resurgence in the clinical use of radiopharmaceuticals for the curative or palliative treatment of... (Review)
Review
Radiation oncologists and nuclear medicine physicians have seen a resurgence in the clinical use of radiopharmaceuticals for the curative or palliative treatment of cancer. To enable the discovery and the development of new targeted radiopharmaceutical treatments, the United States National Cancer Institute has adapted its clinical trial enterprise to accommodate the requirements of a development program with investigational agents that have a radioactive isotope as part of the studied drug product. One change in perspective has been the consideration of investigational radiopharmaceuticals as drugs, with maximum tolerable doses determined by normal organ toxicity frequency like in drug clinical trials. Other changes include new clinical trial enterprise elements for biospecimen handling, adverse event reporting, regulatory conduct, writing services, drug master files, and reporting of patient outcomes. Arising from this enterprise, the study and clinical use of alpha-particle and beta-particle emitters have emerged as an important approach to cancer treatment. Resources allocated to this enterprise have brought forward biomarkers of molecular pathophysiology now used to select treatment or to evaluate clinical performance of radiopharmaceuticals. The clinical use of diagnostic and therapeutic radionuclide pairs is anticipated to accelerate radiopharmaceutical clinical development.
Topics: Drug Development; Humans; National Cancer Institute (U.S.); Neoplasms; Radiopharmaceuticals; United States
PubMed: 33246634
DOI: 10.1016/j.semradonc.2020.07.006