Peptide Receptor Radionuclide Therapy with <sup>67</sup>Cu-CuSarTATE Is Highly Efficacious Against a Somatostatin-Positive Neuroendocrine Tumor Model

Cullinane, Carleen; Jeffery, Charmaine M.; Roselt, Peter; Dam, Ellen M. van; Jackson, Susan; Kuan, K.; Jackson, Price; Binns, David; Zuylekom, Jessica Van; Harris, Matthew J; Hicks, Rodney J.; Donnelly, Paul S.

doi:10.2967/jnumed.120.243543

Cited by 53 publications

(55 citation statements)

References 29 publications

(17 reference statements)

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“…For the present study, however, no data are available relating tumor size to tracer uptake. The results of this [ 67 Cu]Cu-SARTATE therapy study in a NB model of hepatic metastases are in agreement with the results of previous preclinical PRRT studies in NB [36,37], as well as other tumor models [28,39,40]. A single PRRT treatment did not lead to cure in any of these preclinical studies, but rather to some degree of tumor growth control and consequent survival extension.…”

Section: Early Treatment With [ 67 Cu]cu-sartate Improves Survival Insupporting

confidence: 89%

“…7, confirming uptake of the tracer in the tumors (red arrow). In this case, a significant extension of survival time of the [28]. Targeting SSTR2 in NB was previously demonstrated clinically using 68 Ga-, 177 Luand 90 Y-labeled DOTA-TATE [16,18,20], although a recent study failed to show a benefit of [ 177 Lu]Lu-DOTA-TATE in NB patients, possibly due to the relatively low administered dose in this study [19].…”

Section: Early Treatment With [ 67 Cu]cu-sartate Improves Survival Inmentioning

confidence: 66%

“…A single PRRT treatment did not lead to cure in any of these preclinical studies, but rather to some degree of tumor growth control and consequent survival extension. Either multiple PRRT treatments or a combination of PRRT with chemotherapy appears to be necessary in order to achieve a complete response [28,39,40]. It is important to note that these studies were carried out with relatively large subcutaneous tumors whereas we found that [ 67 Cu]Cu-SARTATE therapy was significantly more successful in smaller, orthotopic, tumors.…”

Section: Early Treatment With [ 67 Cu]cu-sartate Improves Survival Inmentioning

confidence: 70%

“…In a first-in-human PET/CT imaging study, [ 64 Cu]Cu-SAR-TATE compared favorably to [ 68 Ga]Ga-DOTATATE, especially for liver lesions, in patients with neuroendocrine tumors [27]. The therapeutic potential of [ 67 Cu]Cu-SARTATE was recently demonstrated in a mouse model of rat pancreatic exocrine tumors in which it inhibited tumor growth and increased survival [28], and a clinical trial using this agent to treat neuroblastoma is currently underway [29].…”

Section: Introductionmentioning

confidence: 99%

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Detection and therapy of neuroblastoma minimal residual disease using [64/67Cu]Cu-SARTATE in a preclinical model of hepatic metastases

Dearling

Dam²,

Harris³

et al. 2021

EJNMMI Res

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Background A major challenge to the long-term success of neuroblastoma therapy is widespread metastases that survive initial therapy as minimal residual disease (MRD). The SSTR2 receptor is expressed by most neuroblastoma tumors making it an attractive target for molecularly targeted radionuclide therapy. SARTATE consists of octreotate, which targets the SSTR2 receptor, conjugated to MeCOSar, a bifunctional chelator with high affinity for copper. Cu-SARTATE offers the potential to both detect and treat neuroblastoma MRD by using [64Cu]Cu-SARTATE to detect and monitor the disease and [67Cu]Cu-SARTATE as the companion therapeutic agent. In the present study, we tested this theranostic pair in a preclinical model of neuroblastoma MRD. An intrahepatic model of metastatic neuroblastoma was established using IMR32 cells in nude mice. The biodistribution of [64Cu]Cu-SARTATE was measured using small-animal PET and ex vivo tissue analysis. Survival studies were carried out using the same model: mice (6–8 mice/group) were given single doses of saline, or 9.25 MBq (250 µCi), or 18.5 MBq (500 µCi) of [67Cu]Cu-SARTATE at either 2 or 4 weeks after tumor cell inoculation. Results PET imaging and ex vivo biodistribution confirmed tumor uptake of [64Cu]Cu-SARTATE and rapid clearance from other tissues. The major clearance tissues were the kidneys (15.6 ± 5.8% IA/g at 24 h post-injection, 11.5 ± 2.8% IA/g at 48 h, n = 3/4). Autoradiography and histological analysis confirmed [64Cu]Cu-SARTATE uptake in viable, SSTR2-positive tumor regions with mean tumor uptakes of 14.1–25.0% IA/g at 24 h. [67Cu]Cu-SARTATE therapy was effective when started 2 weeks after tumor cell inoculation, extending survival by an average of 13 days (30%) compared with the untreated group (mean survival of control group 43.0 ± 8.1 days vs. 55.6 ± 9.1 days for the treated group; p = 0.012). No significant therapeutic effect was observed when [67Cu]Cu-SARTATE was started 4 weeks after tumor cell inoculation, when the tumors would have been larger (control group 14.6 ± 8.5 days; 9.25 MBq group 9.5 ± 1.6 days; 18.5 MBq group 15.6 ± 4.1 days; p = 0.064). Conclusions Clinical experiences of peptide-receptor radionuclide therapy for metastatic disease have been encouraging. This study demonstrates the potential for a theranostic approach using [64/67Cu]Cu-SARTATE for the detection and treatment of SSTR2-positive neuroblastoma MRD.

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Section: Early Treatment With [ 67 Cu]cu-sartate Improves Survival Insupporting

confidence: 89%

Section: Early Treatment With [ 67 Cu]cu-sartate Improves Survival Inmentioning

confidence: 66%

Section: Early Treatment With [ 67 Cu]cu-sartate Improves Survival Inmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

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Detection and therapy of neuroblastoma minimal residual disease using [64/67Cu]Cu-SARTATE in a preclinical model of hepatic metastases

Dearling

Dam²,

Harris³

et al. 2021

EJNMMI Res

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“…For years, challenges in the large-scale production of 67 Cu have impeded its use in nuclear medicine, although recent advances are expected to dramatically increase its availability (56,57). Furthermore, the advent of highly stable copper chelators based on bicyclo [6.6.6] icosane-termed "sarcophagines"-has also reinvigorated interest in 67 Cu as a therapeutic radionuclide, as illustrated by the recent development of [ 64/67 Cu]Cu-SarTATE for the PET imaging and peptide receptor radiotherapy of patients with neuroendocrine tumors (58)(59)(60)(61).…”

Section: Significancementioning

confidence: 99%

Harnessing ⁶⁴ Cu/ ⁶⁷ Cu for a theranostic approach to pretargeted radioimmunotherapy

Keinänen

Fung

Brennan

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Over the past decade, theranostic imaging has emerged as a powerful clinical tool in oncology for identifying patients likely to respond to targeted therapies and for monitoring the response of patients to treatment. Herein, we report a theranostic approach to pretargeted radioimmunotherapy (PRIT) based on a pair of radioisotopes of copper: positron-emitting copper-64 (64Cu, t1/2 = 12.7 h) and beta particle-emitting copper-67 (67Cu, t1/2 = 61.8 h). This strategy is predicated on the in vivo ligation between a trans-cyclooctene (TCO)-bearing antibody and a tetrazine (Tz)-based radioligand via the rapid and bioorthogonal inverse electron-demand Diels–Alder reaction. Longitudinal therapy studies were conducted in a murine model of human colorectal carcinoma using an immunoconjugate of the huA33 antibody modified with TCO (huA33-TCO) and a 67Cu-labeled Tz radioligand ([67Cu]Cu-MeCOSar-Tz). The injection of huA33-TCO followed 72 h later by the administration of 18.5, 37.0, or 55.5 MBq of [67Cu]Cu-MeCOSar-Tz produced a dose-dependent therapeutic response, with the median survival time increasing from 68 d for the lowest dose to >200 d for the highest. Furthermore, we observed that mice that received the highest dose of [67Cu]Cu-MeCOSar-Tz in a fractionated manner exhibited improved hematological values without sacrificing therapeutic efficacy. Dual radionuclide experiments in which a single administration of huA33-TCO was followed by separate injections of [64Cu]Cu-MeCOSar-Tz and [67Cu]Cu-MeCOSar-Tz revealed that the positron emission tomography images produced by the former accurately predicted the efficacy of the latter. In these experiments, a correlation was observed between the tumoral uptake of [64Cu]Cu-MeCOSar-Tz and the subsequent therapeutic response to [67Cu]Cu-MeCOSar-Tz.

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Emerging Therapeutic Radiopharmaceuticals and Their Theranostic Pairs

Carbo-Bague

Ramogida

2021

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Nuclear medicine is a rapidly evolving multidisciplinary research field that has been intensively investigated in the past decades. The successful clinical application of various metal‐based radiopharmaceuticals for cancer imaging and therapy is based on the modular assembly of the drug complex through the popular bifunctional chelate (BFC) strategy. In targeted radionuclide therapy (TRT), potent radiation is selectively delivered to the cancer cells using radiopharmaceuticals that incorporate therapeutic radiometals which emit α ‐particles, β − ‐particles, or Meitner–Auger electrons (MAEs). Radiotheranostics is an emerging concept that connects nuclear imaging (via positron emission tomography (PET) or single‐photon emission computed tomography (SPECT)) and therapy for personalized cancer diagnosis and treatment. This article outlines the fundamentals of radiopharmaceutical design and radiotheranostics and presents a general description of the therapeutic emissions accompanied by literature examples of the most promising radionuclides; 212 Pb, 213 Bi, 225 Ac, 227 Th, and 149 Tb for α therapy; 47 Sc, 67 Cu, 77 As, and 161 Tb for β − therapy; and 119 Sb, 135 La, and 197m/g Hg for MAE therapy. A comparison of the currently used or proposed theranostic pairs of each radiometal is presented.

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Peptide Receptor Radionuclide Therapy with ⁶⁷Cu-CuSarTATE Is Highly Efficacious Against a Somatostatin-Positive Neuroendocrine Tumor Model

Cited by 53 publications

References 29 publications

Detection and therapy of neuroblastoma minimal residual disease using [64/67Cu]Cu-SARTATE in a preclinical model of hepatic metastases

Detection and therapy of neuroblastoma minimal residual disease using [64/67Cu]Cu-SARTATE in a preclinical model of hepatic metastases

Harnessing ⁶⁴ Cu/ ⁶⁷ Cu for a theranostic approach to pretargeted radioimmunotherapy

Emerging Therapeutic Radiopharmaceuticals and Their Theranostic Pairs

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Peptide Receptor Radionuclide Therapy with 67Cu-CuSarTATE Is Highly Efficacious Against a Somatostatin-Positive Neuroendocrine Tumor Model

Cited by 53 publications

References 29 publications

Detection and therapy of neuroblastoma minimal residual disease using [64/67Cu]Cu-SARTATE in a preclinical model of hepatic metastases

Detection and therapy of neuroblastoma minimal residual disease using [64/67Cu]Cu-SARTATE in a preclinical model of hepatic metastases

Harnessing 64 Cu/ 67 Cu for a theranostic approach to pretargeted radioimmunotherapy

Emerging Therapeutic Radiopharmaceuticals and Their Theranostic Pairs

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Product

Resources

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Peptide Receptor Radionuclide Therapy with ⁶⁷Cu-CuSarTATE Is Highly Efficacious Against a Somatostatin-Positive Neuroendocrine Tumor Model

Harnessing ⁶⁴ Cu/ ⁶⁷ Cu for a theranostic approach to pretargeted radioimmunotherapy