Neoadjuvant targeting of glioblastoma multiforme with radiolabeled DOTAGA–substance P—results from a phase I study

Cordier, Dominik; Forrer, Flavio; Kneifel, Stefan; Sailer, Martin; Mariani, Luigi; Mäcke, Helmut R.; Müller-Brand, Jan; Merlo, Adrian

doi:10.1007/s11060-010-0153-5

Cited by 54 publications

(39 citation statements)

References 35 publications

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“…Success on overcoming β radio‐ and chemoresistance has been previously demonstrated by the use of α emitters . Studies on treatment of glioblastoma cells with SP labeled with the α emitter 213 Bi ( t 1/2 = 46 min) demonstrated already a positive outcome in patients . 213 Bi‐SP is well tolerated with low toxicity, but the short half‐life limits diffusion in large tumors, and it might be insufficient to reach tumor margins as well as metastasis .…”

Section: Discussionmentioning

confidence: 97%

“…The endogenous neuropeptide SP shows high affinity to NK‐1 receptors which are consistently expressed at high levels in primary malignant gliomas and in intratumoral and peritumoral vasculature. There are several studies showing the potential of SP by targeting glioblastoma cells and especially GSCs . To this aim, the effects of 225 Ac‐DOTA‐SP were examined on the cellular level using glioblastoma cell lines and GSCs.…”

Section: Discussionmentioning

confidence: 99%

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In vitro evaluation of ²²⁵Ac‐DOTA‐substance P for targeted alpha therapy of glioblastoma multiforme

et al. 2018

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Glioblastoma multiforme (GBM) is the most malignant form of brain tumors with dismal prognosis despite treatment by surgery combined with radiotherapy and chemotherapy. The neuropeptide Substance P (SP) is the physiological ligand of the neurokinin-1 receptor, which is highly expressed in glioblastoma cells. Thus, SP represents a potential ligand for targeted alpha therapy. In this study, a protocol for the synthesis of SP labeled with the alpha emitter Ac was developed and binding affinity properties were determined. The effects of Ac-DOTA-SP were investigated on human glioblastoma cell lines (T98G, U87MG, U138MG) as well as GBM stem cells. A significant dose-dependent reduction in cell viability was detected up to 6 days after treatment. Also, colony-forming capacity was inhibited at the lower doses tested. In comparison, treatment with the conventional agent temozolomide showed higher cell viability and colony-forming capacity. Ac-DOTA-SP treatment caused induction of late apoptosis pathways. Cells were arrested to G2/M-phase upon treatment. Increasing doses and treatment time caused additional S-phase arrest. Similar results were obtained using human glioblastoma stem cells, known to show radioresistance. Our data suggest that Ac-DOTA-SP is a promising compound for treatment of GBM.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

In vitro evaluation of ²²⁵Ac‐DOTA‐substance P for targeted alpha therapy of glioblastoma multiforme

et al. 2018

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“…Initial results with 90 Y and 177 Lu indicated clinical potential (31,32); however, recent studies focused on the a emitters 213 Bi and 225 Ac, allowing more selective tumor cell irradiation and limiting toxicity to adjacent healthy brain tissue. 213 Bi-DOTA-SP has been examined in 61 patients with grade II-IV gliomas (up to a cumulative activity of 14.1 GBq) (33,34).…”

Section: Substance P In Gliomamentioning

confidence: 99%

New Developments in Peptide Receptor Radionuclide Therapy

et al. 2018

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Peptide receptor radionuclide therapy (PRRT) is an established treatment for nonoperable or metastatic neuroendocrine neoplasms that highly and frequently express somatostatin receptors. More generally, PRRT is an attractive therapy option for delivering cytotoxic radiation to tumor cells through specific binding of a radiolabeled peptide to a molecular target. The development of imaging companions gave rise to the concept of radiotheranostics, important for in vivo tumor detection, characterization, and staging but also, and more importantly, for individual patient selection and treatment. The success of somatostatin receptor targeting paved the way for the clinical translation of other peptide-based radiopharmaceuticals targeting, for example, the receptors cholecystokinin 2, gastrin-releasing peptide, neurokinin-1, and C-X-C motif chemokine 4. Although historically the Auger emitter 111 In and the high-energy β − emitter 90 Y were used, most PRRT are currently performed with the medium-energy β − emitter 177 Lu, whereas α emitters are increasingly studied in various clinical applications. New Developments in Peptide ReceptorRadionuclide Therapy http://jnm.snmjournals.org/content/60/2/167 This article and updated information are available at: http://jnm.snmjournals.org/site/subscriptions/online.xhtml Information about subscriptions to JNM can be found at: http://jnm.snmjournals.org/site/misc/permission.xhtml

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“…Therefore, a study (118) analyzed whether neoadjuvant treatment before tumor resection is also a valid concept for improved therapy of malignant brain tumors. Seventeen glioblastoma patients were treated by local injection of 90 Y-DOTAGA-substance P before tumor resection.…”

Section: Radiolabeled Substance P and Chloratoxinmentioning

confidence: 99%

Radiopeptide Imaging and Therapy in Europe

Ambrosini¹,

Fani²,

Fanti³

et al. 2011

J Nucl Med

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183

116

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Receptor targeting with radiolabeled peptides has become an important topic, particularly in nuclear oncology. Strong research efforts are under way in radiopharmaceutical science laboratories and in nuclear medicine departments in Europe. The target receptors belong to the large family of G-proteincoupled receptors. The prototypes of these radiopeptides are based on analogs of somatostatin targeting somatostatin receptor-positive tumors, particularly well-differentiated neuroendocrine tumors. These radiopeptides have an important impact not only on diagnosis but also on targeted radionuclide therapy of these tumors. Besides the registered radiopeptide 111 In-pentetreotide, efficient SPECT tracers labeled with 99m Tc and PET agents based on generator-produced 68 Ga have been developed and used in the clinic. In parallel to the development of diagnostic agents, radiopeptides labeled with the b 2 emitters 90 Y and 177 Lu are also widely used. Because the same chelators and therefore the same conjugates can be used in diagnosis and therapy, they constitute ideal theranostic pairs. This progress is driven not only by scientists and clinicians but also by patient interest groups. New radiopeptides targeting other G-protein-coupled receptors are entering the clinic, among them glucagon-like peptide 1 receptor-targeting molecules. This receptor is overexpressed on literally all benign insulinomas. 111 In-labeled derivatives of the insulinotropic 39-mer peptide exendin-4 were beneficial in the pre-and perioperative localization of these benign lesions. In contrast, lack of localization may indicate malignant insulinoma. The bombesin-and gastrin-releasing peptide receptor family is potentially important because these receptors are overexpressed on major human tumors such as prostate tumors, breast tumors, gastrointestinal stromal tumors, and vessels of ovarian cancer. 99m Tc-labeled peptides for SPECT and 68 Ga-, as well as 64 Cu-labeled agonists or antagonists, have been studied in breast tumors, prostate tumors, gastrointestinal stromal tumors, and gliomas with considerable success. A phase I therapeutic study with a 177 Lu-labeled agonist has been completed. There are not enough clinical data available to reveal the significance of these new modalities in patient care, but several phase I studies are under way in larger patient cohorts using PET agents. Another G-protein-coupled receptor with high overexpression on human tumors is the gastrin/ cholecystokinin-2 receptor. It is overexpressed in more than 90% of cases of medullary thyroid cancer, in small cell lung cancer, and in a subgroup of neuroendocrine tumors. Correlating with in vitro receptor localization using autoradiography of 27 patients with metastasized medullary thyroid cancer, SPECT or planar imaging of these patients resulted in a 95% sensitivity of tumor localization. Finally, another G-protein-coupled receptor is found in brain tumors and peritumoral vessels. Literally all cases of glioblastoma multiforme overexpress the neurokinin type 1 receptor; th...

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Neoadjuvant targeting of glioblastoma multiforme with radiolabeled DOTAGA–substance P—results from a phase I study

Cited by 54 publications

References 35 publications

In vitro evaluation of ²²⁵Ac‐DOTA‐substance P for targeted alpha therapy of glioblastoma multiforme

In vitro evaluation of ²²⁵Ac‐DOTA‐substance P for targeted alpha therapy of glioblastoma multiforme

New Developments in Peptide Receptor Radionuclide Therapy

Radiopeptide Imaging and Therapy in Europe

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Neoadjuvant targeting of glioblastoma multiforme with radiolabeled DOTAGA–substance P—results from a phase I study

Cited by 54 publications

References 35 publications

In vitro evaluation of 225Ac‐DOTA‐substance P for targeted alpha therapy of glioblastoma multiforme

In vitro evaluation of 225Ac‐DOTA‐substance P for targeted alpha therapy of glioblastoma multiforme

New Developments in Peptide Receptor Radionuclide Therapy

Radiopeptide Imaging and Therapy in Europe

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In vitro evaluation of ²²⁵Ac‐DOTA‐substance P for targeted alpha therapy of glioblastoma multiforme

In vitro evaluation of ²²⁵Ac‐DOTA‐substance P for targeted alpha therapy of glioblastoma multiforme