Differentiated expression of somatostatin receptor subtypes in experimental models and clinical neuroblastoma

Georgantzi, Kleopatra; Tsolakis, Apostolos V.; Stridsberg, Mats; Jakobson, Åke; Christofferson, Rolf; Janson, Eva Tiensuu

doi:10.1002/pbc.22913

Cited by 32 publications

(38 citation statements)

References 32 publications

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“…10 SSR2s have also been identified on PNETs and neuroblastomas. 10,11,15,16 Their presence and in vitro evidence that SSR2-positive tumor cells are partially inhibited by the SSR2 agonist octreotide suggest that targeting SSR2 may represent a new therapeutic option. 14,17 Somatostatin analogs act, in part, by activating protein tyrosine phosphatases, which deactivate/dephosphorylate key growth-stimulating pathways especially the MAPK kinase (Raf-1)-MAPK/ERK kinase (MEK-1)-mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) cascade and phosphoinositide 3 kinase (PI3K)-protein kinase PKB/Akt-mTOR pathway.…”

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confidence: 96%

“…[1][2][3] Despite improvements in chemotherapy, long-term survival rates are still suboptimal, and current treatments of surgery and radiotherapy with or without chemotherapy are associated with a lower IQ, defects in memory, and hearing impairment. 4 Several studies suggest that somatostatin receptors (SSRs) or octreotide-binding sites are expressed on medulloblastomas [5][6][7][8][9] or primitive neuroectodermal tumors (PNETs) [10][11][12] and might be targeted by somatostatin ligands, such as octreotide, as a novel chemotherapy. 10,[13][14][15][16] SSR2A has been found to be overexpressed in primary and recurrent medulloblastomas.…”

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confidence: 99%

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Differential Expression of Somatostatin Receptors, P44/42 MAPK, and mTOR Activation in Medulloblastomas and Primitive Neuroectodermal Tumors

Johnson¹,

O’Connell²,

Silberstein³

et al. 2013

Applied Immunohistochemistry &Amp; Molecular Morphology

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Recently, somatostatin receptors (SSR) have been identified on medulloblastomas and proposed as a new target for chemotherapy including inhibitory somatostatin analogs. Activation of SSRs inhibit growth, in part, by activating phosphatases that dephosphorylate/deactivate growth stimulatory signaling of the MEK1-p44/42 MAPK and PI3K-Akt-mTOR pathways. These SSR-inhibited signaling pathways have not been characterized or correlated with SSR expression in medulloblastomas or primitive neuroectodermal tumors (PNETs), yet may represent additional targets for combined chemotherapy. We evaluated the distribution and extent of SSR1 and SSR2 expression and correlated it with activation of downstream MEK1-p44/42 MAPK and PI3K-Akt-mTOR pathways in medulloblastomas and PNETs. Sections from 22 medulloblastomas and 9 PNETs were compared using immunohistochemistry with monoclonal antibodies to SSR1, SSR2, p44/42 MAPK, phosphorylated p44/42 MAPK, and phosphorylated mTOR. SSR1 was detected in 50% of medulloblastomas, extensive in 46%, and similar in classic, desmoplastic, and large cell/anaplastic subtypes. SSR1 was detected in 78% of PNETs and extensive in the majority. SSR2 was found in 18% of medulloblastomas and 33% of PNETs. Activated/phosphorylated pMAPK 44/42 was detected in 82% of medulloblastomas, all subtypes, and in 62.5% of PNETs with coexpression of SSR1 in one third. Activated/phosphorylated mTOR was found in only 18% of medulloblastomas but in 88% of PNETs. SSR1 coexpression with activated/phosphorylated mTOR was identified in 75% of PNETs. These findings suggest that addition of an mTOR inhibitor may potentiate growth inhibitory effects of SSR agonists in the treatment of PNETs. Immunohistochemical identification of mTOR activation/phosphorylation in biopsies of initial and treatment-resistant PNETs may facilitate development of clinical trials and therapeutic decisions.

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confidence: 96%

mentioning

confidence: 99%

Differential Expression of Somatostatin Receptors, P44/42 MAPK, and mTOR Activation in Medulloblastomas and Primitive Neuroectodermal Tumors

Johnson¹,

O’Connell²,

Silberstein³

et al. 2013

Applied Immunohistochemistry &Amp; Molecular Morphology

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“…Somatostatin receptors (particularly subtype 2) are expressed on the surface of some neuroblastomas, making molecular radiotherapy with somatostatin analogs an attractive therapeutic option in carefully selected patients (5)(6)(7).…”

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confidence: 99%

¹⁷⁷Lu-DOTATATE Molecular Radiotherapy for Childhood Neuroblastoma

Gains¹,

Bomanji²,

Fersht³

et al. 2011

J Nucl Med

148

141

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This study tested the principle that 68 Ga-DOTATATE PET/CT may be used to select children with primary refractory or relapsed high-risk neuroblastoma for treatment with 177 Lu-DOTATATE and evaluated whether this is a viable therapeutic option for those children. Methods: Between 2008 and 2010, 8 children with relapsed or refractory high-risk neuroblastoma were studied with 68 Ga-DOTATATE PET/CT. The criterion of eligibility for 177 Lu-DOTATATE therapy was uptake on the diagnostic scan equal to or higher than that of the liver. Results: Of the 8 children imaged, 6 had abnormally high uptake on the 68 Ga-DOTATATE PET/CT scan and proceeded to treatment. Patients received 2 or 3 administrations of 177 Lu-DOTATATE at a median interval of 9 wk and a median administered activity of 7.3 GBq. Of the 6 children treated, 5 had stable disease by the response evaluation criteria in solid tumors (RECIST). Of these 5 children, 2 had an initial metabolic response and reduction in the size of their lesions, and 1 patient had a persistent partial metabolic response and reduction in size of the lesions on CT, although the disease was stable by RECIST. One had progressive disease. Three children had grade 3 and 1 child had grade 4 thrombocytopenia. No significant renal toxicity has been seen. Conclusion: 68 Ga-DOTATATE can be used to image children with neuroblastoma and identify those suitable for molecular radiotherapy with 177 Lu-DOTATATE. We have shown, for what is to our knowledge the first time, that treatment with 177 Lu-DOTATATE is safe and feasible in children with relapsed or primary refractory high-risk neuroblastoma. We plan to evaluate this approach formally in a phase I-II clinical trial.

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“…In addition, gene expression in neuroblastoma overlaps to a large extent with gene expression in other neuroendocrine tumors, such as SI-NETs, with for example expression of members of the chromogranin family [31]. Moreover, SSTRs are often highly expressed by neuroblastoma [32]. …”

Section: Neuroblastomamentioning

confidence: 99%

Virotherapy of Neuroendocrine Tumors

Essand

2012

Neuroendocrinology

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Most patients with small intestinal neuroendocrine tumors (SI-NETs), also referred to as midgut carcinoids, present with systemic disease at the time of diagnosis with metastases primarily found in regional lymph nodes and the liver. Curative treatment is not available for these patients and there is a need for novel and specific therapies. Engineered oncolytic viruses may meet the need and play an important role in the future management of SI-NET liver metastases. This review focuses on adenovirus as the oncolytic anti-cancer agent and its potential curative role for SI-NET liver metastases, but it also summarizes the use of oncolytic viruses for NETs in general. It discusses how specific features of neuroendocrine cell biology can be used to engineer viruses to become selective for infection of NET cells and/or replication within NET cells. In addition, it points out the advantages and shortcomings of using replicating viruses in the treatment of cancer and addresses research fields that can increase the efficacy of virus-based therapy.

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Differentiated expression of somatostatin receptor subtypes in experimental models and clinical neuroblastoma

Abstract: The frequent expression of SSTRs indicates that treatment with unlabeled or radiolabeled SS analogs should be further explored in NB.

Cited by 32 publications

References 32 publications

Differential Expression of Somatostatin Receptors, P44/42 MAPK, and mTOR Activation in Medulloblastomas and Primitive Neuroectodermal Tumors

Differential Expression of Somatostatin Receptors, P44/42 MAPK, and mTOR Activation in Medulloblastomas and Primitive Neuroectodermal Tumors

¹⁷⁷Lu-DOTATATE Molecular Radiotherapy for Childhood Neuroblastoma

Virotherapy of Neuroendocrine Tumors

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Differentiated expression of somatostatin receptor subtypes in experimental models and clinical neuroblastoma

Abstract: The frequent expression of SSTRs indicates that treatment with unlabeled or radiolabeled SS analogs should be further explored in NB.

Cited by 32 publications

References 32 publications

Differential Expression of Somatostatin Receptors, P44/42 MAPK, and mTOR Activation in Medulloblastomas and Primitive Neuroectodermal Tumors

Differential Expression of Somatostatin Receptors, P44/42 MAPK, and mTOR Activation in Medulloblastomas and Primitive Neuroectodermal Tumors

177Lu-DOTATATE Molecular Radiotherapy for Childhood Neuroblastoma

Virotherapy of Neuroendocrine Tumors

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Product

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¹⁷⁷Lu-DOTATATE Molecular Radiotherapy for Childhood Neuroblastoma