scholarly journals 177Lu-octreotate therapy for neuroendocrine tumours is enhanced by Hsp90 inhibition

2019 ◽  
Vol 26 (4) ◽  
pp. 437-449 ◽  
Author(s):  
Tobias Hofving ◽  
Viktor Sandblom ◽  
Yvonne Arvidsson ◽  
Emman Shubbar ◽  
Gülay Altiparmak ◽  
...  
Keyword(s):  
Neuroendocrine Tumours ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Xenograft Model ◽  
Progression Free Survival ◽  
Tumour Volume ◽  
Tumour Cells ◽  
Hsp90 Inhibition ◽  
Killing Effect

177Lu-octreotate is an FDA-approved radionuclide therapy for patients with gastroenteropancreatic neuroendocrine tumours (NETs) expressing somatostatin receptors. The 177Lu-octreotate therapy has shown promising results in clinical trials by prolonging progression-free survival, but complete responses are still uncommon. The aim of this study was to improve the 177Lu-octreotate therapy by means of combination therapy. To identify radiosensitising inhibitors, two cell lines, GOT1 and P-STS, derived from small intestinal neuroendocrine tumours (SINETs), were screened with 1224 inhibitors alone or in combination with external radiation. The screening revealed that inhibitors of Hsp90 can potentiate the tumour cell-killing effect of radiation in a synergistic fashion (GOT1; false discovery rate <3.2 × 10−11). The potential for Hsp90 inhibitor ganetespib to enhance the anti-tumour effect of 177Lu-octreotate in an in vivo setting was studied in the somatostatin receptor-expressing GOT1 xenograft model. The combination led to a larger decrease in tumour volume relative to monotherapies and the tumour-reducing effect was shown to be synergistic. Using patient-derived tumour cells from eight metastatic SINETs, we could show that ganetespib enhanced the effect of 177Lu-octreotate therapy for all investigated patient tumours. Levels of Hsp90 protein expression were evaluated in 767 SINETs from 379 patients. We found that Hsp90 expression was upregulated in tumour cells relative to tumour stroma in the vast majority of SINETs. We conclude that Hsp90 inhibitors enhance the tumour-killing effect of 177Lu-octreotate therapy synergistically in SINET tumour models and suggest that this potentially promising combination should be further evaluated.

scholarly journals Somatostatin receptors in gastroentero-pancreatic neuroendocrine tumours.

2003 ◽  
pp. 451-458 ◽  
Author(s):  
W W de Herder ◽  
L J Hofland ◽  
A J van der Lely ◽  
S W J Lamberts
Keyword(s):  
Neuroendocrine Tumours ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Somatostatin Analogues ◽  
Carcinoid Tumours ◽  
High Affinity ◽  
Pancreatic Neuroendocrine Tumours ◽  
Predominant Expression ◽  
Somatostatin 14

Five somatostatin receptor (sst) subtype genes, sst(1), sst(2), sst(3), sst(4) and sst(5), have been cloned and characterised. The five sst subtypes all bind natural somatostatin-14 and somatostatin-28 with high affinity. Endocrine pancreatic and endocrine digestive tract tumours also express multiple sst subtypes, but sst(2) predominance is generally found. However, there is considerable variation in sst subtype expression between the different tumour types and among tumours of the same type. The predominant expression of sst(2) receptors on pancreatic endocrine or carcinoid tumours is essential for the control of hormonal hypersecretion by the octapeptide somatostatin analogues such as octreotide and lanreotide. Somatostatin and its octapeptide analogues are also able to inhibit proliferation of normal and tumour cells. The high density of sst(2) or sst(5) on pancreatic endocrine or carcinoid tumours further allows the use of radiolabelled somatostatin analogues for in vivo visualisation. The predominant expression of sst(2) receptors in these tumours and the efficiency of sst(2) receptors to undergo agonist-induced internalisation is also essential for the application of radiolabelled octapeptide somatostatin analogues. Currently, [(111)In-DTPA(0)]octreotide, [(90)Y-DOTA(0),Tyr(3)]octreotide, [(177)Lu-DOTA(0)Tyr(3)]octreotate, [(111)In-DOTA(0)]lanreotide and [(90)Y-DOTA(0)]lanreotide can be used for this purpose.

scholarly journals Selection of the First 99mTc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation—Preclinical Assessment of Two Optimized Candidates

2020 ◽  
Vol 14 (1) ◽  
pp. 19
Author(s):  
Melpomeni Fani ◽  
Viktoria Weingaertner ◽  
Petra Kolenc Peitl ◽  
Rosalba Mansi ◽  
Raghuvir H. Gaonkar ◽  
...  
Keyword(s):  
Protein Binding ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Preclinical Study ◽  
Clinical Translation ◽  
Hek293 Cells ◽  
Neuroendocrine Neoplasms ◽  
Receptor Subtype ◽  
Selection Of

Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project “TECANT” two 99mTc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log D, protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [99mTc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [99mTc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [99mTc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (<30%, at 2 h/37 °C). In vivo, [99mTc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [99mTc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [99mTc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [99mTc]Tc-TECANT-1 for clinical translation of the first 99mTc-based SST2 antagonist.

lncRNA SNHG14 promotes the proliferation, migration, and invasion of thyroid tumour cells by regulating miR-93-5p

Zygote ◽  
2021 ◽  
pp. 1-11
Author(s):  
Fang Tian ◽  
Huimin Ying ◽  
Shuaiju Liao ◽  
Yuanyuan Wang ◽  
Quansheng Wang
Keyword(s):  
Wound Healing ◽  
Xenograft Model ◽  
Tumour Cells ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Thyroid Tumour ◽  
Invasion And Migration ◽  
Vital Functions ◽  
And Migration

Summary Long non-coding RNAs (lncRNAs) exert vital functions in the occurrence and development of various tumours. The aim of this study was to examine the regulatory effect and underlying molecular mechanism of lncRNA small nucleolar RNA host gene 14 (SNHG14) on the proliferation, invasion and migration of thyroid tumour cells. The expression of SNHG14 in thyroid tumour cell lines was determined using qRT-PCR. CCK-8 and western blot were used to detect the effects of SNHG14 on proliferation and apoptosis of thyroid tumour cells. The effect of SNHG14 on the migration and invasion of thyroid tumour cells was analyzed using immunofluorescence, wound-healing and transwell assays. A targeting relationship between SNHG14 and miR-93-5p was determined using bioinformatics software and luciferase reporter assays. In addition, CCK-8, immunofluorescence, wound-healing and transwell assays were applied to demonstrate that SNHG14 promoted the proliferation, migration and invasion of thyroid tumour cells by targeting miR-93-5p. The biological function of SNHG14 in vivo was explored through a xenograft model and immunohistochemistry. SNHG14 was upregulated in thyroid tumour cells compared with normal cells. Downregulation of SNHG14 effectively reduced the proliferation, migration and invasion of TPC-1 cells, and induced cell apoptosis. Moreover, SNHG14 directly targeted miR-93-5p and there was a negative correlation between them. Further functional experiments illustrated that miR-93-5p overexpression dramatically reversed the promoting role of SNHG14 in proliferation, migration and invasion of TPC-1 cells. Our results demonstrated that SNHG14 promotes the proliferation, invasion and migration of thyroid tumour cells by downregulating miR-93-5p.

Novel insights in somatostatin receptor physiology

2007 ◽  
Vol 156 (suppl_1) ◽  
pp. S3-S11 ◽  
Author(s):  
Giovanni Tulipano ◽  
Stefan Schulz
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Somatostatin Analogs ◽  
Receptor Subtypes ◽  
Ligand Complex ◽  
Endosomal Sorting ◽  
Intracellular Vesicle ◽  
Molecular Events ◽  
Somatostatin Receptor Subtypes

The experimental data reviewed in the present paper deal with the molecular events underlying the agonist-dependent regulation of the distinct somatostatin receptor subtypes and may suggest important clues about the clinical use of somatostatin analogs with different pattern of receptor specificity for the in vivo targeting of tumoral somatostatin receptors. Somatostatin receptor subtypes are characterized by differential β-arrestin trafficking and endosomal sorting upon agonist binding due, at least in part, to the differences in their C-terminal tails. Moreover, the subcellular expression pattern of somatostatin receptor subtypes and their activity in response to agonist treatment are affected by intracellular complements, such as proteins involved in intracellular vesicle trafficking. Different somatostatin analogs may induce distinct conformations of the receptor/ligand complex, preferentially coupled to either receptor signaling or receptor endocytosis.

Phase 2 trial of Lu-177-DOTATATE in inoperable pheochromocytoma/paraganglioma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS4159-TPS4159 ◽  
Author(s):  
Frank Lin ◽  
Jaydira Del Rivero ◽  
Jorge A. Carrasquillo ◽  
Abhishek Jha ◽  
Melissa K Gonzales ◽  
...  
Keyword(s):  
Amino Acid ◽  
Performance Status ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Progression Free Survival ◽  
Fixed Dose ◽  
Phase 2 ◽  
Open Label ◽  
Ecog Performance Status ◽  
Eligibility Criteria

TPS4159 Background: Pheochromocytoma/paraganglioma (PHEO/PGL) is a rare malignancy that arises from chromaffin cells of typically the adrenal medulla but can also be of extra-adrenal origin. These tumors produce excessive catecholamines such as epinephrine and norepinephrine which causes labile hypertension, tachycardia, and flushing. Lu-177-DOTATATE (Lu-177-dodecanetetraacetic acid‐tyrosine-3-octreotate) is a radiolabeled somatostatin analog that is FDA approved for somatostatin receptor-positive neuroendocrine tumors. It is being being investigated in PHEO/PGL, which overexpress somatostatin receptors. Amino acid solutions containing lysine/arginine (L/A) are routinely co-administered with Lu-177-DOTATATE for renal radioprotection, although solutions containing other amino acids are also used. Methods: This is a prospective, single center, open label Phase 2 study evaluating the efficacy of Lu-177-DOTATATE in PHEO/PGL. Ninety patients will be enrolled, divided into two cohorts of 45 patients each ( SDHx mutation vs. apparent sporadic). Lu-177-DOTATATE is given at a fixed dose of 200 mCi with a co-administration of L/A amino acid solution q8 weeks for 4 cycles. The primary endpoint is the progression-free-survival (PFS) rate at 6 months. Secondary endpoints include response rate, overall survival, time to progression, quality of life measures, and examination of potential biomarkers such as biochemical profiles, Ga-68-DOTATATE PET, and F-18-FDG PET scans. Eligibility criteria include inoperable disease (including non-metastatic), histological confirmation of PHEO/PGL, evidence of disease progression by RECIST 1.1, ECOG performance status of 1 or better, and a positive Ga-68-DOTATATE PET scan. Exclusion criteria include prior treatment with systemic radionuclide therapy such as I-131-MIBG, brain parenchymal metastases, and standard organ dysfunction limitations. Interim analysis using a Simon two-stage optimal design will be performed separately for each cohort after enrollment of 18 patients. First patient accrual to this ongoing study was in the Fall of 2017, and as of February 2019, fourteen patients have been accrued. Preliminary results will be reported at the completion of stage 1 for each cohort. Clinical trial information: NCT03206060.

scholarly journals Inhibition of Serum Response Factor Improves Response to Enzalutamide in Prostate Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3540
Author(s):  
R. William Watson ◽  
Haleema Azam ◽  
Claudia Aura ◽  
Niamh Russell ◽  
Janet McCormack ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Serum Response Factor ◽  
Specific Antigen ◽  
Xenograft Model ◽  
Tumour Volume ◽  
Lead Target ◽  
Response Factor ◽  
Serum Response

Castrate-resistant prostate cancer (CRPC) is challenging to treat with the androgen receptor (AR), the main target and key focus of resistance. Understanding the mechanisms of AR interaction with co-regulators will identify new therapeutic targets to overcome AR resistance mechanisms. We previously identified the serum response factor (SRF) as a lead target in an in vitro model of CRPC and showed that SRF expression in tissues of CRPC patients was associated with shorter survival. Here, we tested SRF inhibition in vitro and in vivo to assess SRF as a potential target in CRPC. Inhibition of SRF with the small-molecule inhibitor CCG1423 resulted in enhanced response to enzalutamide in vitro and reduced tumour volume of LuCaP 35CR, a CRPC patient-derived xenograft model. Nuclear localisation of AR post-CCG1423 was significantly decreased and was associated with decreased α-tubulin acetylation in vitro and decreased prostate specific antigen (PSA) levels in vivo. SRF immunoreactivity was tested in metastatic tissues from CRPC patients to investigate its role in enzalutamide response. Kaplan–Meier curves showed that high SRF expression was associated with shorter response to enzalutamide. Our study supports the use of SRF inhibitors to improve response to enzalutamide.

scholarly journals A phenotypic screen identifies a compound series that induces differentiation of acute myeloid leukemia cells in vitro and shows anti-tumour effects in vivo

2020 ◽  
Author(s):  
Laia Josa-Culleré ◽  
Katrina S. Madden ◽  
Thomas J. Cogswell ◽  
Thomas R. Jackson ◽  
Tom S. Carter ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Xenograft Model ◽  
Tumour Volume ◽  
Specific Patient ◽  
Phenotypic Screen ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

AbstractInduction of differentiation is a promising therapeutic strategy against acute myeloid leukemia. However, current differentiation therapies are effective only to specific patient populations. To identify novel differentiation agents with wider efficacy, we developed a phenotypic high-throughput screen with a range of genetically diverse cell lines. From the resulting hits, one chemical scaffold was optimised in terms of activity and physicochemical properties to yield OXS007417, which was also able to decrease tumour volume in a murine in vivo xenograft model.

scholarly journals Better way to image and manage Neuroendocrine Tumours: Role of 68Gallium DOTA-Peptide PET-CT scan

2018 ◽  
Vol 20 (2) ◽  
pp. 136
Author(s):  
Shankar Kumar Dey
Keyword(s):  
Molecular Imaging ◽  
Ct Scan ◽  
Significant Role ◽  
Neuroendocrine Tumours ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Somatostatin Analogues ◽  
Pet Ct ◽  
Receptor Scintigraphy ◽  
Pet Ct Scan

<p>Neuroendocrine tumours (NETs) are special entity of neoplasms arising from nervous and endocrine systems and involving variety of organs. Over expression of somatostatin receptors is an unique characteristic of these tumours. This allows molecular imaging to play a significant role in evaluation of NETs using somatostatin analogues. <sup>111</sup> In Pentetreotide scintigraphy has been playing a significant role as molecular imaging of choice to locate the primary tumor, evaluate extent of disease and plan for surgical management. Recently <sup>68 </sup>Ga labelled peptides have emerged as promising PET tracers for scintigraphy of these tumours. Several recent studies have demonstrated the superiority of <sup>68</sup>Ga DOTA- Peptide PET-CT scan with a number of advantages over conventional somatostatin receptor scintigraphy.</p><p>Bangladesh J. Nuclear Med. 20(2): 136-142, July 2017</p>

Peptide Receptor Radionuclide Therapy for Gastroenteropancreatic Neuroendocrine Tumors

2019 ◽  
Vol 03 (01) ◽  
pp. 071-080
Author(s):  
Ghassan El-Haddad
Keyword(s):  
Neuroendocrine Tumors ◽  
Radionuclide Therapy ◽  
Large Scale ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Peptide Receptor Radionuclide Therapy ◽  
Progression Free Survival ◽  
Multicenter Trial ◽  
Gastroenteropancreatic Neuroendocrine Tumors ◽  
Peptide Receptor

AbstractPeptide receptor radionuclide therapy (PRRT), a targeted form of systemic radiotherapy allowing the delivery of radionuclides directly to tumor cells, has been used for more than three decades in the treatment of advanced neuroendocrine tumors (NETs) exhibiting high levels of somatostatin receptors. Recently, 177Lu-DOTATATE, a radiolabeled somatostatin analog, was approved by the US Food and Drug administration for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults. Early phase I and II studies have shown the benefits of PRRT, but it was the NETTER-1 trial (a large-scale randomized multicenter trial for progressive well-differentiated advanced or metastatic somatostatin receptor-positive midgut carcinoid tumors) that provided high-level evidence of improved overall response rate, and progression-free survival compared with long-acting octreotide. In this article, we will discuss the evolution, clinical applications, and implementation of PRRT, as well as potential future strategies to enhance its clinical efficacy in the treatment of GEP-NETs.

scholarly journals Expression of somatostatin receptors 2 and 5 in circulating tumour cells from patients with neuroendocrine tumours

2016 ◽  
Vol 115 (12) ◽  
pp. 1540-1547 ◽  
Author(s):  
Alexa Childs ◽  
Clare Vesely ◽  
Leah Ensell ◽  
Helen Lowe ◽  
Tu Vinh Luong ◽  
...  
Keyword(s):  
Neuroendocrine Tumours ◽  
Somatostatin Receptors ◽  
Tumour Cells ◽  
Circulating Tumour Cells
Sign in / Sign up

Export Citation Format

Share Document