| 1. |
- Hofving, Tobias, 1989, et al.
(författare)
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177 Lu-octreotate therapy for neuroendocrine tumours is enhanced by Hsp90 inhibition
- 2019
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Ingår i: Endocrine-Related Cancer. - 1479-6821 .- 1351-0088. ; 26:4, s. 437-449
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Tidskriftsartikel (refereegranskat)abstract
- Lu-177-octreotate is an FDA-approved radionuclide therapy for patients with gastroenteropancreatic neuroendocrine tumours (NETs) expressing somatostatin receptors. The Lu-177-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 Lu-177-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 x 10(-11)). The potential for Hsp90 inhibitor ganetespib to enhance the anti-tumour effect of Lu-177-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 Lu-177-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 Lu-177-octreotate therapy synergistically in SINET tumour models and suggest that this potentially promising combination should be further evaluated.
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| 2. |
- Elf, Anna-Karin, et al.
(författare)
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NAMPT inhibitor GMX1778 enhances the efficacy of 177Lu-DOTATATE treatment of neuroendocrine tumors.
- 2017
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 58:2, s. 288-292
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Tidskriftsartikel (refereegranskat)abstract
- Neuroendocrine tumors (NETs) can be treated by peptide receptor radionuclide therapy using radiolabeled somatostatin analogs. However, the efficacy of such treatment is low and needs to be optimized.To evaluate the potential radiosensitizing effects of NAMPT inhibition on (177)Lu-DOTATATE treatment in a NET model.Nude mice xenografted with the human NET cell line GOT1 were treated with semi-efficient doses of (177)Lu-DOTATATE (7,5 MBq, i.v.) and/or GMX1778 (100 mg/kg/week, p.o.).Median time to tumor progression (tumor volume larger than at day 0) was 3 days for controls, 7 days for single dose GMX1778, 28 days for single dose (177)Lu-DOTATATE and 35 days for 3 weekly doses of GMX1778. Combined treatment with (177)Lu-DOTATATE and GMX1778 x1 resulted in a median time to progression of 98 days. After (177)Lu-DOTATATE and 3 weekly doses of GMX1778 none of the tumors progressed within 120 days.The NAMPT inhibitor GMX1778 enhances the efficacy of (177)Lu-DOTATATE treatment and induces a prolonged antitumor response. Combinations of radiolabeled somatostatin analogs and radiosensitizing drugs should be further evaluated to optimize the efficacy of peptide receptor radionuclide therapy in NETs.
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| 3. |
- Mehrara, Esmaeil, 1971, et al.
(författare)
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A new method to estimate parameters of the growth model for metastatic tumours.
- 2013
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Ingår i: Theoretical biology & medical modelling. - : Springer Science and Business Media LLC. - 1742-4682. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Knowledge of natural tumour growth is valuable for understanding tumour biology, optimising screening programs, prognostication, optimal scheduling of chemotherapy, and assessing tumour spread. However, mathematical modelling in individuals is hampered by the limited data available. We aimed to develop a method to estimate parameters of the growth model and formation rate of metastases in individual patients. MATERIALS AND METHODS: Data from one patient with liver metastases from a primary ileum carcinoid and one patient with lung metastases from a primary renal cell carcinoma were used to demonstrate this new method. Metastatic growth models were estimated by direct curve fitting, as well as with the new proposed method based on the relationship between tumour growth rate and tumour volume. The new model was derived from the Gompertzian growth model by eliminating the time factor (age of metastases), which made it possible to perform the calculations using data from all metastases in each patient. Finally, the formation time of each metastasis and, consecutively, the formation rate of metastases in each patient were estimated. RESULTS: With limited measurements in clinical studies, fitting different growth curves was insufficient to estimate true tumour growth, even if patients were followed for several years. Growth of liver metastases was well described with a general growth model for all metastases. However, the lung metastases from renal cell carcinoma were better described by heterogeneous exponential growth with various growth rates. CONCLUSION: Analysis of the regression of tumour growth rate with the logarithm of tumour volume can be used to estimate parameters of the tumour growth model and metastasis formation rates, and therefore the number and size distribution of metastases in individuals.
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| 4. |
- Nilsson, Ola, 1957, et al.
(författare)
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New medical strategies for midgut carcinoids.
- 2010
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Ingår i: Anti-cancer agents in medicinal chemistry. - 1875-5992. ; 10:3, s. 250-269
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Forskningsöversikt (refereegranskat)abstract
- Patients with well-differentiated neuroendocrine tumours of the gastrointestinal tract often present with metastases and hormonal symptoms. These patients can be palliated by interventional tumour reduction and medical treatment with somatostatin analogues; no effective chemotherapy is available. Radionuclide therapy via somatostatin receptors is one new therapeutic alternative. The recognition that neuroendocrine tumours express specific receptors for growth factors and chemokines, which are of importance for tumour growth, vascularization, and spread, may open the way for new therapeutic approaches. The signalling pathways in carcinoid tumours are incompletely explored. This review summarizes potential new treatment strategies from clinical and experimental studies, e.g. inhibition of angiogenesis, targeting of growth factors or their receptors by tyrosine kinase inhibitors, interference with specific cellular pathways (mTOR, PI3K, RAS/RAF, Notch), and also inhibition of the proteasome and histone deacetylation. Combining targeted therapy with chemotherapy, or using drugs to sensitize for radionuclide therapy, may enhance the treatment outcome.
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| 5. |
- Swärd, Christina, 1967, et al.
(författare)
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Comparison of [177Lu-DOTA0,Tyr3]-octreotate and [177Lu-DOTA0,Tyr3]-octreotide for receptor-mediated radiation therapy of the xenografted human midgut carcinoid tumor GOT1.
- 2008
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 23:1, s. 114-20
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to compare the tumor uptake versus time and the tumor response in nude mice transplanted with a human midgut carcinoid (GOT1), when treated with either [(177)Lu-DOTA(0),Tyr(3)]-octreotide or [(177)Lu-DOTA(0),Tyr(3)]-octreotate and to evaluate if plasma chromogranin A (P-CgA) was a reliable marker of tumor response. The tumor uptake and retention of activity of a single intravenous (i.v.) dose (15 MBq) of [(177)Lu-DOTA(0),Tyr(3)]-octreotate or [(177)Lu-DOTA(0),Tyr(3)]-octreotide were compared in nude mice xenografted with GOT1. The activity concentration 24 hours after injection was significantly higher in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate versus [(177)Lu-DOTA(0),Tyr(3)]-octreotide (16%+/-1.4% of injected activity per gram [%IA/g] vs. 8.1%+/-2.1% IA/g, mean +/- standard error of the mean) (p=0.00061). The mean absorbed dose was higher in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate (46+/-4.3 vs. 17 +/- 3.4 Gy). The reduction of tumor volume was accordingly more prominent in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate than in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotide (p=0.003). The mean tumor volume for animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate was reduced to 3% of its initial value. P-CgA values were strongly correlated with tumor volume. Octreotate seems to be a more suitable somatostatin analog than octreotide for receptor-mediated radiation therapy. P-CgA is a simple, accurate method for the estimation of tumor response in this animal model.
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| 6. |
- Kölby, Lars, 1963, et al.
(författare)
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Can quantification of VMAT and SSTR expression be helpful for planning radionuclide therapy of malignant pheochromocytomas?
- 2006
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923. ; 1073, s. 491-7
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Tidskriftsartikel (refereegranskat)abstract
- Tumor-specific uptake of the radio-iodinated norepinephrine analogue meta-iodobenzylguanidine (MIBG) or uptake of radiolabeled somatostatin analogues via somatostatin receptors (SSTRs) are possibilities to diagnose and treat malignant pheochromocytomas/paragangliomas (PCs/PGs). The aims of this study were to investigate the quantitative expression of vesicular monoamine transporters (VMAT 1, 2) and all five SSTRs in malignant pheochromocytoma/paraganglioma (PC/PG) to evaluate the possibilities for tumor-specific radionuclide therapy. High scintigraphic 123I-MIBG uptake was found in two malignant PGs with high VMAT expression (500-730 copies of VMAT 1, 1,500-1,700 copies of VMAT 2 per 1,000 beta-actin), while no 123I-MIBG uptake was found in the malignant PG with low VMAT expression (330 copies of VMAT 1, 350 copies of VMAT 2 per 1,000 beta-actin). The two patients with high VMAT expression and high 123I-MIBG uptake were treated with 131I-MIBG (2-3x8 GBq). In vitro, the VMAT antagonist, reserpine, and the membrane pump inhibitor, clomipramine, inhibited the uptake of 123I-MIBG into tumor cells equally well (48% and 53% reduction respectively, P<0.001). SSTR2 was the most abundant receptor subtype, but in the two malignant PGs its expression was only 110-260 copies/1,000 beta-actin. The transporters at the cell membrane and in the vesicular membrane both appear to be of importance for the uptake of 123I-MIBG into malignant PC/PG. Quantitative determination of VMAT expression may be helpful in selecting patients suitable for radionuclide therapy with 131I-MIBG. The present data indicate that SSTR-mediated radionuclide therapy will not be effective treatment of malignant PC/PG.
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| 7. |
- Kölby, Lars, 1963, et al.
(författare)
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Successful receptor-mediated radiation therapy of xenografted human midgut carcinoid tumour
- 2005
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Ingår i: British journal of cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 93:10, s. 1144-51
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Tidskriftsartikel (refereegranskat)abstract
- Somatostatin receptor (sstr)-mediated radiation therapy is a new therapeutic modality for neuroendocrine (NE) tumours. High expression of sstr in NE tumours leads to tumour-specific uptake of radiolabelled somatostatin analogues and high absorbed doses. In this study, we present the first optimised radiation therapy via sstr using [(177)Lu-DOTA(0)-Tyr(3)]-octreotate given to nude mice xenografted with the human midgut carcinoid GOT1. The tumours in 22 out of 23 animals given therapeutic amounts showed dose-dependent, rapid complete remission. The diagnostic amount (0.5 MBq [(177)Lu-DOTA(0)-Tyr(3)]-octreotate) did not influence tumour growth and was rapidly excreted. In contrast, the therapeutic amount (30 MBq [(177)Lu-DOTA(0)-Tyr(3)]-octreotate) induced rapid tumour regression and entrapment of (177)Lu so that the activity concentration of (177)Lu remained high, 7 and 13 days after injection. The entrapment phenomenon increased the absorbed dose to tumours from 1.6 to 4.0 Gy MBq(-1) and the tumours in animals treated with 30 MBq received 120 Gy. Therapeutic amounts of [(177)Lu-DOTA(0)-Tyr(3)]-octreotate rapidly induced apoptosis and gradual development of fibrosis in grafted tumours. In conclusion, human midgut carcinoid xenografts can be cured by receptor-mediated radiation therapy by optimising the uptake of radioligand and taking advantage of the favourable change in biokinetics induced by entrapment of radionuclide in the tumours.
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| 8. |
- Kölby, Lars, 1963, et al.
(författare)
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Chromogranin A as a determinant of midgut carcinoid tumour volume
- 2004
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Ingår i: Regulatory peptides. - : Elsevier BV. - 0167-0115. ; 120:1-3, s. 269-73
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Tidskriftsartikel (refereegranskat)abstract
- Neuroendocrine (NE) tumours are characterized by their capacity to synthesize, store and release hormonal products. These substances are stored in neurosecretory vesicles together with chromogranin A (CgA). The concentration of plasma CgA in patients with NE tumours is thought to reflect the degree of NE differentiation, total tumour burden and effect of medical treatment. The aim of this study was to analyse the correlation between tumour weight and plasma CgA levels as well as the influence of treatment with a long-acting somatostatin analogue (octreotide) using nude mice with xenografted human ileal carcinoid tumours. There was a correlation between tumour weight and plasma CgA levels in all animals (p < 0.00001). In octreotide-treated mice, plasma CgA levels were significantly reduced versus untreated animals (p = 0.037). In conclusion, this study demonstrates that plasma CgA levels are closely correlated to tumour burden, and that plasma CgA is well suited for monitoring the clinical course and outcome of treatment in patients with NE tumours.
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| 9. |
- Nilsson, Ola, 1957, et al.
(författare)
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GOT1 xenografted to nude mice: a unique model for in vivo studies on SSTR-mediated radiation therapy of carcinoid tumors
- 2004
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Ingår i: Annals of the New York Academy of Sciences. - 0077-8923. ; 1014, s. 275-9
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Tidskriftsartikel (refereegranskat)abstract
- Malignant carcinoid tumors express high numbers of somatostatin receptors. Radiation therapy using labeled somatostatin analogs is a novel treatment modality for these tumors. We have analyzed the biokinetics and therapeutic effect of radiolabeled somatostatin analog on a human midgut carcinoid grafted to nude mice. A transplantable human midgut carcinoid (GOT1) was grafted to the back of nude mice. Tumor-bearing mice were injected with (111)In-DTPA-D-Phe(1)-octreotide, followed by measurement of (111)In activity concentration ratios in tumor tissues. Tumor-bearing mice were also injected with (177)Lu-DOTA-Tyr(3)-octreotate and followed for 7 days. The concentration of (111)In-DTPA-D-Phe(1)-octreotide in tumor tissues was very high 4 hours postinjection with 0.4-13% of injected activity per gram. Injection of 30-120 MBq (177)Lu-DOTA-Tyr(3)-octreotate reduced tumor volume to 7-14% of the original tumor volume 7 days postinjection. Microscopic analysis of treated tumors revealed widespread areas of tumor cell necrosis and fibrosis. It was found that grafted GOT1 cells to nude mice represent an authentic model for studying human midgut carcinoids. Radiolabeled somatostatin analogs have a high selectivity for tumor tissue and can induce tumor cell necrosis. Radiotherapy of carcinoid tumors with (177)Lu-DOTA-Tyr(3)-octreotate appears to be a promising treatment modality for either palliative treatment or completion therapy after attempted surgical cure.
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