| 1. |
|
|
| 2. |
- Dalmo, Johanna, et al.
(author)
-
Priming increases the anti-tumor effect and therapeutic window of 177Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1.
- 2017
-
In: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 7:1
-
Journal article (peer-reviewed)abstract
- BACKGROUND: 177Lu-[DOTA0, Tyr3]-octreotate (177Lu-octreotate) is used for treatment of patients with somatostatin receptor (SSTR) expressing neuroendocrine tumors. However, complete tumor remission is rarely seen, and optimization of treatment protocols is needed. In vitro studies have shown that irradiation can up-regulate the expression of SSTR1, 2 and 5, and increase 177Lu-octreotate uptake. The aim of the present study was to examine the anti-tumor effect of a 177Lu-octreotate priming dose followed 24 h later by a second injection of 177Lu-octreotate compared to a single administration of 177Lu-octreotate, performed on the human small intestine neuroendocrine tumor cell line, GOT1, transplanted to nude mice. RESULTS: Priming resulted in a 1.9 times higher mean absorbed dose to the tumor tissue per administered activity, together with a reduced mean absorbed dose for kidneys. Priming gave the best overall anti-tumor effects. Magnetic resonance imaging showed no statistically significant difference in tumor response between treatment with and without priming. Gene expression analysis demonstrated effects on cell cycle regulation. Biological processes associated with apoptotic cell death were highly affected in the biodistribution and dosimetry study, via differential regulation of, e.g., APOE, BAX, CDKN1A, and GADD45A. CONCLUSIONS: Priming had the best overall anti-tumor effects and also resulted in an increased therapeutic window. Results indicate that potential biomarkers for tumor regrowth may be found in the p53 or JNK signaling pathways. Priming administration is an interesting optimization strategy for 177Lu-octreotate therapy of neuroendocrine tumors, and further studies should be performed to determine the mechanisms responsible for the reported effects.
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
- Spetz, Johan, et al.
(author)
-
Effects of internal irradiation from 177Lu-octreotate on transcriptional expression in GOT1 midgut carcinoid in nude mice
- 2014
-
In: SweRays Workshop, Malmö, Sweden, Aug 20-22.
-
Conference paper (other academic/artistic)abstract
- Introduction: Neuroendocrine (NE) tumors expressing somatostatin receptors (SSTR) are often treated with 177Lu-octreotate. The treatment is highly successful in animal models, but low cure rates in clinical studies suggests optimization of treatment protocol is needed. Little is known about which cellular responses play a crucial role in neuroendocrine tumors after irradiation. It is therefore important to identify the effects of 177Lu-octreotate on biological functions for future optimization of treatment parameters and the identification of biomarkers predicting treatment response. The aim of this study was to investigate the transcriptional response of GOT1 midgut carcinoid in nude mice following 177Lu-octreotate treatment. Methods: GOT1 bearing BALB/c nude mice were i.v. injected with 15 MBq 177Lu-octreotate and tumor size was measured twice a week using calipers. Animals were killed after 1, 3, 7 or 41 days and tumor samples excised and snap frozen in liquid nitrogen. Total RNA was extracted from tumor samples and subjected to Illumina microarray expression analysis. Differential transcriptional profiles were identified by comparing treated and untreated tumor samples using Nexus Expression 3.0 software. Associated biological functions and biological pathways (according to Gene Ontology terms) were compared using Nexus Expression 3.0 and Ingenuity IPA. Results: The mean tumor volume was clearly reduced after 177Lu-octreotate treatment. Microarray analysis showed clear difference in regulation pattern between the time points. The analysis of associated biological functions revealed clear effect on cell death and survival, and cell cycle after 1, 3, and 7 days, while cellular movement and cellular development were clearly influenced after 41 days. Cellular growth and proliferation was also affected after 1 day but not at the other time points studied. Conclusions: : Analysis of the transcriptional regulation in GOT1 tumors in nude mice following 177Lu-octreotate treatment revealed responses in different cellular functions that were distinct for each time point. These findings indicate potential venues for increasing clinical effectiveness of midgut carcinoid therapy with 177Lu-octreotate.
|
|
| 7. |
|
|
| 8. |
- Spetz, Johan, et al.
(author)
-
Fractionated 177Lu-octreotate therapy of human GOT1 tumors in nude mice increases treatment efficacy, possibly via SSTR up-regulation
- 2014
-
In: 3rd Swedish Cancer Research Meeting, Stockholm, Sweden, September 2-3, 2014.
-
Conference paper (other academic/artistic)abstract
- Introduction: The radiolabelled somatostatin analogue 177Lu-octreotate is a promising treatment option for malignant neuroendocrine tumors that overexpress somatostatin receptors. The human midgut carcinoid GOT1 cell line has shown promising treatment response to 177Lu-octreotate in xenografted mice. In clinical studies, however, only low cure rates have been achieved to date. In vitro and preclinical in vivo studies have shown that irradiation can up-regulate the expression of somatostatin receptors and thereby give an increased uptake of 177Lu-octreotate. The cellular processes that underlie positive treatment response to 177Lu-octreotate are otherwise largely unknown. Genome-wide analysis of tumor cell responses in this successful mouse model offers a venue to identify critical treatment parameters and to optimize clinical effectiveness of 177Lu-octreotate therapy. Aim: To investigate the genome-wide transcriptional response of xenografted GOT1 midgut carcinoid after fractionated treatment giving a priming administration before the main administration of 177Lu-octreotate. Methods: GOT1 bearing BALB/c nude mice were i.v. injected with 5, 10, 15 or 30 MBq 177Lu-octreotate. The groups receiving 5 and 10 MBq 177Lu-octreotate were given an additional 10 or 5 MBq 177Lu-octreotate 24 h after the first injection, respectively. Control animals were injected with NaCl. Animals were killed after 1, 3, 7 or 41 days for the 5+10, 10+5 and 15 MBq treatments and controls and after 41 days for the 30 MBq treatment. Tumor samples were excised and snap frozen in liquid nitrogen, followed by total RNA extraction. Microarray analysis was performed on samples from treated animals and untreated controls (Illumina HumanHT-12 Beadchips) and differentially regulated transcripts were identified (change, ≥1.5-fold; P-adjusted < 0.05). Associated biological functions and affected biological pathways (according to Gene Ontology terms, P-adjusted < 0.05) were analyzed using Nexus Expression and Ingenuity IPA. Results: The mean tumor volume was clearly reduced after 177Lu-octreotate treatment in all groups. The mean absorbed dose to the tumor tissue was almost 110 % higher for the 5+10 MBq than for the 15 MBq group. The best overall therapeutic effects were obtained in the 5+10 MBq group. Microarray analysis showed clear differences in transcriptional response between treated groups and time points. Affected associated biological processes were e.g. cell death and survival, and cell cycle regulation after 1, 3, and 7 days; cellular movement and cellular development were influenced after 41 days. Cellular growth and proliferation was affected after 1 day but not at later time points. Conclusions: Microarray analysis of 177Lu-octreotate-induced effects in xenografted GOT1 tumors showed distinct differences in transcriptional responses and associated cellular functions, both with regard to treatment fractionation and time-of-response. The use of priming activity offers a new venue for increasing clinical effectiveness of 177Lu-octreotate therapy of midgut carcinoid tumors, probably due to increased somatostatin receptor expression.
|
|
| 9. |
- Spetz, Johan, et al.
(author)
-
Hedgehog inhibitor Sonidegib potentiates 177Lu-octreotate therapy of GOT1 human small intestine neuroendocrine tumors in nude mice
- 2015
-
In: Cancerfondens riksplaneringsgrupp för onkologisk radionuklidterapi, Höstmöte, Linköping, Sweden, November 25-27, 2015.
-
Conference paper (other academic/artistic)abstract
- Background: 177Lu-octreotate is commonly used for treatment of patients with somatostatin receptor (SSTR) expressing neuroendocrine (NE) tumors. It is a highly successful treatment in animal models (e.g. the human midgut carcinoid cell line GOT1 transplanted to nude mice) although clinical studies have still only demonstrated low cure rates. In order to overcome treatment resistance, combination therapy has been proposed and some studies have shown synergistic effects (radiosensitizing). The Hedgehog signaling pathway is involved in normal embryo development, and remains important in the adult. Abnormal activation of the hedgehog pathway has been implicated in the development of cancers in various organs. Hedgehog inhibitors have previously shown therapeutic effect in NE tumors and might be one venue to enhance the effect from 177Lu-octreotate therapy. The aim of this study was to determine the therapeutic effect of combination therapy of GOT1 tumors using 177Lu-octreotate and the hedgehog signalling pathway inhibitor Sonidegib. Methods: GOT1 bearing BALB/c nude mice were divided into three groups with five mice in each group. The groups were treated with either Sonidegib (80 mg/kg twice a week via oral gavage), or 30 MBq 177Lu-octreotate i.v., or a combination of both. Tumor size was measured twice a week using calipers. Animals were killed 41 days after injection and tumors were excised. Samples from each tumor were snap frozen and total RNA was extracted and subjected to microarray analysis. Gene expression patterns and associated biological functions were compared to untreated controls using Nexus Expression 3.0, IPA, and Gene Ontology terms. Results: The mean tumor volume was clearly reduced after 177Lu-octreotate and combination treatment, while Sonidegib treatment alone resulted in a stable mean tumor volume over time. This difference was statistically significant up to more than 20 days after injection, when the tumors in the 177Lu-octreotate and combination treatment groups began to re-grow. The microarray analysis demonstrated a more profound effect on transcript regulation in the combination treatment group than in the other treatment groups. Conclusions: Comparisons between treatment groups show that combination therapy could be beneficial to patients with NE-tumors. Substantial differences in gene expression suggest a synergistic effect on cellular tumor functions at late time points following combination therapy. Further studies should be performed to optimize protocols for combination therapy with these drugs.
|
|
| 10. |
|
|
