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- 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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| 3. |
- Sandblom, Viktor, 1987, et al.
(författare)
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Gemcitabine potentiates the anti-tumour effect of radiation on medullary thyroid cancer.
- 2019
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Ingår i: PloS One. - : Public Library of Science (PLoS). - 1932-6203. ; 14:11
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Tidskriftsartikel (refereegranskat)abstract
- Patients with medullary thyroid cancer (MTC) are often diagnosed with spread tumour disease and the development of better systemic treatment options for these patients is important. Treatment with the radiolabelled somatostatin analogue 177Lu-octreotate is already a promising option but can be optimised. For example, combination treatment with another substance could increase the effect on tumour tissue. Gemcitabine is a nucleoside analogue that has been shown to sensitise tumour cells to radiation. The aim of this study was to investigate potentially additive or synergistic effects of combining radiation with gemcitabine for treatment of MTC. Nude mice transplanted with patient-derived MTC tumours (GOT2) were divided into groups and treated with radiation and/or gemcitabine. Radiation treatment was given as 177Lu-octreotate or external beam radiotherapy (EBRT). The volume of treated and untreated tumours was followed. The absorbed dose and amount of gemcitabine were chosen to give moderate tumour volume reduction when given as monotherapy to enable detection of increased effects from combination treatment. After follow-up, the mice were killed and tumours were immunohistochemically (IHC) analysed. Overall, the animals that received a combination of EBRT and gemcitabine showed the largest reduction in tumour volume. Monotherapy with EBRT or gemcitabine also resulted in a clear detrimental effect on tumour volume, while the animals that received 177Lu-octreotate monotherapy showed similar response as the untreated animals. The GOT2 tumour was confirmed in the IHC analyses by markers for MTC. The IHC analyses also revealed that the proliferative activity of tumour cells was similar in all tumours, but indicated that fibrotic tissue was more common after EBRT and/or gemcitabine treatment. The results indicate that an additive, or even synergistic, effect may be achieved by combining radiation with gemcitabine for treatment of MTC. Future studies should be performed to evaluate the full potential of combining 177Lu-octreotate with gemcitabine in patients.
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| 4. |
- Sandblom, Viktor, 1987, et al.
(författare)
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Local treatment of liver metastases by administration of 177Lu-octreotate via isolated hepatic perfusion – A preclinical simulation of a novel treatment strategy
- 2019
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Ingår i: Surgical Oncology. - : Elsevier BV. - 0960-7404. ; 29, s. 148-156
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Tidskriftsartikel (refereegranskat)abstract
- Introduction. Systemic 177Lu-octreotate treatment for metastatic neuroendocrine tumours is restricted by organs at risk. By administering 177Lu-octreotate during isolated hepatic perfusion (IHP), the uptake in organs at risk might be strongly reduced. The aim of this study was to investigate the feasibility to use the combination of IHP and radionuclide therapy. Methods. To simulate IHP, the liver of a pig was prepared for ex vivo perfusion. Blood containing 490 MBq 177Lu-octreotate was circulated through the liver for 60min, after which the liver was rinsed. After IHP, the liver was examined by SPECT/CT. Lastly, an intraoperative gamma detector (IGD) was used to determine 177Lu activity concentration in the liver and results were compared with the activity concentration in corresponding liver biopsies. Results. Detector measurements over the liver during the IHP showed a fast increase with a maximum after approximately 10–15min. After IHP, about 75% of the 177Lu in the liver could be washed out. The SPECT/CT images revealed a relatively inhomogeneous distribution. Nevertheless, the IGD values of 177Lu activity concentration showed acceptable agreement with the biopsy values. Conclusions. Our results in pig show that it could be feasible to treat patients with liver metastases from NETs with 177Lu-octreotate via IHP 177. However, an inhomogeneous distribution of 177Lu-octreotate in normal liver tissue is expected, and in order to determine the activity concentration with satisfactory accuracy using an IGD, measurements need to be performed at several positions over the liver.
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| 5. |
- Sandblom, Viktor, 1987
(författare)
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Strategies for optimisation of 177Lu-octreotate therapy – exploring local administration and combination therapy regimens
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroendocrine tumours (NETs) are a group of heterogeneous tumour types that originate in hormone-producing organs. Patients with NETs are often diagnosed after the primary tumour has metastasised. One treatment option for these patients that has shown very promising results is systemic treatment using the radiolabelled somatostatin analogue 177Lu-octreotate. However, the outcome of this treatment is currently restricted by healthy organs at risk. The aim of this work was to optimise 177Lu-octreotate therapy of NETs by investigating strategies based on local administration and on combination therapy regimens. The feasibility of local treatment of liver metastases was evaluated by administering 177Lu-octreotate via isolated hepatic perfusion (IHP) in a pig animal model. During IHP, the liver was completely isolated from the systemic circulation. An intraoperative gamma detector was evaluated for the purpose of determining 177Lu activity concentration in vivo during treatment. This detector was also evaluated by assessment of its technical performance parameters using phantoms. In summary, the results showed that it could be feasible to treat patients with liver metastases from NETs with 177Luoctreotate via IHP. A relatively inhomogeneous uptake was obtained and to accurately quantify 177Lu activity concentration using an intraoperative gamma detector, measurements may need to be performed at several positions over the liver. In the combination therapy experiments, nude mice transplanted with NETs were treated with radiation therapy alone (as 177Lu-octreotate or external beam radiotherapy) and in combination with one of the drugs gemcitabine, vandetanib, cabozantinib, or ganetespib. After treatment, tumour volume was followed and compared with that in control mice. Overall, combination treatment resulted in the largest decrease in tumour volume and the longest time to progression. The results indicated that additive, and sometimes synergistic, effects could be obtained when combining 177Luoctreotate with another drug for treatment of patients with NETs.
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| 7. |
- Sandblom, Viktor, 1987, et al.
(författare)
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Tyrosinkinashämmare kan öka effekten från strålbehandling av medullär tyreoideacancer
- 2019
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Ingår i: Nationellt möte om sjukhusfysik.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- SYFTE Medullär tyreoideacancer (MTC) är en neuroendokrin cancertyp som har sitt ursprung i sköldkörtelns hormonproducerande C-celler. Många MTC överuttrycker receptorer för somatostatin vilket möjliggör radionuklidterapi med exempelvis 177Lu-oktreotat. Få patienter botas dock helt och optimering av behandlingen behövs. Ett sätt att optimera behandlingen är att kombinera 177Lu-oktreotat med ett annat läkemedel i syfte att öka effekten från strålningen. Nyligen godkändes två tyrosinkinashämmare (vandetanib och cabozantinib) för behandling av MTC. Syftet med denna studie var att undersöka ifall en ökad effekt kan fås då strålbehandling kombineras med tyrosinkinashämmare för behandling av MTC. METOD Nakna möss (BALB/c) transplanterades med humana MTC-celler (GOT2) och behandlades med extern strålbehandling och/eller tyrosinkinashämmare. Behandlings-effekten, som tumörvolym efter behandling, jämfördes med den hos obehandlade möss. För att möjliggöra detektion av en eventuellt ökad behandlingseffekt hos de möss som fick kombinationsbehandling (både strålbehandling och tyrosinkinas¬hämmare) valdes den absorberade dosen och mängden läkemedel så att en suboptimal effekt erhölls då respektive behandling gavs som singelbehandling. RESULTAT Kombinationsbehandling resulterade i störst minskning av tumörvolym och längst tid till progression. Exempelvis hade tumörvolymen hos de möss som fick kombinationsbehandling minskat med ca 70-75% efter två veckor jämfört med obehandlade möss. Även som singelbehandling resulterade båda behandlingar i en tydlig effekt på tumörvolymen, med en minskning på ca 50-65% efter två veckor. KONKLUSIONER Effekten från strålbehandling av möss med MTC-tumörer kan ökas genom kombinationsbehandling med tyrosinkinashämmare. Framtida studier bör utvärdera möjligheten att använda en kombination av 177Lu-oktreotat och tyrosinkinashämmare för behandling av patienter med MTC.
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