Doctoral Theses from Sahlgrenska Academy

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Browsing Doctoral Theses from Sahlgrenska Academy by Subject "177Lu-octreotate"

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    Biomarker discovery and assessment for prediction of kidney response after 177Lu-octreotate therapy
    (2014-11-28) Schüler, Emil
    Patients suffering from neuroendocrine tumors are oftentimes presented with spread disease at the time of diagnosis. Therapy using somatostatin analogs is today the only potentially curative treatment option for these patients. However, the kidneys are the dose-limiting organs in this type of therapy and the biological impact from radiopharmaceutical treatment is not fully understood. Furthermore, considering the large inter-individual variations in renal absorbed dose and toxicity, biomarkers for radiation damage would be of great significance in this type of therapy. The aims of this project were to study the normal kidney tissue response in vivo in mice following 177Lu and 177Lu-octreotate administration, to identify potential biomarkers following 177Lu exposure and evaluate their dependencies of absorbed dose, dose-rate, and time after injection, and to correlate these results with functional and morphological effects. The injected activity ranged between 0.3 and 150 MBq following 177Lu/177Lu-octreotate administration and the biological effect was investigated between 15 minutes and one year after administration. Transcriptional and miRNA variations were studied using microarray analysis and protein expression was investigated using mass spectrometry. Correlations between the transcriptional and protein variations were performed with functional parameters, as determined by 99mTc-DTPA/99mTc-DMSA scintigraphy, and with the morphological effects following 177Lu-octreotate administration. The number of differentially regulated transcripts following 177Lu/177Lu-octreoate administration was dependent on absorbed dose, dose-rate, time after injection, and tissue (kidney cortex or medulla) investigated. No transcript was found to be differentially regulated at all exposure conditions. The most recurrently regulated genes were the Serpina10 gene in kidney cortex, and the Egr1, Pck1, and Hmgcs2 genes in kidney medulla. Substantial differences in response were found between 177Lu-octreotate and 177LuCl3. Concerning the miRNA and protein data, a high absorbed dose-specificity was found, with few miRNAs/proteins found recurrently regulated at most exposure conditions. The transcriptional analyses showed a strong and diverse transcriptional response and the functional analyses revealed clear negative effects on renal function, with enhanced negative effects with absorbed dose and time after administration. Several potentially useful biomarkers were detected at the transcriptional level, markers with potential applicability in early prediction of late renal injury after 177Lu/177Lu-octreotate exposure.
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    Multiparametric MRI for evaluation of tumour treatment response
    (2016-11-18) Montelius, Mikael
    Clinical assessment of tumour response to treatment largely relies on estimates of tumour size by, e.g., measuring the largest tumour diameters on magnetic resonance (MR) or computed tomography (CT) images, weeks or months after treatment. However, most tumours are heterogeneous, and treatment may result in different effects in different parts of the tumour. Therefore, non-invasive methods sensitive to biological effects that precede changes in tumour size would improve our understanding of tumour biology and therapeutic effects, facilitate personalized treatments and speed up development of anti-cancer therapeutics. MR methods have the potential to provide non-invasive imaging biomarkers of the relevant tumour biology, but the understanding of the information provided by MR methods is still limited. The aim of this project to was to improve the understanding and evaluate the feasibility of multiparametric MR methods for therapy response assessment of tumours after radionuclide therapy. Mice xenografted with human neuroendocrine tumours received 15 MBq 177Lu-octreotate i.v. on day 0, and MR imaging experiments were performed on days -1, 1, 3, 8 and 13, using dynamic contrast enhanced-, quantitative T1 and T2*- and diffusion weighted MR on a 7T small animal MR system. Optimization studies were performed to improve tissue model parameter estimates, and to ensure accurate MR based tumour volume estimation for response verification. MR parameter maps were spatially registered to corresponding histologically stained tumour section for correlation analysis, and tumour tissue samples were analysed using quantitative proteomics. Several statistically significant correlations were found between MR parameters and histological tumour characteristics, as well as with proteins associated with radiobiological effects on tumours, and collectively evaluated they provided information on apoptotic and proliferative activity, microvascular density and fibrosis in tumours, which are all important prognostic tumour characteristics. Spatial and temporal MR parameter variations before and after therapy seem to be predictive of tumour shrinkage or stabilization. Most effects on MR parameters were seen already one day after treatment initiation. This work demonstrates the feasibility of multiparametric MR for therapy response assessment in an animal tumour model, and highlights the importance of spatial and temporal evaluation of the MR parameters. Future efforts should include improvement of methods for spatial registration of in vivo MR images and ex vivo histological sections. For clinical applications, MR acquisition times need to be reduced.
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    Strategies for optimisation of 177Lu-octreotate therapy – exploring local administration and combination therapy regimens
    (2019-04-12) Sandblom, Viktor
    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.