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- Almstedt, Elin, 1988-
(författare)
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New targeted therapies for malignant neural tumors : From systematic discovery to zebrafish models
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancers in the neural system presents a major health challenge. The most aggressive brain tumor in adults, glioblastoma, has a median survival of 15 months and few therapeutic options. High-risk neuroblastoma, a childhood tumor originating in the sympathetic nervous system, has a 5-year survival under 50%, despite extensive therapy. Molecular characterization of these tumors has had some, but so far limited, clinical impact. In neuroblastoma, patients with ALK mutated tumors can benefit from treatment with ALK inhibitors. In glioblastoma, molecular subgroups have not yet revealed any subgroup-specific gene dependencies due to tumor heterogeneity and plasticity. In this thesis, we identify novel treatment candidates for neuroblastoma and glioblastoma. In paper I, we discover novel drug targets for high-risk neuroblastoma by integrating patient data, large-scale pharmacogenomic profiles, and drug-protein interaction maps. Using a novel algorithm, TargetTranslator, we identify more than 80 targets for this patient group. Activation of cannabinoid receptor 2 (CNR2) or inhibition of mitogen-activated protein kinase 8 (MAPK8) reduces tumor growth in zebrafish and mice models of neuroblastoma, establishing TargetTranslator as a useful tool for target discovery in cancer. In paper II, we screen approximately 1500 compounds across 100 molecularly characterized cell lines from patients to uncover heterogeneous responses to drugs in glioblastoma. We identify several connections between pathway activities and drug response. Sensitivity to proteasome inhibition is linked to oxidative stress response and p53 activity in cells, and can be predicted using a gene signature. We also discover sigma receptors as novel drug targets for glioblastoma and find a synergistic vulnerability in targeting cholesterol homeostasis.In paper III, we systematically explore novel targets for glioblastoma using an siRNA screen. Downregulation of ZBTB16 decreases cell cycle-related proteins and transcripts in patient-derived glioblastoma cells. Using a zebrafish assay, we find that ZBTB16 promotes glioblastoma invasion in vivo. In paper IV, we characterized the growth of seven patient-derived glioblastoma cell lines in orthotopic zebrafish xenografts. Using automated longitudinal imaging, we find that tumor engraftment strongly correlates with tumor initiation capacity in mice xenografts and that the heterogeneous response to proteasome inhibitors is maintained in vivo. In summary, this thesis identifies novel targets for glioblastoma and neuroblastoma using systematic approaches. Treatment candidates are evaluated in novel zebrafish xenograft models that are developed for high-throughput glioblastoma and neuroblastoma drug evaluation. Together, this thesis provides promising evidence of new therapeutic options for malignant neural tumors.
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| 4. |
- Backman, Samuel, 1994-
(författare)
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Molecular studies of endocrine tumors : Insights from genetics and epigenetics
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Endocrine tumors may be benign or malignant and may occur in any of the hormone producing tissues. They share several biological characteristics, including a low mutation-burden, and may co-occur in several hereditary tumor syndromes. The aim of this thesis was to identify genetic and epigenetic aberrations in endocrine tumors.In paper I we performed a comprehensive DNA methylation analysis of 39 pheochromocytomas/paragangliomas as well as 4 normal adrenal medullae on the HumanMethylation27 BeadChip array. We validated two previously described clusters based on DNA methylation with distinct genetic associations.In Paper II we performed a transcriptomic analysis of 15 aldosterone producing adenomas. CTNNB1-mutated tumors were found to form a distinct subgroup based on gene expression and to share gene expression similarities with non-aldosterone producing adrenocortical tumors with CTNNB1 mutations, including overexpression of AFF3 and ISM1.In paper III we used whole genome sequencing to identify germline genetic variants in 14 patients with Multiple Endocrine Neoplasia type 1 previously found to be wildtype for the MEN1 gene on routine clinical testing. Three patients were found to carry previously undetected MEN1 mutations. Two patients were confirmed to have phenocopies caused by variants affecting CASR or CDC73. In total 9/14 patients were not found to have a disease-causing germline variant, suggesting that the syndrome may in some cases be due to chance co-occurrence of several sporadic tumors.In paper IV RNA-Seq and whole genome sequencing of a cohort of SI-NETs selected on the basis of unusually short or long survival was performed in order to identify disease causing genes and potential prognostic factors. We confirmed known genetic aberrations and found rare variants in known cancer driver genes. Based on gene expression two clusters that differ in prognosis were detected. Moreover, through integration of copy number variation data and gene expression, we identied novel potential disease causing genes.
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| 5. |
- Hayden, Jane M.
(författare)
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The effect of intra-abdominal local anaesthetics following major gynaecological surgery. Clinical and experimental studies
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Local anaesthetics (LA), in addition to inhibition of pain signalling, also have anti-inflammatory properties. In vitro studies have demonstrated anti-proliferative and cytotoxic effect of LAs on cancer cells when administered in therapeutic concentrations. Intraperitoneal administrated LA is shown to reduce pain, improve surgical recovery and to blunt the postsurgical inflammatory response. Retrospective studies have indicated beneficial oncological outcome of regional anaesthesia on cancer recurrence when used in cancer surgery. Abdominal hysterectomy causes moderate to severe pain, and assessing new tools for pain treatment is crucial. The postoperative period of extensive surgery for advanced ovarian cancer is associated with high morbidity. When the patients have recovered from cancer surgery, chemotherapy can be initiated. New therapeutic approaches to enhanced recovery with reduced postoperative pain and inflammation is of great interest. Methods and aim: The thesis aimed to evaluate the efficacy of intra-abdominal local anaesthetics on pain, inflammatory response, serum concentration of LA and patient recovery after gynaecological surgery (study I, II and III). The aim of study IV was to determine the effects of LA on ovarian cancer cells in vitro. The clinical studies were prospective, double blind, randomized and placebo-controlled. In study I, women scheduled for abdominal hysterectomy, were randomised to local infiltration analgesia (Group LIA) or placebo (group C). Rescue analgesic consumption and opioid related side effects were analysed. In study II and III, women undergoing cytoreductive surgery for advanced ovarian cancer were randomised to receive either intraperitoneal ropivacaine (Group IPLA) or saline (Group Control) peroperatively. Inflammatory markers in serum, LA concentrations (study II), and objective measures of patient comfort, postoperative complications, pain, home readiness and time to initiation of chemotherapy (study III) were analysed. In study IV proliferation and migration in two ovarian cancer cell lines, exposed to LA in concentrations corresponding to doses used in study II and III, were analysed. Analysis of cancer stem cells (CSC) phenotypes were performed. Results: The median supplemental requirements of morphine during 0–24 hours after abdominal hysterectomy was significantly lower in group LIA compared to group C (18 mg vs. 27 mg, p = 0.028) and the median time to first analgesic injection was significantly longer in group LIA (40 min vs. 20 min, p = 0.005) (Study I). Perioperative intraperitoneal LA resulted in significantly decreased serum cortisol levels. Serum concentrations of ropivacaine were well below toxic concentrations (study II). Time to initiation of chemotherapy was significantly shorter in group IPLA (Median 21, IQR 19-29 vs. 29 days, IQR 21-40, p = 0.021). No differences in standardised recovery endpoints were found between the groups (Study III) . The laboratory study showed a significantly reduced cell number and an inhibited cell migration. Cell size were significantly increased and CSC phenotype analysis showed a reduction in all cells by up to 50% (Study IV). Discussion: Local infiltration analgesia results in a significantly lower rescue morphine consumption following abdominal hysterectomy. Intraperitoneal local anestetics can be administered in ovarian cancer cytoreductive surgery safely, without achieving toxic doses. Although IPLA do not provide further anti-inflammatory effects, the stress response is briefly blunted and there might be positive effects such as earlier start of chemotherapy. LA reduce the ability of cancer cells to metastasise. Intra-abdominal LA offers a potential to have beneficial effects on pain, recovery and circulating tumour cells after gynaecological surgery.
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| 6. |
- Rosenblatt, Robert, 1982-
(författare)
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Neoadjuvant chemotherapy in muscle-invasive urinary bladder cancer : studies on treatment response, tumor draining lymph nodes and blood transfusion
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Muscle-invasive urinary bladder cancer is a deadly disease. Mortality rates remained unchanged for decades despite radical surgery.After several randomized trials, we today know that cisplatin based chemotherapy given prior to cystectomy, improves survival for every tenth patient. Markers that predict responsiveness to chemotherapy would spare unnecessary treatment to the majority of patients. In the search for signs of chemosensitivity, we performed a retrospective analysis of the Nordic cystectomy trials 1 & 2: Chemo treated patients had an almost doubled increase in tumor downstaging compared to the controls. More importantly, this group presented with a reduced absolute risk of death of more than 30% compared to the rest of the patients. These results were presented in paper I.Many cancers spread through the lymphatic system. Usually, there is at least one tumor draining lymph node, referred to as the sentinel node. If this node is free of metastases, there is no lymphatic spread of the disease, and consequently, no use of excavating all neighboring lymph nodes.Sentinel node detection, is an established method in breast cancer, penile cancer and malignant melanoma. Based on the same principles, members of our group developed a similar detection technique in bladder cancer. Unfortunately, sensitivity and specificity were too low to rely on this method as a diagnostic tool for lymphatic spread. Instead, it turned out in recent years that sentinel nodes in muscle invasive bladder cancer are valuable for translational research-lines - mainly in tumor immunology. As for example, sentinel nodes contain tumor specific T cells that are useful in adoptive immunotherapy.In paper II, we set out to test whether sentinel node detection was feasible after chemotherapy and/or tumor downstaging. In a prospective cohort of patients, we saw no difference in detection rates between the groups. Thus, we concluded, neither chemotherapy nor downstaging appeared to hamper the identification of sentinel nodes.The concept was expanded in paper III. After recruiting more patients to the cohort mentioned above, the average numbers of sentinel nodes in different categories of patients were compared. We saw a pattern of decreased number of sentinel nodes in those with locally advanced tumors. It seemed that the number of sentinel nodes had prognostic implications.In the last study, published in paper IV, we wanted to widen our knowledge on the clinical effects of blood transfusion. Mounting data suggests that perioperative blood products have a negative impact on long term survival after cancer surgery. How much allogenic blood was given during the chemotherapy prior to surgery ? It turned out that one third of the bladder cancer patients received blood, and these patients demonstrated a significantly worse overall survival.Neoadjuvant chemotherapy has added a new beneficial dimension to the treatment of muscle invasive bladder cancer. In these four studies, we addressed the effects of chemotherapy on pathoanatomical outcomes, on tumor lymphatics and further; we are suggesting consequences of neoadjuvant chemotherapy in conjunction with blood transfusion. It appears that the immune system is involved in all aspects investigated above. Most likely, an improved scientific understanding of the immune system will be crucial for future bladder cancer treatment options.
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| 8. |
- Bjerg, Anders, et al.
(författare)
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Shorter time to clinical decision in work-related asthma using a digital tool
- 2020
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Ingår i: ERJ open research. - Lausanne, Switzerland : European Respiratory Society (ERS). - 2312-0541. ; 6:3
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- PEF curves are a useful but cumbersome tool in diagnosing work-related asthma. Using a digital spirometer and smartphone app, time to clinical decision could be shortened by 6-7 weeks. Physician's time spent analysing PEF data is also shortened.
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| 10. |
- Lindström, Jonathan
(författare)
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Modelling the evolution of treatment-induced resistance in Ph+ leukaemias
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Targeted therapies are a mainstay of modern cancer treatments. Rather than harming rapidly dividing cells in general, targeted therapies work by directly interfering with oncogenic molecular pathways present in a tumour. Consequently, a targeted therapy typically has less severe side effects. However, specificity comes at a price as comparatively small changes to the target can render the treatment ineffective. Much like the natural selection among plants and animals, individual cancer cells compete with one another for space and resources. Hence, if a single cancer cell acquires a resistance adaptation, the forces of evolution can turn that advantage in a single cell into an untreatable resistant cancer.This thesis is principally concerned with chronic myeloid leukaemia (CML), characterized by a chromosomal translocation called the Philadelphia chromosome which creates the constitutively active tyrosine kinase Bcr-Abl1. The discovery of tyrosine kinase inhibitors (TKIs) targeting Bcr-Abl1 greatly improved treatment outcomes. Eventually however, resistance emerges. An important mechanism in CML is mutations in the kinase domain of Bcr-Abl1 that affect how well the drugs bind. A number of drugs have been developed that target the mutated kinase to varying degrees, but it is still desirable to prevent drug resistance from occurring in the first place, as the accumulation of multiple mutations is almost certain to create untreatable resistance.The fitness effects of a drug resistance adaptation depend on the drug treatment, so it may be possible to alter the fitness landscape by modifying the treatment. This work examines different approaches, mainly in CML, to delay or prevent the onset of resistance through modifying the treatment protocol.Periodically switching between different TKIs, i.e. drug rotations, was shown through modelling to increase the expected time to resistance and seems to have some protective benefits in vitro. Also apparently promising were drug combinations involving a novel inhibitor asciminib, currently in phase III trials, which can reduce overall drug burden while also being seemingly effective against known resistance mutations. Finally, a model of the interaction between resistance mutations and less potent alternate resistance mechanisms revealed how a drug holiday may have resensitizing, or even beneficial effects.
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