Bakgrund: Prostatacancer är idag den vanligaste cancerformen i Sverige ochvanligaste cancerrelaterade dödsorsaken. Personer med prostatacancer påverkas i sinsexuella hälsa på ett multifaktoriellt sätt av cancerbehandlingen och dess biverkningar.Motiv: Boende i glesbygden kan ha olika förutsättningar till jämlik vård.Glesbygdsperspektivet är inte väl utforskat när det gäller sexuell hälsa vidprostatacancer utan fokus ligger på behandlingsutfallet och dess biverkningar.Syfte: Syftet med denna studie var att undersöka hur personer med prostatacancerboende på Gotland respektive i Norrbotten skattar sin sexuella hälsa med hjälp av ettfrågeformulär som är specifikt för prostatacancer.Metod: En deskriptiv, komparativ enkätstudie med kvantitativ ansats genomfördesdär totalt 30 konsekutivt inkluderade patienter från Norrbotten och Gotland besvaradeprostatacancerspecifika enkäten EORTC QLQ-PR25.Resultat: Områdena urinvägssymtom, hormonbehandlingsrelaterade symtom ochsexuell aktivitet visade högre andel förekomst av besvär. Respondenterna skattade lågtintresse för sex och stor påverkan på manlighet. Gotland hade sämre utfall i de flestaanalyserade delområden och frågor; särskilt stor skillnad finns i användning avinkontinensskydd, sexuell aktivitet och sexuell funktion.Konklusion: Sexuell hälsa är för prostatacancerpatienter en problematik som är mernyanserad än erektil funktion, exempelvis i respondentgruppen spelade variabler somintresse för sex och upplevelse av manlighet stor roll. Tillgång till vård är viktig förpatienterna och gruppens skattningsresultat hade kunnat vara annorlunda omboenderegionerna hade gett bättre förutsättningar. Studien antyder också att det finnsen skillnad mellan Norrbotten och Gotland, vilket kan bero på bakomliggande variablerkopplade till regionerna, exempelvis att Gotland har en betydligt högre incidens avprostatacancer och en högre andel äldre än Norrbotten. Gotland har en lägretätortsgrad och nästan lika lång körsträcka per bil och år som Norrbotten som är 31gånger större till yta, men fynden är ändå överraskande.Svaret till fynden kan inte förklaras i denna studie men framtida forskning som belyserglesbygdperspektivet rekommenderas. / Background: Prostate cancer is currently the most common form of cancer inSweden and the most common cancer-related cause of death. Individuals withprostate cancer are affected in their sexual health in a multifactorial way by thecancer treatment and its side effects.Motive: Residents in sparsely populated areas may have different conditions forequal care. The sparsely populates area perspective is not well explored when itcomes to sexual health in prostate cancer, with the focus being on the treatmentoutcome and its side effects.Aim: The purpose of this study was to investigate how people with prostate cancerliving on Gotland and Norrbotten rate their sexual health using a questionnairespecific to prostate cancer.Methods: A descriptive, comparative questionnaire study with a quantitativeapproach was conducted where a total of 30 consecutively included patients fromNorrbotten and Gotland answered the prostate cancer-specific questionnaire EORTCQLQ-PR25.Results: The areas urinary tract symptoms, hormone treatment-related symptomsand sexual activity showed a higher prevalence of complaints. The respondentsestimated a low interest in sex and a high impact on masculinity. Gotland had worseoutcomes in most analyzed sub-areas and questions; a particularly large difference isfound in the use of incontinence aid, sexual activity and sexual function.Conclusion: Sexual health is for prostate cancer patients a problem that is morenuanced than erectile function, for example in the respondent group variables such asinterest in sex and experience of masculinity played a significant role. Access to careis important for patients, and the group's estimation results could have been differentif the residential regions had provided better conditions. The study also suggests thatthere is a difference between Norrbotten and Gotland, which may be due tounderlying variables related to the regions, for example that Gotland has asignificantly higher incidence of prostate cancer and a higher proportion of elderlypeople than Norrbotten. Gotland has a lower density of urban areas and almost thesame mileage per car per year as Norrbotten, which is 31 times larger in surface area,but the findings are still surprising.Those findings cannot be explained in this study, but future research that highlightsthe sparsely populated perspective is recommended.

<p>Prostate cancer is the second leading cause of cancer-related death among American men. Prostate tumor cells exhibit significant tropism for the bone and once metastasis occurs, survival rates fall significantly. Current treatment options are not curative and focus on symptom management. Immunotherapies are rapidly emerging as a possible therapeutic option for a variety of cancers including prostate cancer, however, variable patient response remains a concern. Chemotherapies, like cabozantinib, can have immune-priming effects which sensitize tumors to immunotherapies. Additionally, lower doses of chemotherapy can be used in this context which can reduce patient side effects. It was hypothesized that a combination of chemotherapy (cabozantinib) and immunotherapy (Interleukin-27 (IL-27)) could treat bone-metastatic prostate cancer and also exert pro-osteogenic effects. IL-27 is a multi-functional cytokine, which promotes immune cell recruitment to tumors, while also promoting bone repair. To test this hypothesis, <i>in vivo</i> experiments were performed where syngeneic C57BL/6J mice were implanted intratibially with TRAMP-C2ras-Luc cells able to form tumors in bone. Immunotherapy was administered in the form of intramuscular gene therapy, delivering plasmid DNA encoding a reporter gene (Lucia), or a therapeutic gene (IL-27). Ultrasound was used to aid gene delivery. Various gene delivery methods were tested and optimized through <i>in vivo</i> studies, with microbubbles in combination with ultrasound (sonoporation) emerging as the best method. Following immunotherapy, the animals received either cabozantinib or a vehicle control by oral gavage. Bioluminescence imaging was used to monitor tumor size over time. Combinatorial therapy inhibited tumor growth and improved survival. Further, RNA sequencing and cytokine arrays were used to investigate the mechanisms involved. Microcomputed tomography and differentiation assays indicated that the combination therapy improved bone health by improving osteoblast differentiation and inhibiting osteoclast differentiation. Our conclusion is that a chemo-immunotherapy approach such as the one examined in this work has potential to emerge as a novel therapeutic strategy for treating bone-metastatic prostate cancer. This approach should enable a significant reduction in chemotherapy-associated toxicity, improving sensitivity to immunotherapy, and simultaneously improving bone quality.</p>

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Combining chemotherapeutics to treat malignant tumors has been shown to be effectivein preventing drug resistance, tumor recurrence, and reducing tumor size. We modeledcombination drug therapy in PC-3 human prostate cancer cells using mixture design responsesurface methodology (MDRSM), a statistical technique designed to optimize compositions thatwe applied in a novel manner to design combinations of chemotherapeutics. Conventionalchemotherapeutics (mitoxantrone, cabazitaxel, and docetaxel) and natural bioactive compounds(resveratrol, piperlongumine, and flavopiridol) were used in twelve different combinationscontaining three drugs at varying concentrations. Cell viability and cell cycle data werecollected and used to plot response surfaces in MDRSM that identified the most effectiveconcentrations of each drug in combination. MDRSM allows for extrapolation of data fromthree or more compounds in variable ratio combinations, unlike the Chou-Talalay method.MDRSM combinations were compared with combination index data from the Chou-Talalaymethod and were found to coincide. We propose MDRSM as an effective tool in devisingcombination treatments that can improve treatment effectiveness, and increase treatmentpersonalization because MDRSM measures effectiveness rather than synergism, potentiation orantagonism.

Background: To explore cross‐sectional and longitudinal differences in general health‐related and prostate cancer‐specific quality of life (QoL) after robotic‐assisted (RARP) and laparoscopic (LRP) radical prostatectomy and to analyze predictive variables for QoL outcomes. Methods: In this multicenter, randomized controlled trial, prostate cancer patients were randomly assigned 3:1 to undergo either RARP or LRP. Patient‐reported outcomes were prospectively collected before and 1, 3, 6, 12 months after radical prostatectomy and included QoL as a secondary outcome. Validated questionnaires were used to assess general health‐related (EORTC QLQ‐C30) and prostate cancerspecific (QLQ‐PR25) QoL. Cross‐sectional and longitudinal contrasts were analyzed through linear mixed models. Predictive variables for QoL outcomes were identified by general linear modeling. Results: Of 782 randomized patients, QoL was evaluable in 681 patients. In terms of general QoL, the cross‐sectional analysis showed only small differences between study arms, whereas longitudinal comparison indicated an advantage of RARP on recovery: RARP patients reported an earlier return to baseline in global health status (3 vs. 6 months) and social functioning (6 vs. 12 months). In role functioning, only the RARP arm regained baseline scores. Regarding prostate‐specific QoL, LRP patients experienced more urinary symptoms and reported 3.2 points (95% confidence interval 0.4–6, p = 0.024) higher mean scores at 1‐month follow‐up and in mean 2.9 points (0.1–5, p = 0.042) higher urinary symptoms scores at 3‐month follow‐up than RARP patients. There were no other significant differences between treatment groups. Urinary symptoms, sexual activity, and sexual function remained significantly worse compared with baseline at all time points in both arms. Conclusions: Compared with LRP, the robotic approach led to an earlier return to baseline in several domains of general health‐related QoL and better short‐term recovery of urinary symptoms. Predictive variables such as the scale‐specific baseline status and bilateral nerve‐sparing were confirmed.:1 Abkürzungsverzeichnis 3 2 Einführung 4 2.1 Das Prostatakarzinom 4 2.1.1 Vorsorge und Diagnostik 4 2.1.2 Grundsätze der Therapie 5 2.1.3 Die radikale Prostatektomie 6 2.2 Lebensqualität 8 2.2.1 Gesundheitsbezogene Lebensqualität 8 2.2.2 Lebensqualität von Prostatakarzinompatienten 9 2.2.3 Prädiktoren der Lebensqualität nach radikaler Prostatektomie 12 2.3 Die LAP-01 Studie 13 2.3.1 Studiendesign 13 2.3.2 Lebensqualität im Rahmen der LAP-01 Studie 15 2.4 Zielsetzung und Fragestellung 16 3 Publikationsmanuskript 17 4 Zusammenfassung der Arbeit 28 5 Literaturverzeichnis 33 6 Anlagen 39 6.1 EORTC QLQ-C30 39 6.2 EORTC QLQ-PR25 42 7 Darstellung des eigenen Beitrags 44 8 Selbstständigkeitserklärung 45 9 Lebenslauf 46 10 Danksagung 48

New chimeric inhibitors targeting the epidermal growth factor (EGFR) and histone deacetylases (HDACs) were synthesized and tested for antineoplastic efficiency in solid cancer (prostate and hepatocellular carcinoma) and leukemia/lymphoma cell models. The most promising compounds, 3BrQuin-SAHA and 3ClQuin-SAHA, showed strong inhibition of tumor cell growth at one-digit micromolar concentrations with IC50 values similar to or lower than those of clinically established reference compounds SAHA and gefitinib. Target-specific EGFR and HDAC inhibition was demonstrated in cell-free kinase assays andWestern blot analyses, while unspecific cytotoxic effects could not be observed in LDH release measurements. Proapoptotic formation of reactive oxygen species and caspase-3 activity induction in PCa and HCC cell lines DU145 and Hep-G2 seem to be further aspects of the modes of action. Antiangiogenic potency was recognized after applying the chimeric inhibitors on strongly vascularized chorioallantoic membranes of fertilized chicken eggs (CAM assay). The novel combination of two drug pharmacophores against the EGFR and HDACs in one single molecule was shown to have pronounced antineoplastic effects on tumor growth in both solid and leukemia/lymphoma cell models. The promising results merit further investigations to further decipher the underlying modes of action of the novel chimeric inhibitors and their suitability for new clinical approaches in tumor treatment.

Prostate cancer is one of the most common types of cancer worldwide and claims hundreds of thousands of lives annually. Currently the most common treatment for prostate cancer is external beam radiotherapy, however, this treatment comes with serious side effects since it lacks selectivity for the cancer cells. Therefore, less harmful treatments are needed and sought for, such as targeted treatments that are intended to only affect cancer cells and thereby reduce the side effects. Targeted treatments require a target that differentiates the cancer cells from healthy cells. A promising target candidate that has gained attention in recent years is gastrin releasing peptide receptor (GRPR), a protein commonly overexpressed in prostate cancer cells. Furthermore, a targeting molecule intended to bind to the target is also required. For this purpose, the bombesin analogue RM26, a high affinity GRPR binder, shows promise. Previous studies have led to the development of RM26-conjugates for the purpose of targeted prostate cancer radiotherapy. In these conjugates RM26 has been linked to a DOTA-chelator for radiolabeling, and an albumin binding domain (ABD) to prolong the conjugate’s half-life in vivo by binding to human serum albumin (HSA). The idea is that the RM26-conjugate will bind to both HSA in the blood and to GRPR on the prostate cancer cells and eliminate the cancer cells with the radiation from the radionuclide attached to the DOTA-chelator. Although these earlier studied conjugates have been very promising some improvements of certain aspects need to be achieved, mainly to improve the biodistribution with retained GRPR binding affinity. Therefor the purpose of this project was to produce three new versions of previous RM26- conjugates and evaluate if they are suitable for further prostate cancer therapy studies. The three RM26-conjugates were developed with primarily recombinant expression in E. coli cells and solid phase peptide synthesis (SPPS). The characterization phase in this project was carried out with mainly five different methods: matrix-assisted laser desorption ionization time- of-flight mass spectrometry (MALDI-TOF-MS), electrospray ionization- mass spectrometry (ESI-MS), circular dichroism (CD), surface plasmon resonance (SPR) and flow cytometry. The results showed that all three new RM26-conjugates were possible to produce and yielded final products corresponding to the expected molecular weights. Furthermore, the results indicate that all three RM26-conjuagtes are stable and maintain their structural properties under in vivo- temperatures and that they have high binding affinity for HSA. Further studies need to be conducted before drawing any certain conclusions regarding GRPR binding affinity. / Prostatacancer är en av de mest vanligt förekommande cancertyperna världen över och skördar hundratusentals liv årligen. I nuläget är extern strålbehandling det vanligaste terapialternativet mot prostatacancer, men denna behandling kommer med allvarliga biverkningar på grund av att den saknar selektivitet för cancerceller. Därför finns ett stort behov av mindre skadliga behandlingsformer, såsom riktade behandlingar som endast är avsedda att påverka cancerceller och därigenom minska biverkningarna. Riktade behandlingar kräver ett mål som skiljer cancercellerna från friska celler. En lovande målkandidat som har uppmärksammats de senaste åren är gastrinfrisättande peptidreceptor (GRPR), ett protein som vanligtvis överuttrycks i prostatacancerceller. I tillägg så krävs också en målsökande molekyl avsedd att binda till målet. För detta ändamål visar bombesinanalogen RM26, en GRPR-bindare med hög affinitet, sig vara lovande. Tidigare studier har utvecklat RM26-konjugat för målinriktad strålbehandling av prostatacancer. Dessa konjugat består av en RM26-peptid bunden till en DOTA-kelator för radioinmärkning och en albuminbindande domän (ABD) för att förlänga konjugatens halveringstid in vivo genom att binda till humant serumalbumin (HSA). Syftet med RM26- konjugaten är att de ska binda till både HSA i blodet och GRPR på prostatacancercellerna, och därmed eliminera cancercellerna med strålning från den radioinmärkta DOTA-kelatorn. Även om de tidigare RM26-konjugaten har varit mycket lovande krävs det att vissa förbättringar av några aspekter uppnås, främst affiniteten för GRPR. Syftet med detta projekt var därför att producera tre nya versioner av tidigare RM26-konjugat och utvärdera ifall de uppvisar tillfredsställande egenskaper. De tre RM26-konjugaten utvecklades primärt rekombinant i E. coli-celler och fastfas- peptidsyntes (SPPS). Karaktäriseringsfasen i detta projekt genomfördes med huvudsakligen fem olika metoder: MALDI-TOF-MS, elektrosprejjonisering-masspektrometri (ESI-MS), cirkulär dikroism (CD), ytplasmonresonans (SPR) och flödescytometri. Resultaten visade att alla tre nya RM26-konjugat var möjliga att producera och gav slutprodukter motsvarande de förväntade molekylvikterna. Vidare indikerar resultaten att alla tre RM26-konjugat är stabila och bibehåller sina strukturella egenskaper under in vivo-temperaturer och att de har hög affinitet för HSA. Ytterligare studier bör utföras innan säkrare slutsatser kan dras angående GRPR-bindningsaffinitet.

Castration-resistant prostate cancer (CRPC) remains an aggressive incurable disease in men mainly due to treatment resistance. Current treatments do not effectively eradicate cancer stem cells (CSCs), which play a pivotal role in tumour maintenance, progression and drug resistance. Aldehyde dehydrogenases (ALDHs) have been used in some tumour types as CSC markers. Their high expression and high functional activity found in CSCs is also associated with drug resistance. Emerging evidence suggests deregulation of certain ALDH isoforms have implications in cancer. The role of ALDHs in prostate cancer as potential biomarkers and therapeutic targets has not been fully explored yet. Accordingly, this study investigated the expression, regulation and function of selected ALDH isoforms in prostate cancer. This study showed that ALDH1A3, ALDH1B1, ALDH2 and ALDH7A1 are highly expressed in primary prostate cancer cells (n=9) compared to benign (n=9) prostate cells. The expression of ALDH1A3 was high in the stem cells (SCs) (n=3) as well as the more differentiated counterparts (n=16). Treatment of both benign and malignant primary prostate cancer cells with all-trans retinoic acid (atRA) also resulted in increased expression of ALDH1A3 and ALDH3A1, supporting a feedback loop between atRA and ALDHs. Furthermore, SerBob, Bob and LNCaP cells were sensitive to treatment with epigenetic drugs and led to significantly higher expression of ALDH1A2, ALDH3A1 and ALDH7A1 respectively. Importantly, siRNA suppression of ALDH1A3 and ALDH7A1 led to reduced SC properties of primary prostate cultures including reduced cell viability, migration and colony formation, and increased differentiation of transit amplifying (TA) cells to committed basal (CB) cells. Novel ALDH-affinic probes showed reduced cell viability of primary prostate epithelial cultures as a single agent and also when used in combination with docetaxel. The results indicate the potential of using ALDH-affinic compounds as single agents for therapeutic intervention or in combination with docetaxel to sensitise resistant cells to this anticancer drug. The data in this thesis provides novel findings, which supports ALDH1A2, -1A3 and -7A1 as potential biomarkers and/or therapeutic targets for drug intervention. Although, a study analysing a larger number of samples is necessary to fully understand ALDH isoform expression in CSC, TA and CB cells it is envisaged that an ALDH-targeted therapy have potential in future treatment strategies for prostate cancer. / Prostate Cancer UK

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