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Dutch literature

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Prinses Mathilde bracht op 13 december een bezoek aan de dienst gynaecologische kanker. Ze praatte er met de onderzoeksgroep van het project 'Kanker tijdens zwangerschap'.

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Establishment of preclinical endometrial carcinoma models and evaluation of new treatment optionsEndometrial cancer isnbsp;most common gynecological cancer innbsp;Western World. Endometrial carcinoma (EC) is the most frequent subtype of endometrial cancer and can be divided into two classes.nbsp;I, endometrioid EC, represents 80% of the cases and 15-20% of the recurrences. Type II, non-endometrioid EC, is less common but 50% of the patients show recurrences.nbsp;with advanced or recurrent disease have a poor overall survival, since conventional therapies are not effective at this stage. Therefore, new treatment options are needed.Many anticancer therapeutics show favorable tumor response in preclinical models. However, only 5% of anticancer therapeutics succeed to perform better responses than conventional therapies when transitioned into clinical trials. One of the reasons is the lack of preclinical models representing the heterogenic histologic and genetic characteristics of the patients’ tumors. Hence, there is need of in vitro and in vivo clinical relevant models, which retain the heterogenic features of the original tumor and therefore reflect better the response of patients on therapies.In this doctoral study, the first aim was to establish preclinical models which retain the heterogenic histologic and genetic characteristics of the primary tumor. We established seven primary EC cellnbsp;which reflected the epithelial and genetic characteristics of the corresponding original tumors. In addition, we demonstrated that microsatellite instability status in the original tumor seems to determine the success rate ofnbsp;of primary cell cultures.Next, we established subcutaneously (s.c.) xenografts and an orthotopic mouse model, based on the inoculation of the established primary cell cultures. Furthermore, we established eight patient-derived tumor xenograft (PDTX) models by s.c. implanting of patientsnbsp;tumor tissues in immune-deficient mice. Xenograft tumors of the several models retained the histologic and genetic features of the corresponding primary tumor. In addition, the orthotopic mouse model showed metastasis to clinical relevant organs. The established preclinical models preserved the heterogenic characteristics of the corresponding primary tumor and therefore are useful models to investigate newnbsp;strategies for EC.The second aim of this study was to determine new treatment options for EC. Metformin is used as treatment for diabetes mellitus type II.nbsp;and clinical studies demonstrated an antitumor effect by metformin, with and without conventional treatments, for solid malignancies. However, a possible anticancer effect of metformin on EC is still debated. Therefore, we investigated the in vitro and in vivo efficacy of metformin, with and without carboplatin, on primary endometrioid EC cells. We demonstrated that metformin showed antitumor effects in vitro, although only at high concentrations. In vivo, metformin showed no tumor growth reduction at clinical relevant concentrations in the corresponding xenografts. In addition, combination treatment with carboplatin showed no enhanced effect, both in vitro and in vivo.Targeted therapies are compounds which inhibit key drivers in cellular signaling pathways involved in tumor development. Therefore, these compounds may be useful to treat cancer. In this study, we used primary endometrioid EC cells to determine the in vitro and in vivo efficacy of two targeted therapies, NVP-BEZ235 (dual pan-PI3K/mTOR inhibitor) and AZD6244 (MEK1/2 inhibitor) on EC. In vitro, combination treatment showed an enhanced antitumor effect compared to single treatment. In addition, in vivo results showed a reduced tumor growth in NVP-BEZ235-treated mice, established by inoculation of the corresponding primary cell cultures. Moreover, combination treatment of NVP-BEZ235 and AZD6244 showed an increased antitumor effect compared to single treatment in one PDTX model, which harbors a PIK3CA and KRAS mutation.To conclude, we established in vitro and in vivo models which represent the heterogenic characteristics of the corresponding primary tumor. Therefore these models are useful to validate new treatment strategies for EC, since theynbsp;reflect the response of patients on treatment.Furthermore, we used these established preclinical models to investigate new treatment options for EC. In our study, metformin induced antitumor effects in vitro, but not in vivo. However, targeted therapies against the PI3K/AKT/mTOR and Ras/Raf/MEK signaling pathways seem promising treatment strategies for EC.

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-Background: Assess unplanned pregnancies during cancer diagnosis and treatment. -Methods: Retrospective review of patients who became pregnant during cancer diagnosis or cancer treatment. The prospective European registration study of INCIP was used. -Conclusion: The results of this study show that the lack of contraception - and not failure of contraception - was the mean reason of unplanned pregnancy during cancer diagnosis and treatment. We propose that all young women diagnosed with cancer should have an appointment with a gynaecologist to discuss both fertility preservation and contraception before start of treatment. This demands education of oncology teams and awareness.