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  1. Article ; Online: HUS1 as a Potential Therapeutic Target in Urothelial Cancer

    Andrea Katharina Lindner / Tobias Furlan / Jacob J. Orme / Gennadi Tulchiner / Nina Staudacher / David D’Andrea / Zoran Culig / Renate Pichler

    Journal of Clinical Medicine, Vol 11, Iss 2208, p

    2022  Volume 2208

    Abstract: Platinum-based chemotherapy is the standard of care with concern to first-line systemic therapy for metastatic disease in urothelial cancer (UC). Resistance to chemotherapy despite an initial response is linked with the ability to remove platinum-based ... ...

    Abstract Platinum-based chemotherapy is the standard of care with concern to first-line systemic therapy for metastatic disease in urothelial cancer (UC). Resistance to chemotherapy despite an initial response is linked with the ability to remove platinum-based DNA adducts and to repair chemotherapy-induced DNA lesions by various DNA repair proteins. The Rad9-Rad1-HUS1 complex that is loaded onto DNA at sites of damage is involved in checkpoint activation as well as DNA repair. Here, we addressed for the first time the potential influence of HUS1 expression in urothelial carcinogenesis (using two human basal urothelial cancer cell lines UM-UC-3 and HT1197) and its role as a potential therapeutic target for predicting responses to platinum-based chemotherapy. Specific inhibition of HUS1 expression in both cell lines was achieved by specific siRNA and validated by Western blot. In order to define the possible importance of HUS1 in the regulation of cellular proliferation, parental and resistant cells were treated with increasing concentrations of either control or HUS1 siRNA. HUS1 protein expression was observed in both human basal urothelial cancer cell lines UM-UC-3 and HT1197. In cisplatin-sensitive cells, knock-down of HUS1 inhibited cellular proliferation in the presence of cisplatin. On the contrary, knock-down of HUS1 in resistant cells did not result in a re-sensitization to cisplatin. Finally, RNAseq data from the Cancer Genome Atlas provided evidence that HUS1 expression is a significant prognostic factor for poor survival in UC patients. In summary, HUS1 may acts as an oncogene in UC and might be a key determinant of the cellular response to cisplatin-based chemotherapy.
    Keywords bladder cancer ; prognosis ; biomarker ; chemotherapy ; platinum-based ; HUS1 ; Medicine ; R
    Subject code 610 ; 616
    Language English
    Publishing date 2022-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Sex hormones influence survival of patients with metastatic urothelial carcinoma undergoing immune checkpoint therapy

    Andrea Katharina Lindner / Felizian Lackner / Piotr Tymoszuk / Dominik Andreas Barth / Andreas Seeber / Florian Kocher / Bettina Toth / Margarethe Hochleitner / Martin Pichler / Renate Pichler

    Biology of Sex Differences, Vol 14, Iss 1, Pp 1-

    2023  Volume 17

    Abstract: Abstract Introduction Clinical trials investigating efficacy of immune checkpoint inhibitors (ICI) revealed sex-specific divergent outcomes in urothelial cancer (UC), suggesting that sex hormones might play an important role in gender-specific ... ...

    Abstract Abstract Introduction Clinical trials investigating efficacy of immune checkpoint inhibitors (ICI) revealed sex-specific divergent outcomes in urothelial cancer (UC), suggesting that sex hormones might play an important role in gender-specific dimorphisms of response upon ICI. However, further clinical investigations are still needed to understand the influence of sex hormones in UC. The aim of this study was to get further insights on the prognostic and predictive value of sex hormone levels in patients with metastatic UC (mUC) who underwent ICI. Material and methods Sex hormone levels of patients with mUC including luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH ratio, prolactin, testosterone and 17β-estradiol (E2) were evaluated at baseline and during ICI at 6/8 weeks and 12/14 weeks. Results Twenty-eight patients (10 women, 18 men) with a median age of 70 years were included. Metastatic disease was confirmed in 21 patients (75%) after radical cystectomy while seven patients showed mUC at first diagnosis. Twelve patients (42.8%) received first line and 16 patients second line pembrolizumab. The objective response rate (ORR) was 39% (CR in 7%). The median progression-free survival (PFS) and overall survival (OS) was 5.5 and 20 months. Focusing on changes of sex hormone levels during ICI, a significant increase in FSH levels and decrease of the LH/FSH ratio was noticed in responders (p = 0.035), yet without sex-specific significance. When adjusted for sex and treatment line, a significant increase of FSH levels was confirmed in men during second line pembrolizumab. Focusing on baseline levels, LH/FSH ratio was significantly higher in female responders (p = 0.043) compared to non-responders. In women, increased LH levels and LH/FSH ratio were associated with better PFS (p = 0.014 for LH, p = 0.016 for LH/FSH ratio) and OS (p = 0.026 and p = 0.018). In male patients, increased E2 levels were linked with improved PFS (p < 0.001) and OS (p = 0.039). Conclusion Increased LH and LH/FSH values ...
    Keywords Metastatic urothelial carcinoma ; Immunotherapy ; Overall survival ; Sex hormones ; Gonadotropins ; Prognostic ; Medicine ; R ; Physiology ; QP1-981
    Language English
    Publishing date 2023-06-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Lynch Syndrome

    Andrea Katharina Lindner / Gert Schachtner / Gennadi Tulchiner / Martin Thurnher / Gerold Untergasser / Peter Obrist / Iris Pipp / Fabian Steinkohl / Wolfgang Horninger / Zoran Culig / Renate Pichler

    International Journal of Molecular Sciences, Vol 22, Iss 2, p

    Its Impact on Urothelial Carcinoma

    2021  Volume 531

    Abstract: Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1 , MSH2 , ...

    Abstract Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1 , MSH2 , MSH6 , and PMS2 , and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis. UC is the third most common cancer type in LS-associated tumors. The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in MSH2 mutation carriers. In this review, we will focus on LS-associated UC of the upper urinary tract (UUT) and bladder, their germline profiles, and outcomes compared to sporadic UC, the impact of genetic testing, as well as urological follow-up strategies in LS. In addition, we present a case of metastatic LS-associated UC of the UUT and bladder, achieving complete response during checkpoint inhibition since more than 2 years.
    Keywords Lynch syndrome ; urothelial cancer ; upper urinary tract ; DNA mismatch repair genes ; MMR ; microsatellite instability ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 610
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Expression of ADAM Proteases in Bladder Cancer Patients with BCG Failure

    Renate Pichler / Andrea Katharina Lindner / Georg Schäfer / Gennadi Tulchiner / Nina Staudacher / Martin Mayr / Eva Comperat / Jacob J. Orme / Gert Schachtner / Martin Thurnher

    Journal of Clinical Medicine, Vol 10, Iss 4, p

    A Pilot Study

    2021  Volume 764

    Abstract: Although Bacillus Calmette Guérin (BCG) remains a mainstay of adjuvant treatment in high-risk, non-muscle-invasive bladder cancer, BCG failure occurs in up to 40% of patients, with radical cystectomy (RC) as the inevitable therapeutic consequence. ... ...

    Abstract Although Bacillus Calmette Guérin (BCG) remains a mainstay of adjuvant treatment in high-risk, non-muscle-invasive bladder cancer, BCG failure occurs in up to 40% of patients, with radical cystectomy (RC) as the inevitable therapeutic consequence. Current data suggest that PD-L1 immunosuppressive signaling is responsible for BCG failure, supporting the therapeutic rationale of combining checkpoint inhibitors with BCG. To address the immune cascade in 19 RC specimens obtained after BCG failure, we applied a small immunohistochemical (IHC) panel consisting of selected markers (PD-L1, GATA-3, a disintegrin and metalloproteinase (ADAM) proteases, IL-10/IL-10R). A modified quick score was used for IHC semi-quantification of these markers in tumor cells (TC) and immune cells (IC) within two different regions: muscle-invasive bladder cancer (MIBC) and primary/concurrent carcinoma in situ (CIS). Contrary to expectation, PD-L1 was consistently low, irrespective of tumor region and cell type. Intriguingly, expression of ADAM17, which has been reported to release membrane-bound PD-L1, was high in both tumor regions and cell types. Moreover, expression of GATA3, IL-10, and IL-10R was also increased, indicative of a generally immunosuppressive tumor microenvironment in BCG failure. ADAM10 expression was associated with advanced tumor disease at RC. Our findings raise the possibility that ADAM proteases may cleave PD-L1 from the surface of bladder TC and possibly also from IC. Therefore, IHC assessment of PD-L1 expression seems to be insufficient and should be supplemented by ADAM10/17 in patients with BCG failure.
    Keywords bacillus calmette guéri (BCG) failure ; bladder cancer ; a disintegrin and metalloproteinase (ADAM) proteases ; soluble PD-L1 ; PD-L1 biomarkers ; checkpoint inhibition ; Medicine ; R
    Subject code 610 ; 616
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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