@article{HoubenHesbacherSchmidetal.2011, author = {Houben, Roland and Hesbacher, Sonja and Schmid, Corinna P. and Kauczok, Claudia S. and Flohr, Ulrike and Haferkamp, Sebastian and M{\"u}ller, Cornelia S. L. and Schrama, David and Wischhusen, J{\"o}rg and Becker, J{\"u}rgen C.}, title = {High-Level Expression of Wild-Type p53 in Melanoma Cells is Frequently Associated with Inactivity in p53 Reporter Gene Assays}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69012}, year = {2011}, abstract = {Background: Inactivation of the p53 pathway that controls cell cycle progression, apoptosis and senescence, has been proposed to occur in virtually all human tumors and p53 is the protein most frequently mutated in human cancer. However, the mutational status of p53 in melanoma is still controversial; to clarify this notion we analysed the largest series of melanoma samples reported to date. Methodology/Principal Findings: Immunohistochemical analysis of more than 180 melanoma specimens demonstrated that high levels of p53 are expressed in the vast majority of cases. Subsequent sequencing of the p53 exons 5-8, however, revealed only in one case the presence of a mutation. Nevertheless, by means of two different p53 reporter constructs we demonstrate transcriptional inactivity of wild type p53 in 6 out of 10 melanoma cell lines; the 4 other p53 wild type melanoma cell lines exhibit p53 reporter gene activity, which can be blocked by shRNA knock down of p53. Conclusions/Significance: In melanomas expressing high levels of wild type p53 this tumor suppressor is frequently inactivated at transcriptional level.}, subject = {Krebs }, language = {en} } @article{HaferkampHesbacherWeyandtetal.2014, author = {Haferkamp, Sebastian and Hesbacher, Sonja and Weyandt, Gerhard and Vetter-Kauczok, Claudia S. and Becker, J{\"u}rgen C. and Motschenbacher, Stephanie and Wobser, Marion and Maier, Melissa and Schmid, Corinna P. and Houben, Roland}, title = {p53 regulation by TRP2 is not pervasive in melanoma}, doi = {10.1371/journal.pone.0087440}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111396}, year = {2014}, abstract = {p53 is a central tumor suppressor protein and its inhibition is believed to be a prerequisite for cancer development. In approximately 50\% of all malignancies this is achieved by inactivating mutations in the p53 gene. However, in several cancer entities, including melanoma, p53 mutations are rare. It has been recently proposed that tyrosinase related protein 2 (TRP2), a protein involved in melanin synthesis, may act as suppressor of the p53 pathway in melanoma. To scrutinize this notion we analyzed p53 and TRP2 expression by immunohistochemistry in 172 melanoma tissues and did not find any correlation. Furthermore, we applied three different TRP2 shRNAs to five melanoma cell lines and could not observe a target specific effect of the TRP2 knockdown on either p53 expression nor p53 reporter gene activity. Likewise, ectopic expression of TRP2 in a TRP2 negative melanoma cell line had no impact on p53 expression. In conclusion our data suggest that p53 repression critically controlled by TRP2 is not a general event in melanoma.}, language = {en} } @article{GlutschKneitzGesierichetal.2021, author = {Glutsch, Valerie and Kneitz, Hermann and Gesierich, Anja and Goebeler, Matthias and Haferkamp, Sebastian and Becker, J{\"u}rgen C. and Ugurel, Selma and Schilling, Bastian}, title = {Activity of ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma}, series = {Cancer Immunology, Immunotherapy}, volume = {70}, journal = {Cancer Immunology, Immunotherapy}, number = {7}, issn = {14320851}, doi = {10.1007/s00262-020-02832-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265635}, pages = {2087-2093}, year = {2021}, abstract = {Background Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cutaneous malignancy with poor prognosis. In Europe, approved systemic therapies are limited to the PD-L1 inhibitor avelumab. For avelumab-refractory patients, efficient and safe treatment options are lacking. Methods At three different sites in Germany, clinical and molecular data of patients with metastatic MCC being refractory to the PD-L1 inhibitor avelumab and who were later on treated with combined IPI/NIVO were retrospectively collected and evaluated. Results Five patients treated at three different academic sites in Germany were enrolled. Three out of five patients investigated for this report responded to combined IPI/NIVO according to RECIST 1.1. Combined immunotherapy was well tolerated without any grade II or III immune-related adverse events. Two out of three responders to IPI/NIVO received platinum-based chemotherapy in between avelumab and combined immunotherapy. Conclusion In this small retrospective study, we observed a high response rate and durable responses to subsequent combined immunotherapy with IPI/NIVO in avelumab-refractory metastatic MCC patients. In conclusion, our data suggest a promising activity of second- or third-line PD-1- plus CTLA-4-blockade in patients with anti-PD-L1-refractory MCC.}, language = {en} } @article{GlutschSchummerKneitzetal.2022, author = {Glutsch, Valerie and Schummer, Patrick and Kneitz, Hermann and Gesierich, Anja and Goebeler, Matthias and Klein, Detlef and Posch, Christian and Gebhardt, Christoffer and Haferkamp, Sebastian and Zimmer, Lisa and Becker, J{\"u}rgen C and Leiter, Ulrike and Weichenthal, Michael and Schadendorf, Dirk and Ugurel, Selma and Schilling, Bastian}, title = {Ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma: a multicenter study of the prospective skin cancer registry ADOREG}, series = {Journal for ImmunoTherapy of Cancer}, volume = {10}, journal = {Journal for ImmunoTherapy of Cancer}, number = {11}, issn = {2051-1426}, doi = {10.1136/jitc-2022-005930}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304613}, year = {2022}, abstract = {Merkel cell carcinoma is a rare, highly aggressive skin cancer with neuroendocrine differentiation. Immune checkpoint inhibition has significantly improved treatment outcomes in metastatic disease with response rates to programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) inhibition of up to 62\%. However, primary and secondary resistance to PD-1/PD-L1 inhibition remains a so far unsolved clinical challenge since effective and safe treatment options for these patients are lacking.Fourteen patients with advanced (non-resectable stage III or stage IV, Union international contre le cancer 2017) Merkel cell carcinoma with primary resistance to the PD-L1 inhibitor avelumab receiving subsequent therapy (second or later line) with ipilimumab plus nivolumab (IPI/NIVO) were identified in the prospective multicenter skin cancer registry ADOREG. Five of these 14 patients were reported previously and were included in this analysis with additional follow-up. Overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events were analyzed.All 14 patients received avelumab as first-line treatment. Thereof, 12 patients had shown primary resistance with progressive disease in the first tumor assessment, while two patients had initially experienced a short-lived stabilization (stable disease). Six patients had at least one systemic treatment in between avelumab and IPI/NIVO. In total, 7 patients responded to IPI/NIVO (overall response rate 50\%), and response was ongoing in 4 responders at last follow-up. After a median follow-up of 18.85 months, median PFS was 5.07 months (95\% CI 2.43—not available (NA)), and median OS was not reached. PFS rates at 12 months and 24 months were 42.9\% and 26.8 \%, respectively. The OS rate at 36 months was 64.3\%. Only 3 (21\%) patients did not receive all 4 cycles of IPI/NIVO due to immune-related adverse events.In this multicenter evaluation, we observed high response rates, a durable benefit and promising OS rates after treatment with later-line combined IPI/NIVO. In conclusion, our patient cohort supports our prior findings with an encouraging activity of second-line or later-line IPI/NIVO in patients with anti-PD-L1-refractory Merkel cell carcinoma.}, language = {en} }