Stefan Kubicka
Research interests
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InterestsClinical Oncology: focus on GI cancer (phase I-III studies) Cancer Research: development of oncolytic viruses, immunotherapy of cancer with oncolytic viruses
Other
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Languages
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Other InterestsNature, Science, Cell, PNAS, Immunity, JEM, Journal of Virology, Cancer Research, Journal of Immunology, Molecular Therapy,
NEJM, Lancet, JCO, Lancet Oncology, Roger Penrose: The road to reality
Publications
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Combination of conservative and interventional therapy strategies for intra- and extrahepatic cholangiocellular carcinoma: a retrospective survival analysis.
Gastroenterology research and practice. 01/2012; 2012:190708.
Background. Due to the predominantly advanced stage at the time of diagnosis treatment of cholangiocarcinoma is difficult. Apart from surgical resection, interventional treatment strategies are increasingly used in advanced stage tumours. The aim of the study was a retrospective comparison of the ef... [more] Background. Due to the predominantly advanced stage at the time of diagnosis treatment of cholangiocarcinoma is difficult. Apart from surgical resection, interventional treatment strategies are increasingly used in advanced stage tumours. The aim of the study was a retrospective comparison of the effect of the various forms of treatment on morbidity and mortality. Method. A total of 195 patients, received either chemotherapy or a combination of photodynamic therapy (PDT) or transarterial chemoembolization (TACE) and chemotherapy. Results. The median survival rate for all patients was 15.6 months, 50.8% were still alive 1 year after diagnosis. Patients, who had previously undergone surgery, survived 17.1 months longer than those without surgical treatment (P < .01). Chemotherapy prolonged the survival by 9.2 months (P = .47). Palliative patients under combination of chemotherapy and PDT survived on average 1.8 months longer (P = .28), with chemotherapy and TACE 9.8 months longer (P = .04) compared to chemotherapy alone. Conclusions. It appears that surgical treatment and chemotherapy combined with PDT or TACE may prolong survival.
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34.48Impact points
Senescence surveillance of pre-malignant hepatocytes limits liver cancer development.
Nature. 11/2011; 479(7374):547-51.
Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo. Senescent cells communicate with their environment by secreting various cytokines and grow... [more] Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4(+) T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras(G12V). We also found that CD4(+) T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.
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19.53Impact points
The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication.
Nature cell biology. 07/2011; 13(8):1004-9.
Deregulated centrosome duplication can result in genetic instability and contribute to tumorigenesis. Here, we show that centrosome duplication is regulated by the activity of an E3-ubiquitin ligase that employs the F-box protein FBXW5 (ref. 3) as its targeting subunit. Depletion of endogenous FBXW5... [more] Deregulated centrosome duplication can result in genetic instability and contribute to tumorigenesis. Here, we show that centrosome duplication is regulated by the activity of an E3-ubiquitin ligase that employs the F-box protein FBXW5 (ref. 3) as its targeting subunit. Depletion of endogenous FBXW5 or overexpression of an F-box-deleted mutant version results in centrosome overduplication and formation of multipolar spindles. We identify the centriolar protein HsSAS-6 (refs 4,5) as a critical substrate of the SCF-FBXW5 complex. FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo. The activity of SCF-FBXW5 is in turn negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6. FBXW5 is a cell-cycle-regulated protein with expression levels peaking at the G1/S transition. We show that FBXW5 levels are controlled by the anaphase-promoting (APC/C) complex, which targets FBXW5 for degradation during mitosis and G1, thereby helping to reset the centrosome duplication machinery. In summary, we show that a cell-cycle-regulated SCF complex is regulated by the kinase PLK4, and that this in turn restricts centrosome re-duplication through degradation of the centriolar protein HsSAS-6.
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15.39Impact points
Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice.
The Journal of clinical investigation. 06/2011; 121(7):2570-82.
Vaccination using DCs pulsed with tumor lysates or specific tumor-associated peptides has so far yielded limited clinical success for cancer treatment, due mainly to the low immunogenicity of tumor-associated antigens. In this study, we have identified intratumoral virus-induced inflammation as a pr... [more] Vaccination using DCs pulsed with tumor lysates or specific tumor-associated peptides has so far yielded limited clinical success for cancer treatment, due mainly to the low immunogenicity of tumor-associated antigens. In this study, we have identified intratumoral virus-induced inflammation as a precondition for effective antitumor DC vaccination in mice. Administration of a tumor-targeted DC vaccine during ongoing virus-induced tumor inflammation, a regimen referred to as oncolysis-assisted DC vaccination (ODC), elicited potent antitumoral CD8+ T cell responses. This potent effect was not replicated by TLR activation outside the context of viral infection. ODC-elicited immune responses mediated marked tumor regression and successful eradication of preestablished lung colonies, an essential prerequisite for potentially treating metastatic cancers. Unexpectedly, depletion of Tregs during ODC did not enhance therapeutic efficacy; rather, it abrogated antitumor cytotoxicity. This phenomenon could be attributed to a compensatory induction of myeloid-derived suppressor cells in Treg-depleted and thus vigorously inflamed tumors, which prevented ODC-mediated immune responses. Consequently, Tregs are not only general suppressors of immune responses, but are essential for the therapeutic success of multimodal and temporally fine-adjusted vaccination strategies. Our results highlight tumor-targeting, replication-competent viruses as attractive tools for eliciting effective antitumor responses upon DC vaccination.
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1.19Impact points
Peripapillary duodenal varices as a rare cause of severe bleeding in a patient with no other signs of portal hypertension--successful endoscopic treatment with cyanoacrylate injection.
Zeitschrift für Gastroenterologie. 05/2011; 49(5):591-5.
Duodenal varices (DVs) are a rare cause of upper gastrointestinal bleeding and rather suspected in patients with portal hypertension. Bleeding DVs are difficult to manage and often fatal due to delayed diagnosis. We report on a 71-year-old patient with massive upper gastrointestinal haemorrhage, who... [more] Duodenal varices (DVs) are a rare cause of upper gastrointestinal bleeding and rather suspected in patients with portal hypertension. Bleeding DVs are difficult to manage and often fatal due to delayed diagnosis. We report on a 71-year-old patient with massive upper gastrointestinal haemorrhage, who did not show any clinical signs of portal hypertension; however, he had a history of duodenal segmental resection 8 years before. The source of bleeding could not be detected with different imaging methods such as angiography and computed tomography. Upper gastrointestinal endoscopy finally revealed DVs, which were located just adjacent to the papilla. After endoscopic injection therapy with n-butyl 2-cyanoacrylate the bleeding stopped immediately and the patient soon stabilised. Despite the peripapillar localisation no signs of pancreatitis or cholestasis occurred; during 10-month follow-up a marked regression of the varices without further signs of variceal bleeding was observed.
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2.97Impact points
Grading of hypervascular hepatocellular carcinoma using late phase of contrast enhanced sonography - a prospective study.
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 03/2011; 43(6):484-90.
Outcome of patients with hepatocellular carcinoma is influenced by their histological grade. Invasive biopsy of the lesions is the gold standard in this regard. We therefore analysed the diagnostic accuracy of contrast enhanced ultrasound for non-invasive grading of hypervascular hepatocellular carc... [more] Outcome of patients with hepatocellular carcinoma is influenced by their histological grade. Invasive biopsy of the lesions is the gold standard in this regard. We therefore analysed the diagnostic accuracy of contrast enhanced ultrasound for non-invasive grading of hypervascular hepatocellular carcinoma in liver cirrhosis. According to the tumour perfusion kinetics on contrast enhanced ultrasound two grading groups were prospectively defined: well-differentiated hepatocellular carcinoma (US-G1) and higher grade hepatocellular carcinoma (US-G2/G3). Immediately after contrast enhanced ultrasound-grading, biopsies of hepatocellular carcinoma-lesions (n=95, 1.2-12.5 cm) were obtained and analysed for tumour grading (G). Descriptive statistics, sensitivity, specificity positive and negative predictive values, diagnostic likelihood ratios and interoperator reproducibility were calculated (κ). Histologically 77 (81.1%) patients had G2-G3 and 18 (18.9%) had G1 tumours. Higher grade hepatocellular carcinoma showed more often a washout in the portal or late phase (p<0.0001). The sensitivity, specificity, positive predictive values and negative predictive values of contrast enhanced ultrasound for grading of hepatocellular carcinoma for all patients were 94% (CI: 72-99%), 95% (CI: 88-99%), 81% and 99% and for patients with tumours<5 cm 100%(95% CI: 79-100), 96% (95% CI: 80-99), 92% and 100%. Positive and negative diagnostic likelihood ratios' were 18 and 26 and 0.06 and 0, respectively. κ=0.941 (p<0.001). Contrast enhanced ultrasound has a high diagnostic value and reproducibility for non-invasive grading of hypervascular hepatocellular carcinoma >1cm in patients with liver cirrhosis.
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1.23Impact points
[Gastrointestinal tumors--interdisciplinary discussion over new data].
Onkologie. 01/2011; 34 Suppl 3:1-31.
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5.65Impact points
Cetuximab with irinotecan, folinic acid and 5-fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multi-center biomarker-oriented phase II study.
Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 11/2010; 22(6):1358-66.
Cetuximab plus irinotecan/folinic acid/5-fluorouracil (5-FU) (IF) was evaluated as first-line treatment of patients with advanced gastric cancer and gastroesophageal junction tumors. Preplanned analyses of the influence of tumor biomarkers on treatment outcome were carried out. Patients received wee... [more] Cetuximab plus irinotecan/folinic acid/5-fluorouracil (5-FU) (IF) was evaluated as first-line treatment of patients with advanced gastric cancer and gastroesophageal junction tumors. Preplanned analyses of the influence of tumor biomarkers on treatment outcome were carried out. Patients received weekly cetuximab (400 mg/m(2) on day 1, subsequently 250 mg/m(2)) plus irinotecan (80 mg/m(2)) and a 24-hour continuous infusion of folinic acid (200 mg/m(2)) and 5-FU (1500 mg/m(2)) on days 1, 8, 15, 22, 29 and 36 of a 50-day cycle, until progressive disease (PD). The most common grade 3/4 toxic effects in 49 patients were diarrhea (15%) and skin toxic effects (14%). In 48 assessable patients, the overall response rate was 46% and disease control rate was 79%. Median progression-free survival (PFS) and overall survival (OS) was 9.0 months [95% confidence interval (CI) 7.1-15.6] and 16.5 months (95% CI 11.7-30.1), respectively. Tumor response was more common than nonresponse in epidermal growth factor receptor-expressing tumors (P = 0.041). Tumor PTEN expression was associated with longer PFS (P = 0.035) and OS (P = 0.0127) than no PTEN expression. Cetuximab plus IF was well tolerated and efficacy data were encouraging. This treatment combination and the role of selected biomarkers are under investigation in the ongoing phase III EXPAND trial.
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6.24Impact points
Selectivity of oncolytic viral replication prevents antiviral immune response and toxicity, but does not improve antitumoral immunity.
Molecular therapy : the journal of the American Society of Gene Therapy. 11/2010; 18(11):1972-82.
Oncolytic infection elicits antitumoral immunity, but the impact of tumor-selective replication on the balance between antiviral and antitumoral immune responses has not yet been investigated. To address this question, we constructed the highly tumor-selective adenovirus Ad-p53T whose replication in... [more] Oncolytic infection elicits antitumoral immunity, but the impact of tumor-selective replication on the balance between antiviral and antitumoral immune responses has not yet been investigated. To address this question, we constructed the highly tumor-selective adenovirus Ad-p53T whose replication in target tumor cells is governed by aberrant telomerase activity and transcriptional p53 dysfunction. Telomerase-dependent or nonselective adenoviruses were constructed as isogenic controls. Following infection of mice with the nonselective adenovirus, viral DNA and mRNA levels correlated with strong stimulation of innate immune response genes and severe liver toxicity, whereas telomerase-/p53-specific replication did not trigger innate immunity and prevented liver damage. Compared to telomerase-dependent or unselective viral replication, telomerase-/p53-specific virotherapy significantly decreased antiviral CD8-specific immune responses and antiviral cytotoxicity in vivo. Consistent with our hypothesis, telomerase-selective replication led to intermediate results in these experiments. Remarkably, all viruses efficiently lysed tumors and induced a therapeutically effective tumor-directed CD8 cytotoxicity. In immunocompetent mice with extended lung metastases burden, treatment of subcutaneous primary tumors with Ad-p53T significantly prolonged survival by inhibition of lung metastases, whereas unselective viral replication resulted in death by liver failure. In summary, the degree of tumor selectivity of viral replication marginally influences antitumoral immune responses, but is a major determinant of antivector immunity and systemic toxicity.
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1.18Impact points
Evaluation of sound speed for detection of liver fibrosis: prospective comparison with transient dynamic elastography and histology.
Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine. 11/2010; 29(11):1581-8.
The degree of liver fibrosis determines the prognosis and treatment of patients with chronic viral hepatitis. Transient elastography (TE) has been accepted as a noninvasive method for assessment of liver fibrosis. Sound velocity (SV) changes are also dependent on elastic properties of tissue. The ai... [more] The degree of liver fibrosis determines the prognosis and treatment of patients with chronic viral hepatitis. Transient elastography (TE) has been accepted as a noninvasive method for assessment of liver fibrosis. Sound velocity (SV) changes are also dependent on elastic properties of tissue. The aim of this pilot study was to evaluate whether SV estimation of liver tissue allows the determination of fibrosis stages in patients with chronic viral hepatitis. Prospectively, 50 healthy volunteers and 149 patients received stiffness (TE, 50-Hz vibrator, 5-MHz array) and SV (conventional ultrasound, C5-2-MHz transducer) measurements. Eighty-four patients received representative liver biopsies. The estimated SV and stiffness were compared using liver biopsy as a reference (METAVIR fibrosis stage [F] scoring system [Hepatology 1996; 24:289-293]). Descriptive statistics, analysis of variance, receiver operating characteristic curve analysis, and box plot analysis as well as intra-operator and interoperator reproducibility analyses were performed. The SV ranged from 1540 to 1650 m/s. The mean SV ± SD was significantly different between healthy volunteers (1559 ± 11 m/s) and patients with F0-F3 (1575 ± 21 mm/s) and F4 (1594 ± 18 m/s) disease (P < .001). For detection of liver cirrhosis, the area under the receiver operating characteristic curve for SV was 0.80 (95% confidence interval, 0.69-0.89). With a cutoff value of 1589 m/s, the sensitivity, specificity, and positive and negative predictive values of SV for detection of liver cirrhosis were 82%, 76%, 70%, and 86%, respectively. Sound velocity measurements were reproducible (15%) and had acceptable operator independence (19%). The SV of liver tissue depends on the fibrosis stage. An SV of 1589 m/s or higher detects cirrhosis with high sensitivity. Therefore, SV measurement appears to be a promising new method for noninvasive quantification of liver fibrosis.
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0.34Impact points
[Multimodality therapy of colorectal cancer].
Der Internist. 10/2010; 51(11):1366-73.
Adjuvant chemotherapy for resected stage III colon cancer is indicated for all patients, including elderly patients >70 years. In general, adjuvant oxaliplatin-fluoropyrimidine chemotherapy should be started within 6 weeks after tumor resection and should be given for a period of 6 months. Howeve... [more] Adjuvant chemotherapy for resected stage III colon cancer is indicated for all patients, including elderly patients >70 years. In general, adjuvant oxaliplatin-fluoropyrimidine chemotherapy should be started within 6 weeks after tumor resection and should be given for a period of 6 months. However, patients aged >70 should receive fluoropyrimidine mono-chemotherapy. This mono-therapy, but not an oxaliplatin-based combination, can also be considered for patients with standard risk stage II tumors without microsatellite instability. In stage II patients with a high risk constellation adjuvant oxaliplatin-fluoropyrimidine combination therapy should be considered. Patients with stage II and III rectal cancer require neoadjuvant radiochemotherapy with fluoropyrimidine followed by adjuvant fluoropyrimidine treatment. There is no role for the use of VEGF- or EGFR-antibodies in the adjuvant therapy of colon cancer or in neoadjuvant therapy of rectal cancer. The prognosis of patients with primary resectable colorectal liver metastases may be improved by adjuvant or perioperative chemotherapy, while neoadjuvant systemic chemotherapy frequently facilitates potential curative resection of initially non-resectable liver metastases.
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9.36Impact points
Antitumoural immunity by virus-mediated immunogenic apoptosis inhibits metastatic growth of hepatocellular carcinoma.
Gut. 10/2010; 59(10):1416-26.
Viral infection of a dying cell dictates the immune response against intracellular antigens, suggesting that virotherapy may be an effective tool to induce immunogenic cell death during systemic cancer treatment. Since viruses and proteasome inhibitors both induce accumulation of misfolded proteins,... [more] Viral infection of a dying cell dictates the immune response against intracellular antigens, suggesting that virotherapy may be an effective tool to induce immunogenic cell death during systemic cancer treatment. Since viruses and proteasome inhibitors both induce accumulation of misfolded proteins, endoplasmic reticulum (ER) stress and immune responses during treatment of hepatocellular carcinoma (HCC) with bortezomib and the tumour-specifically replicating virus hTert-Ad (human telomerase reverse transcriptase promoter-regulated adenovirus) were investigated. Unfolded protein response (UPR) pathways and ER stress-mediated apoptosis were investigated by western blots, caspase-3 assays, 4',6-diamidino-2-phenylindole (DAPI) and Annexin V staining in HCC cells following hTert-Ad/bortezomib treatment. Oncolysis was assessed in subcutaneous HCC mouse models. Antiviral/antitumoural immune responses were characterised in immunocompetent HCC mouse models by ELISA, ELISpot assays and pentamer staining. Systemic efficacy of antitumoural immunity was investigated by determination of lung metastases burden. Bortezomib and hTert-Ad trigger complementary UPR pathways but negatively interfere with important recovery checkpoints, resulting in enhanced apoptosis of HCC cells in vitro and improved oncolysis in vivo. In immunocompetent mice, bortezomib inhibited antiviral immune responses, whereas ER stress-induced apoptosis of infected HCC resulted in caspase-dependent triggering of antitumoural immunity. In therapeutic settings in immunocompetent, but not in immunodeficient or CD8-depleted mice, virotherapy-induced antitumoural immunity efficiently inhibited outgrowth of non-infected lung metastases. Immunotherapeutic efficacy could be significantly improved by bortezomib in experiments with low viral doses. Proteasome inhibition during virotherapy disrupts the UPR, leading to enhanced ER stress-induced apoptosis, improved local oncolysis and antitumoural immunity. The results suggest that combining intratumoural virotherapy with adjuvant systemic therapies, which specifically support the function of the virotherapy as an antitumoural vaccine, is a promising immunotherapeutic strategy against HCC.
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15.39Impact points
The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells.
The Journal of clinical investigation. 10/2010; 120(11):3820-33.
Cyclin E is often overexpressed in cancer tissue, leading to genetic instability and aneuploidy. Cullin 3 (Cul3) is a component of the BTB-Cul3-Rbx1 (BCR) ubiquitin ligase that is involved in the turnover of cyclin E. Here we show that liver-specific ablation of Cul3 in mice results in the persisten... [more] Cyclin E is often overexpressed in cancer tissue, leading to genetic instability and aneuploidy. Cullin 3 (Cul3) is a component of the BTB-Cul3-Rbx1 (BCR) ubiquitin ligase that is involved in the turnover of cyclin E. Here we show that liver-specific ablation of Cul3 in mice results in the persistence and massive expansion of hepatic progenitor cells. Upon induction of differentiation, Cul3-deficient progenitor cells underwent substantial DNA damage in vivo and in vitro, thereby triggering the activation of a cellular senescence response that selectively blocked the expansion of the differentiated offspring. Positive selection of undifferentiated progenitor cells required the expression of the tumor suppressor protein p53. Simultaneous loss of Cul3 and p53 in hepatic progenitors turned these cells into highly malignant tumor-initiating cells that formed largely undifferentiated tumors in nude mice. In addition, loss of Cul3 and p53 led to the formation of primary hepatocellular carcinomas. Importantly, loss of Cul3 expression was also detected in a large series of human liver cancers and correlated directly with tumor de-differentiation. The expression of Cul3 during hepatic differentiation therefore safeguards against the formation of progenitor cells that carry a great potential for transformation into tumor-initiating cells.
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6.71Impact points
Routine bile collection for microbiological analysis during cholangiography and its impact on the management of cholangitis.
Gastrointestinal endoscopy. 08/2010; 72(2):284-91.
Antibiotic treatment of cholangitis is often insufficient because of inappropriate antibiotic use or bacterial resistance. To evaluate the role of routine bile collection during endoscopic retrograde cholangiography or percutaneous transhepatic cholangiography for microbiological analysis in the ant... [more] Antibiotic treatment of cholangitis is often insufficient because of inappropriate antibiotic use or bacterial resistance. To evaluate the role of routine bile collection during endoscopic retrograde cholangiography or percutaneous transhepatic cholangiography for microbiological analysis in the antibiotic management of cholangitis and to identify risk factors of bacteriobilia. Prospective, observational, diagnostic study. Hannover Medical School, Hannover, Germany. This study involved 243 consecutive patients undergoing endoscopic retrograde cholangiography/percutaneous transhepatic cholangiography for biliary complications after orthotopic liver transplantation (27%), malignancy (27%), primary sclerosing cholangitis (15%), benign strictures (11%), and choledocholithiasis (8%). Microbiological examination of bile samples. Patients with biliary stents or who were receiving repeated interventions after orthotopic liver transplantation were at increased risk of bacteriobilia (P < .05). The rate of gram-positive monomicrobial infection was higher in patients with primary sclerosing cholangitis (P < .01). In 40 examinations, patients presented with preprocedural cholangitis although they were receiving antibiotics. According to bile culture results, the antibiotic treatment was modified to a more specific therapy in 72.5% of patients. In patients who developed cholangitis after endoscopic retrograde cholangiography (27 examinations), specific antibiotic treatment was started or refined in 67% of cases, based on bile culture results. Contamination of samples during intervention cannot be totally excluded. Orthotopic liver transplantation, biliary stenting, and repeated interventions are risk factors of bacteriobilia. In our patients with primary sclerosing cholangitis, gram-positive monomicrobial infections were more common. A bile sample collected during cholangiography for microbiological analysis is a simple, potentially valuable, diagnostic tool in patients with cholangitis. Each center should recognize its own patterns of infection to ensure ideal targeted therapy.
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6.24Impact points
Targeting of p53-transcriptional dysfunction by conditionally replicating adenovirus is not limited by p53-homologues.
Molecular therapy : the journal of the American Society of Gene Therapy. 05/2010; 18(5):936-46.
A hallmark of human tumors is the loss of p53 or its transcriptional functions. In this study, we describe the generation of the conditionally replicating adenovirus Adp53sensor for the treatment of p53-dysfunctional tumors. p53-selective attenuation of viral replication was achieved by using p53-de... [more] A hallmark of human tumors is the loss of p53 or its transcriptional functions. In this study, we describe the generation of the conditionally replicating adenovirus Adp53sensor for the treatment of p53-dysfunctional tumors. p53-selective attenuation of viral replication was achieved by using p53-dependent expression of the transcriptional repressor Gal4-KRAB that was directed against the adenoviral E1A locus. Adp53sensor shows efficient replication in p53-dysfunctional, but not in p53-active cells. In p53-dysfunctional cells, p53-analogous transcriptional activity by other p53 family members was not sufficient to compromise replication of Adp53sensor. In comparison with a genetically similar, but p53-insensitive virus, Adp53sensor replication was inhibited after systemic infection of p53-wt-mice, but not in p53-ko-mice thus confirming the correct function of the chosen approach. Adp53sensor showed efficient lytic and replicative properties in all investigated cells with p53-dysfunction and successfully inhibited the growth of subcutaneous xenotransplants in vivo. We further demonstrated that intravenous injection of Adp53sensor lead to significantly reduced liver damage compared to the control virus. Together, our data show that Adp53sensor is an oncolytic, p53-selective adenovirus for efficient treatment of p53-dysfunctional tumors with a favorable toxicity profile. Moreover, Adp53sensor provides a strategy that should be applicable to other transcriptionally regulated DNA viruses.
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0.34Impact points
[Differentiated therapy of liver tumors].
Der Internist. 01/2010; 51(1):53-62.
Focal nodular hyperplasia is a polyclonal hyperplasia of liver cells as a result of locally enhanced blood flow because of vessel malformations. Only symptomatic FNH is an indication for resection or enucleation. In contrast to FNH growth of adenoma is dependent on sexual hormones. Solitary HNFalpha... [more] Focal nodular hyperplasia is a polyclonal hyperplasia of liver cells as a result of locally enhanced blood flow because of vessel malformations. Only symptomatic FNH is an indication for resection or enucleation. In contrast to FNH growth of adenoma is dependent on sexual hormones. Solitary HNFalpha-inactivated and inflammatory adenomas larger than 5 cm should be removed because of risk of tumor rupture or bleeding, while beta-catenin mutated adenomas should be surgically removed at any stage because of risk of malignant transformation. The prognosis of patients with HCC is dependent on the tumor stage, but also on the liver function. Resection is the treatment of choice for HCC in patients without liver cirrhosis. Patients with liver cirrhosis and early HCC without extrahepatic metastasis can be successfully treated by liver transplantation. If transplantation is not possible these tumors should be removed by local percutaneous ablation. Transarterial chemoembolization is an effective treatment for more advanced HCC in patients with good liver function. Studies showed that the multikinase inhibitor sorafenib significantly improves survival of patients with advanced or metastatic HCC in child A cirrhosis. The only curative option for patients with intrahepatic cholangiocarcinomas is surgical resection. Patients with unresectable cholangiocarcinomas should be treated with a chemotherapy consisting of Gemcitabine-Cisplatin-combination.
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1.23Impact points
[Adjuvant therapy in colon cancer].
Onkologie. 01/2010; 33 Suppl 4:2-7.
The goal of improving adjuvant treatment can be reached in two ways: firstly, by developing more effective drugs and protocols and, secondly, by selecting suitable patients on the basis of clinical and molecular factors. In UICC (Union internationale contre le cancer) stage II, microsatellite instab... [more] The goal of improving adjuvant treatment can be reached in two ways: firstly, by developing more effective drugs and protocols and, secondly, by selecting suitable patients on the basis of clinical and molecular factors. In UICC (Union internationale contre le cancer) stage II, microsatellite instability (MSI) is a strong prognostic factor. Whether it can also be used as a predictive marker is currently a matter of controversy because the available data are contradictory. The question whether or not the MSI status should be checked before treatment decisions are made in stage II patients can therefore not be clearly answered at present. For adjuvant treatment in stage III, with capecitabine/oxaliplatin (XELOX) there is now a new protocol available that is based on the orally administered prodrug capecitabine. With regard to the question of how much older patients in this stage may also benefit from a combination chemotherapy, new--and contradictory--data have emerged recently: firstly, preliminary results of two new studies have given rise to safety concerns and, secondly, an analysis by the 'ACCENT Collaborative Group' indicated lower efficacy of the 'newer' adjuvant protocols in older people. These findings, however, have now been called into question as a result of a new subgroup analysis from the XELOXA study. The expert group therefore recommended that the decision whether to treat patients older than 70 years with an (oral) fluoropyrimidine alone or in combination with oxaliplatin should be based on clinical parameters such as biological age and comorbidities.
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6.71Impact points
Management of major postsurgical gastroesophageal intrathoracic leaks with an endoscopic vacuum-assisted closure system.
Gastrointestinal endoscopy. 10/2009;
BACKGROUND: Endoscopic treatment options for postsurgical intrathoracic leaks include injection of fibrin glue, clip application, and stent placement. Endoscopic vacuum-assisted closure (E-VAC) may be an effective treatment option. OBJECTIVE: To demonstrate that E-VAC is an effective endoscopic trea... [more] BACKGROUND: Endoscopic treatment options for postsurgical intrathoracic leaks include injection of fibrin glue, clip application, and stent placement. Endoscopic vacuum-assisted closure (E-VAC) may be an effective treatment option. OBJECTIVE: To demonstrate that E-VAC is an effective endoscopic treatment option for closure of major intrathoracic postsurgical leaks. DESIGN AND SETTING: A prospective, single-center study at an academic medical center. PATIENTS: Eight consecutive patients with major intrathoracic postsurgical leaks. INTERVENTIONS: Endoscopic placement of transnasal draining tubes, armed with a size-adjusted sponge at their distal end, in the necrotic anastomotic cavities, followed by continuous suction. Sponge and drainage were changed twice weekly. Patients were followed-up for 193 +/- 137 days. MAIN OUTCOME MEASUREMENT: Successful leak closure. RESULTS: Successful closure of leaks was achieved in 7 of 8 patients (88%) after a mean of 23 +/- 8 days. A median of 7 endoscopic interventions was necessary. No major treatment-associated short-term or long-term (follow-up, 193 +/- 137 days) complications were noted. LIMITATIONS: Small sample size, single-center study, and lack of randomization. CONCLUSION: E-VAC is an effective endoscopic treatment modality for major postsurgical intrathoracic leaks. (This study is registered at Clinicaltrials.gov, identifier NCT00876551.).
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7.48Impact points
p53-dependent antiviral RNA-interference facilitates tumor-selective viral replication.
Nucleic acids research. 06/2009;
RNA-interference (RNAi) is a potent tool for specific gene silencing. In this study, we developed an adenovirus for conditional replication in p53-dysfunctional tumor cells that uses p53-selective expression of a microRNA-network directed against essential adenoviral genes. Compared to a control vir... [more] RNA-interference (RNAi) is a potent tool for specific gene silencing. In this study, we developed an adenovirus for conditional replication in p53-dysfunctional tumor cells that uses p53-selective expression of a microRNA-network directed against essential adenoviral genes. Compared to a control virus that expressed a scrambled microRNA-network, antiviral RNAi selectively attenuated viral replication in cells with transcriptionally active p53, but not in p53-dysfunctional tumor cells where both viruses replicated equivalently. Since these results were confirmed by an in vivo comparison of both viruses after infection of p53-knockout and normal mice, we could demonstrate that attenuated replication was indeed a result of p53-selective exhibition of antiviral RNAi. Addressing the therapeutic applicability, we could show that the application of RNAi-controlled virus efficiently lysed p53-dysfunctional tumors in vitro and in vivo but resulted in drastically reduced load of virus-DNA in the liver of treated mice. We have generated a broadly applicable adenovirus for selective destruction of p53-dysfunctional tumors and thereby demonstrate that virus-encoded RNAi-networks represent an efficient and versatile tool to modify viral functions. RNAi-networks can be applied to all transcriptionally regulated DNA-viruses to remodulate viral tropism and thus provide means to generate specifically replicating vectors for clinical applications.
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4.75Impact points
VSV virotherapy improves chemotherapy by triggering apoptosis due to proteasomal degradation of Mcl-1.
Gene therapy. 05/2009;
Overexpression of myeloid cell leukemia 1 protein (Mcl-1), an anti-apoptotic B-cell lymphoma 2 (Bcl-2) family member, contributes to chemotherapy resistance of tumors. The short half-life of Mcl-1 makes it an interesting target for therapeutic agents that negatively interfere with cellular protein b... [more] Overexpression of myeloid cell leukemia 1 protein (Mcl-1), an anti-apoptotic B-cell lymphoma 2 (Bcl-2) family member, contributes to chemotherapy resistance of tumors. The short half-life of Mcl-1 makes it an interesting target for therapeutic agents that negatively interfere with cellular protein biosynthesis, such as oncolytic viruses. Vesicular Stomatitis Virus (VSV) has been established as the oncolytic virus that efficiently disrupts de novo protein biosynthesis of infected cells. Here, we show that after VSV infection, Mcl-1 protein levels rapidly declined, whereas the expression of other members of the Bcl-2 family remained unchanged. Mcl-1 elimination was a consequence of proteasomal degradation, as overexpression of a degradation-resistant Mcl-1 mutant restored Mcl-1 levels. Mcl-1 rescue inhibited apoptosis and thereby confirmed that Mcl-1 downregulation contributes to VSV-induced apoptosis. In vitro, VSV virotherapy in combination with chemotherapy revealed an enhanced therapeutic effect compared with the single treatments, which could be reverted by Mcl-1 rescue or RNA interference (RNAi)-mediated knockdown of pro-apoptotic Bax and Bak proteins. Finally, in a tumor mouse model, combinations of doxorubicin and VSV showed a superior therapeutic efficacy compared with VSV or doxorubicin alone. In summary, our data indicate that VSV virotherapy is an attractive strategy to overcome tumor resistance against conventional chemotherapy by elimination of Mcl-1.Gene Therapy advance online publication, 16 April 2009; doi:10.1038/gt.2009.39.
Following (6)
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Matthias J. Bahr
Sana Kliniken Lübeck GmbH -
Mahaboob Khan
University of Madras -
Ijad Madisch
Massachusetts General Hospital -
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Nikola Kolev
University Hospital
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