Pancreatic Cancer: Basic and Clinical Aspects

Schneider, Günter; Siveke, Jens T.; Eckel, Florian; Schmid, Roland M.

doi:10.1053/j.gastro.2005.04.001

Cited by 269 publications

(213 citation statements)

References 163 publications

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“…The intrinsic resistance of pancreatic carcinoma to established therapies including radiotherapy calls for novel strategies to target tumor cell resistance (Schneider et al, 2005). Since IAPs block apoptosis at the core of the apoptotic machinery, therapeutic modulation of IAPs could addresses a key control point in deciding cell fate (Fulda and Debatin, 2006c).…”

Section: Discussionmentioning

confidence: 99%

“…Pancreatic carcinoma is among the leading causes of cancer deaths in the Western World (Schneider et al, 2005). Since pancreatic carcinoma is a prototype cancer that is usually resistant to current treatment protocols, treatment of pancreatic cancer remains one of the most challenging problems in oncology (Schneider et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Since pancreatic carcinoma is a prototype cancer that is usually resistant to current treatment protocols, treatment of pancreatic cancer remains one of the most challenging problems in oncology (Schneider et al, 2005). This calls for novel strategies to overcome resistance of pancreatic carcinoma cells in order to improve the poor prognosis of this disease.…”

Section: Introductionmentioning

confidence: 99%

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Sensitization of pancreatic carcinoma cells for γ-irradiation-induced apoptosis by XIAP inhibition

et al. 2007

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Resistance of pancreatic cancer to current treatments including radiotherapy remains a major challenge in oncology and may be caused by defects in apoptosis programs. Since 'inhibitor of apoptosis proteins' (IAPs) block apoptosis at the core of the apoptotic machinery by inhibiting caspases, therapeutic modulation of IAPs could tackle a key resistance mechanism. Here, we report that targeting X-linked inhibitor of apoptosis (XIAP) by RNA-interference-mediated knockdown or overexpression of second mitochondria-derived activator of caspase significantly enhanced apoptosis and markedly reduced clonogenic growth of pancreatic carcinoma cells upon c-irradiation. Analysis of signaling pathways revealed that antagonizing XIAP increased activation of caspase-2, -3, -8 and -9 and loss of mitochondrial membrane potential upon c-irradiation. Interestingly, inhibition of caspases also reduced the cooperative effect of XIAP targeting and c-irradiation to trigger mitochondrial perturbations, suggesting that XIAP controls a feedback mitochondrial amplification loop by regulating caspase activity. Importantly, our data demonstrate for the first time that small molecule XIAP inhibitors sensitized pancreatic carcinoma cells for c-irradiation-induced apoptosis, whereas they had no effect on c-irradiation-mediated apoptosis of non-malignant fibroblasts indicating some tumor specificity. In conclusion, targeting XIAP, for example by small molecules, is a promising novel approach to enhance radiosensitivity of pancreatic cancer that warrants further investigation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sensitization of pancreatic carcinoma cells for γ-irradiation-induced apoptosis by XIAP inhibition

et al. 2007

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“…1 Currently, there is no effective treatment for this disease; surgical resection is only applicable to a small proportion of patients with a marginal effect on the overall survival rate, and chemotherapy and radiation also have very limited effects on patient's survival. 2 Therefore, there is a need for new approaches to treat such an aggressive disease.…”

Section: Introductionmentioning

confidence: 99%

Antisense Smo under the control of the PTCH1 promoter delivered by an adenoviral vector inhibits the growth of human pancreatic cancer

Gao

Chen

et al. 2006

Gene Ther

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“…Translation of this endoscopic technique into the clinic should tremendously improve detection of pancreatic neoplasia, thus reforming management of patients at risk for PDAC. is one of the deadliest human malignancies, with an extremely poor 5-y survival rate below 5% (1). Because patients generally present with symptoms relating to late stages of the disease, diagnosis of resectable PDAC is achieved in less than 15% of cases (1).…”

mentioning

confidence: 99%

In vivo diagnosis of murine pancreatic intraepithelial neoplasia and early-stage pancreatic cancer by molecular imaging

Eser

Messer²,

Eser³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor patient outcome often resulting from late diagnosis in advanced stages. To date methods to diagnose early-stage PDAC are limited and in vivo detection of pancreatic intraepithelial neoplasia (PanIN), a preinvasive precursor of PDAC, is impossible. Using a cathepsin-activatable near-infrared probe in combination with flexible confocal fluorescence lasermicroscopy (CFL) in a genetically defined mouse model of PDAC we were able to detect and grade murine PanIN lesions in real time in vivo. Our diagnostic approach is highly sensitive and specific and proved superior to clinically established fluorescein-enhanced imaging. Translation of this endoscopic technique into the clinic should tremendously improve detection of pancreatic neoplasia, thus reforming management of patients at risk for PDAC. is one of the deadliest human malignancies, with an extremely poor 5-y survival rate below 5% (1). Because patients generally present with symptoms relating to late stages of the disease, diagnosis of resectable PDAC is achieved in less than 15% of cases (1). However, investigators have reported that diagnosis and resection of early-stage PDAC (<2 cm in size) can result in a 4-y survival rate of up to 78% (2-5). These data suggest that early detection of PDAC can improve patient outcome. In addition, it has been shown that resection of PDAC combined with adjuvant chemotherapy can improve 5-y survival rates to 25%. Thus, increasing the chance of resection will lead to improved survival.Of the more than 33,000 new cases of PDAC diagnosed in the United States every year, ∼10% occur in families with a high prevalence of PDAC and are thus referred to as familial (6, 7). In a cohort study of twins, it was proposed that inherited factors may be responsible for up to 36% of pancreatic cancers, suggesting that the incidence of familial pancreatic cancer may be even higher than presently assumed (8). To date, several conditions associated with familial PDAC have been described and groups of individuals at low, moderate, or high risk for developing the disease have been defined (9, 10). Although clinical trials are currently testing screening protocols for the high-risk group, aimed at detecting curable precursors of PDAC such as intraductal papillary mucinous neoplasia, pancreatic intraepithelial neoplasia (PanIN), and early-stage PDAC (10-12), the results of these trials show that early lesions are often missed. Furthermore, false positive findings can lead to overtreatment of a significant fraction of the screened population (12). These findings show that better diagnostic tools for the detection of preneoplastic lesions and early-stage PDAC are urgently needed. Recent data demonstrate that preinvasive precursors progress slowly over many years to decades to invasive pancreatic cancer (13). The parental pancreatic cancer founder clone then requires more than 5 y to acquire the capacity to metastasize (13). Thus, there is a time frame of several years for the diagnosi...

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Pancreatic Cancer: Basic and Clinical Aspects

Cited by 269 publications

References 163 publications

Sensitization of pancreatic carcinoma cells for γ-irradiation-induced apoptosis by XIAP inhibition

Sensitization of pancreatic carcinoma cells for γ-irradiation-induced apoptosis by XIAP inhibition

Antisense Smo under the control of the PTCH1 promoter delivered by an adenoviral vector inhibits the growth of human pancreatic cancer

In vivo diagnosis of murine pancreatic intraepithelial neoplasia and early-stage pancreatic cancer by molecular imaging

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