Current management of locally advanced pancreatic cancer

Maheshwari, Vivek; Moser, A. James

doi:10.1038/ncpgasthep0240

Cited by 21 publications

(21 citation statements)

References 53 publications

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“…Most patients with PDAC exhibit marked intrinsic resistance to radiation therapy and chemotherapy. Therefore, surgical resection is the only curative therapy but the disease is so aggressive that only 10% to 20% of patients qualify for surgery at the time of diagnosis (2). Therefore, identification of novel targets and development of new therapeutic approaches are urgently needed.…”

Section: Pancreatic Ductal Adenocarcinoma (Pdac) Is a Serious Healthmentioning

confidence: 99%

Therapeutic Significance of Elevated Tissue Transglutaminase Expression in Pancreatic Cancer

Verma

Guha²,

Diagaradjane

et al. 2008

Clinical Cancer Research

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Purpose: Tissue transglutaminase (TG2) is a multifunctional protein that is implicated in development of drug resistance and metastasis. Therefore, we examined therapeutic targeting of TG2 for inhibiting growth and metastasis of in vivo growing pancreatic ductal adenocarcinoma (PDAC) in nude mice. Experimental Design: We implanted Panc-28 pancreatic cancer cells to induce orthotopic PDAC tumors in nude mice and determined the efficacy of liposomal TG2 small interfering RNA (siRNA) either alone or in combination with gemcitabine. Results: We show that down-regulation of endogenous TG2 by siRNA could effectively block the growth of PDAC. Moreover, down-regulation of TG2 significantly enhanced the therapeutic efficacy of gemcitabine against PDAC and inhibited metastatic spread of the disease. The antitumor activity was related to inhibition of proliferation, angiogenesis, and Akt phosphorylation. Conclusion: siRNA-mediated down-regulation of TG2 represents a promising therapeutic approach for improved treatment of PDAC. Pancreatic ductal adenocarcinoma (PDAC) is a serious healthproblem. In the United States alone, f33,000 new cases are diagnosed annually, and about the same number of patients die of the disease (1). Gemcitabine (Gemzar), the drug of choice for treating PDAC, has had minimal effect on patients' survival. Most patients with PDAC exhibit marked intrinsic resistance to radiation therapy and chemotherapy. Therefore, surgical resection is the only curative therapy but the disease is so aggressive that only 10% to 20% of patients qualify for surgery at the time of diagnosis (2). Therefore, identification of novel targets and development of new therapeutic approaches are urgently needed.Recently, we reported that the majority of PDAC tumors and cell lines have high basal levels of tissue transglutaminase (TG2) expression. TG2 is a unique member of the transglutaminase family of enzymes that can catalyze calciumdependent posttranslational modification of proteins as well as calcium-independent activities, such as protein disulfide isomerase, GTP/ATP hydrolase, and serine/threonine kinase functions (3 -8). In recent years, convincing evidence supporting a role for TG2 in cancer cell survival and invasive functions has accumulated. Thus, development of drug resistance and metastatic phenotypes in various cancer cell types is frequently associated with increased expression of TG2 (9 -17). Studies showed that down-regulation of TG2 expression by antisense, ribozyme, or small interfering RNA (siRNA) reversed drug resistance in lung and breast cancer cells (11,14,15). Conversely, treatment of breast cancer cells with epidermal growth factor induced expression of TG2 and protected the cells against doxorubicin-induced apoptosis (18). Moreover, inhibition of TG2 expression by siRNA significantly inhibited the invasiveness of PDAC cells and increased their propensity to undergo autophagic death (19). These results suggest that aberrant expression of TG2 in cancer cells contributes to the development of drug...

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Section: Pancreatic Ductal Adenocarcinoma (Pdac) Is a Serious Healthmentioning

confidence: 99%

Therapeutic Significance of Elevated Tissue Transglutaminase Expression in Pancreatic Cancer

Verma

Guha²,

Diagaradjane

et al. 2008

Clinical Cancer Research

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“…Furthermore, at present, surgical resection offers the only chance for long-term survival for pancreatic cancer (4,5). However, the disease is so aggressive that only about 20% of patients are indication for surgery at the time of diagnosis (6). Therefore, identification of novel targets and development of new therapeutic approaches are required against pancreatic cancer to improve patient prognosis.…”

Section: Introductionmentioning

confidence: 99%

PCA-1/ALKBH3 Contributes to Pancreatic Cancer by Supporting Apoptotic Resistance and Angiogenesis

et al. 2012

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The PCA-1/ALKBH3 gene implicated in DNA repair is expressed in several human malignancies but its precise contributions to cancer remain mainly unknown. In this study, we have determined its functions and clinical importance in pancreatic cancer. PCA-1/ALKBH3 functions in proliferation, apoptosis and angiogenesis were evaluated in human pancreatic cancer cells in vitro and in vivo. Further, PCA-1/ALKBH3 expression in 116 patients with pancreatic cancer was evaluated by immunohistochemistry. siRNA-mediated silencing of PCA-1/ALKBH3 expression induced apoptosis and suppressed cell proliferation. Conversely, overexpression of PCA-1/ALKBH3 increased anchorage-independent growth and invasiveness. In addition, PCA-1/ALKBH3 silencing downregulated VEGF expression and inhibited angiogenesis in vivo. Furthermore, immunohistochemical analysis showed that PCA-1/ALKBH3 expression was abundant in pancreatic cancer tissues, where it correlated with advanced tumor status, pathological stage and VEGF intensity. Importantly, patients with low positivity of PCA-1/ALKBH3 expression had improved postoperative prognosis compared with those with high positivity. Our results establish PCA-1/ALKBH3 as important gene in pancreatic cancer with potential utility as a therapeutic target in this fatal disease. Cancer Res; 72(18); 4829-39. Ó2012 AACR.

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confidence: 99%

“…Ninety per cent of patients have unresectable disease at diagnosis, of whom 40 -50% have locally advanced disease (White et al, 1999), and reported to have better median survival of 6 -10 months compared to the 3 -6 months noted in metastatic disease (American Cancer Society, 2003). Radiotherapy approaches, with or without chemotherapy, have been frequently used in this subset (Maheshwari and Moser, 2005).…”

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Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy

et al. 2007

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There is no consensus on the management of locally advanced pancreatic cancer, with either chemotherapy or combined modality approaches being employed (Maheshwari and Moser, 2005). No published meta-analysis (Fung et al, 2003;Banu et al, 2005;Liang, 2005;Bria et al, 2006;Milella et al, 2006) has included randomised controlled trials employing radiation therapy. The aim of this systematic review was to compare the following: (i) chemoradiation followed by chemotherapy (combined modality therapy) vs best supportive care (ii) radiotherapy vs chemoradiation (iii) radiotherapy vs combined modality therapy (iv) chemotherapy vs combined modality therapy (v) 5FU-based combined modality treatment vs another-agent-based combined modality therapy. Relevant randomised controlled trials were identified by searching databases, trial registers and conference proceedings. The primary end point was overall survival and secondary end points were progression-free survival/time-to-progression, response rate and adverse events. Survival data were summarised using hazard ratio (HR) and response-rate/adverse-event data with relative risk. Eleven trials involving 794 patients met the inclusion criteria. Length of survival with chemoradiation was increased compared with radiotherapy alone (two trials, 168 patients, HR 0.69; 95% confidence interval (CI) 0.51 -0.94), but chemoradiation followed by chemotherapy did not lead to a survival advantage over chemotherapy alone (two trials, 134 patients, HR 0.79; CI 0.32 -1.95). Meta-analyses could not be performed for the other comparisons. A survival benefit was demonstrated for chemoradiation over radiotherapy alone. Chemoradiation followed by chemotherapy did not demonstrate any survival advantage over chemotherapy alone, but important clinical differences cannot be ruled out due to the wide CI.

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Current management of locally advanced pancreatic cancer

Cited by 21 publications

References 53 publications

Therapeutic Significance of Elevated Tissue Transglutaminase Expression in Pancreatic Cancer

Therapeutic Significance of Elevated Tissue Transglutaminase Expression in Pancreatic Cancer

PCA-1/ALKBH3 Contributes to Pancreatic Cancer by Supporting Apoptotic Resistance and Angiogenesis

Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy

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