Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer

Garrido‐Laguna, Ignacio; Tan, Aik Choon; Uson, Maria; Angenendt, M.; Ma, W W; Villaroel, Maria C.; Zhao, Ming; Rajeshkumar, N. V.; Jimeno, Antonio; Donehower, Ross C.; Iacobuzio‐Donahue, Christine A.; Barrett, Michael T.; Rudek, Michelle A.; Rubio-Viqueira, Belén; Laheru, Daniel A.; Hidalgo, Manuel

doi:10.1038/sj.bjc.6605819

Cited by 68 publications

(52 citation statements)

References 31 publications

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“…Accordingly, Rapa resistance has been reported to be dependent on the expression of AkT and PTEN in different cell lines (39,40). In line with the data presented here, Rapa and its analogues showed rather disappointing effects in clinical studies, and enhancing its efficiency by additional inhibition of PI3k-AkT signaling is currently under intense investigation for PC (19,41).…”

Section: Discussionsupporting

confidence: 69%

Autophagy and cell death signaling following dietary sulforaphane act independently of each other and require oxidative stress in pancreatic cancer

Naumann

Fortunato

Zentgraf³

et al. 2011

Int J Oncol

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Abstract. the broccoli isothiocyanate, sulforaphane (Sfn), was recently identified as being capable of eliminating highly therapy-resistant pancreatic carcinoma (PC) cells without inducing toxic side effects. While SFN has been shown to stimulate autophagy or 'self-eating', it is unclear whether this catabolic process is a pro-or anti-tumorigenic response. To investigate the role of autophagy in SFN-induced cell death, established PC cell lines were treated with SFN, and the induction of autophagy was evaluated by detecting the abundance of autophagic vesicles by electron microscopy, the increase in converted LC3-II by Western blot analysis and the autophagosome puncta of GFP-LC3 by immunofluorescence. SFN-induced autophagy was suppressed by the autophagy inhibitor chloroquine, while the autophagy inducer rapamycin did not further enhance autophagy in PC cells. Importantly, neither modulator altered SFN cytotoxicity, suggesting that SFN-induced autophagy and cell death act independently of each other. In contrast, the antioxidant N-acetyl-cysteine sustained cell viability and prevented autophagy induction after SFN exposure, indicating that both signaling pathways depend on reactive oxygen species (ROS). Our studies provide a valuable new mechanistic insight into the SFN-induced elimination of PC cells and suggest that an SFN-enriched diet potentially enhances ROS-releasing chemotherapeutic agents.

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Section: Discussionsupporting

confidence: 69%

Autophagy and cell death signaling following dietary sulforaphane act independently of each other and require oxidative stress in pancreatic cancer

Naumann

Fortunato

Zentgraf³

et al. 2011

Int J Oncol

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“…19), including breast (30,31), colorectal (32,33), lung (34), pancreatic cancers (35,36), and glioblastoma (37,38). While we were preparing this manuscript, two papers were published on tumor grafts obtained from ovarian tumors, one focusing on a small series of high-grade serous type (13), whereas the other presenting a large tumor bank of ovarian cancer of different histotype (14).…”

Section: Discussionmentioning

confidence: 99%

Patient-Derived Ovarian Tumor Xenografts Recapitulate Human Clinicopathology and Genetic Alterations

et al. 2014

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Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. On the basis of its histopathology and molecular-genomic changes, ovarian cancer has been divided into subtypes, each with distinct biology and outcome. The aim of this study was to develop a panel of patient-derived EOC xenografts that recapitulate the molecular and biologic heterogeneity of human ovarian cancer. Thirty-four EOC xenografts were successfully established, either subcutaneously or intraperitoneally, in nude mice. The xenografts were histologically similar to the corresponding patient tumor and comprised all the major ovarian cancer subtypes. After orthotopic transplantation in the bursa of the mouse ovary, they disseminate into the organs of the peritoneal cavity and produce ascites, typical of ovarian cancer. Gene expression analysis and mutation status indicated a high degree of similarity with the original patient and discriminate different subsets of xenografts. They were very responsive, responsive, and resistant to cisplatin, resembling the clinical situation in ovarian cancer. This panel of patient-derived EOC xenografts that recapitulate the recently type I and type II classification serves to study the biology of ovarian cancer, identify tumor-specific molecular markers, and develop novel treatment modalities. Cancer Res; 74(23); 6980-90. Ó2014 AACR.

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“…The precise mechanism of action of this effect is not known, but reduction of glucose uptake may be important. In this regard, mTOR inhibition with rapamycin has been shown to decrease glucose uptake by reducing the levels of Glut 1 in pancreas cancer (52,53).…”

Section: Nutritional Requirements Of Pdamentioning

confidence: 99%

Translational Therapeutic Opportunities in Ductal Adenocarcinoma of the Pancreas

Hidalgo

Hoff

2012

Clinical Cancer Research

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Pancreatic ductal adenocarcinoma (PDA) remains a devastating disease with nearly equal incidence and mortality rates. Over the past few decades, a litany of randomized clinical trials has failed to improve the outcome of this disease. More recently, the combination chemotherapy regimen FOLFIRINOX has shown improvement in overall survival over the single agent gemcitabine, and nab-paclitaxel (an albumin-coated formulation of paclitaxel) in combination with gemcitabine has shown promising results in phase II studies. Despite limited impact on patient care as of yet, the molecular and biologic understanding of PDA has advanced substantially. This includes understanding the genomic complexity of the disease, the potential importance of the tumor microenvironment, the metabolic adaptation of PDA cells to obtain nutrients in a hypoxic environment, and the role of pancreatic cancer stem cells. These fundamental discoveries are starting to be translated into clinical studies. In this overview, we discuss the implications of biologic understanding of PDA in clinical research and provide insights for future development of novel approaches and agents in this disease.

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Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer

Cited by 68 publications

References 31 publications

Autophagy and cell death signaling following dietary sulforaphane act independently of each other and require oxidative stress in pancreatic cancer

Autophagy and cell death signaling following dietary sulforaphane act independently of each other and require oxidative stress in pancreatic cancer

Patient-Derived Ovarian Tumor Xenografts Recapitulate Human Clinicopathology and Genetic Alterations

Translational Therapeutic Opportunities in Ductal Adenocarcinoma of the Pancreas

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