Abstract
Pancreatic cancer exhibits an extraordinarily high level of resistance to almost any kind of systemic therapy evaluated in clinical trials so far. Therefore, the identification of novel therapeutic targets is urgently required. High-throughput screens have emerged as an important tool to identify putative targets for diagnosis and therapy in an unbiased manner. More than a decade ago, microarray technology was introduced to identify differentially expressed genes in pancreatic cancer as compared to normal pancreas, chronic pancreatitis and other cancer types located in close proximity to the pancreas. In addition, proteomic screens have facilitated the identification of differentially secreted proteins in body fluids of pancreatic cancer patients, serving as possible biomarkers. Recently, RNA interference-based loss-of-function screens have been used to identify functionally relevant genes, whose knock-down has impact on pancreatic cancer cell viability, thereby representing potential new targets for therapeutic intervention. This review summarizes recent results of transcriptional, proteomic and functional screens in pancreatic cancer and discusses potentials and limitations of the respective technologies as well as their impact on future therapeutic developments.
Highlights
Pancreatic cancer carries the most dismal prognosis of all solid tumors
50% of the tumors show inactivating mutations of p53 and about 55% have homozygous deletions or mutations of SMAD4 [3]. Some of these mutations can already be found in preinvasive precursor lesions of pancreatic cancer, such as pancreatic intraepithelial neoplasias or PanIN lesions, which can be graded according to their histomorphological appearance and their accumulating genetic alterations in PanIN I–III
The initial alterations occurring in early PanIN lesions (PanIN I) include
Summary
Pancreatic cancer carries the most dismal prognosis of all solid tumors. It is the fourth leading cause of cancer death in the U.S with approximately 36,800 deaths attributable to pancreatic cancer in. The identification and characterization of these cancer-related genes have increased our understanding of the genetic basis of pancreatic cancer development, but this knowledge has not translated into clinical practice, since survival of patients with this disease has not improved significantly over the past two decades. It appears that a multitude of transcriptional and posttranslational events regulate the expression and function of oncogenic and tumor-suppressive genes. Screening of proteins for their functional impact on cardinal hallmarks of cancer such as survival, invasiveness and proliferation, e.g., by loss-of-function screens, are mandatory to identify novel functionally relevant targets in an unbiased manner
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