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Pancreatic ductal adenocarcinoma (PDA) is a lethal disease. Overall survival is typically 6 months from diagnosis. Numerous phase 3 trials of agents effective in other malignancies have failed to benefit unselected PDA populations, although patients do occasionally respond. Studies in other solid tumors have shown that heterogeneity in response is determined, in part, by molecular differences between tumors. Furthermore, treatment outcomes are improved by targeting drugs to tumor subtypes in which they are selectively effective, with breast and lung cancers providing recent examples. Identification of PDA molecular subtypes has been frustrated by a paucity of tumor specimens available for study. We have overcome this problem by combined analysis of transcriptional profiles of primary PDA samples from several studies, along with human and mouse PDA cell lines. We define three PDA subtypes: classical, quasimesenchymal and exocrine-like, and we present evidence for clinical outcome and therapeutic response differences between them. We further define gene signatures for these subtypes that may have utility in stratifying patients for treatment and present preclinical model systems that may be used to identify new subtype specific therapies.

Thiazolidinediones (TZDs) are insulin-sensitizing drugs and are potent agonists of the nuclear peroxisome proliferator-activated receptor-[gamma] (PPAR-[gamma]). Although muscle is the major organ responsible for insulin-stimulated glucose disposal, PPAR-[gamma] is more highly expressed in adipose tissue than in muscle. To address this issue, we used the Cre-loxP system to knock out Pparg, the gene encoding PPAR-[gamma], in mouse skeletal muscle. As early as 4 months of age, mice with targeted disruption of PPAR-[gamma] in muscle showed glucose intolerance and progressive insulin resistance. Using the hyperinsulinemic-euglycemic clamp technique, the in vivo insulin-stimulated glucose disposal rate (IS-GDR) was reduced by [similar]80% and was unchanged by 3 weeks of TZD treatment. These effects reveal a crucial role for muscle PPAR-[gamma] in the maintenance of skeletal muscle insulin action, the etiology of insulin resistance and the action of TZDs., Author(s): Andrea L Hevener [1, 6]; Weimin He [1, 6]; Yaacov Barak [3, 4, 6]; Jamie Le [1]; Gautam Bandyopadhyay [1]; Peter Olson [2, 4]; Jason Wilkes [1]; Ronald M [...]

Author(s): Enrique Saez [1, 3]; Peter Olson [1, 2]; Ronald M Evans (corresponding author) [1] The role of the nuclear peroxisome proliferator-activated receptor (PPAR)-[gamma] in cancer has been a subject [...]