Person:

Spiegelman, Bruce

Objective: The peroxisome proliferator–activated receptor-(\gamma) coactivator (PGC)-1 family of transcriptional coactivators controls hepatic function by modulating the expression of key metabolic enzymes. Hepatic gain of function and complete genetic ablation of PGC-1(\alpha) show that this coactivator is important for activating the programs of gluconeogenesis, fatty acid oxidation, oxidative phosphorylation, and lipid secretion during times of nutrient deprivation. However, how moderate changes in PGC-1(\alpha) activity affect metabolism and energy homeostasis has yet to be determined. Research Design and Methods: To identify key metabolic pathways that may be physiologically relevant in the context of reduced hepatic PGC-1(\alpha) levels, we used the Cre/Lox system to create mice heterozygous for PGC-1(\alpha) specifically within the liver (LH mice). Results: These mice showed fasting hepatic steatosis and diminished ketogenesis associated with decreased expression of genes involved in mitochondrial (\beta)-oxidation. LH mice also exhibited high circulating levels of triglyceride that correlated with increased expression of genes involved in triglyceride-rich lipoprotein assembly. Concomitant with defects in lipid metabolism, hepatic insulin resistance was observed both in LH mice fed a high-fat diet as well as in primary hepatocytes. Results: These data highlight both the dose-dependent and long-term effects of reducing hepatic PGC-1(\alpha) levels, underlining the importance of tightly regulated PGC-1(\alpha) expression in the maintenance of lipid homeostasis and glucose metabolism.

Purpose Current therapy for lung cancer involves multimodality therapies. However, many patients are either refractory to therapy or develop drug resistance. KRAS and epidermal growth factor receptor (EGFR) mutations represent some of the most common mutations in lung cancer, and many studies have shown the importance of these mutations in both carcinogenesis and chemoresistance. Genetically engineered murine models of mutant EGFR and KRAS have been developed that more accurately recapitulate human lung cancer. Recently, using cell-based experiments, we showed that platinum-based drugs and the antidiabetic drug rosiglitazone (PPARg ligand) interact synergistically to reduce cancer cell and tumor growth. Here, we directly determined the efficacy of the PPARγ/carboplatin combination in these more relevant models of drug resistant non – small cell lung cancer.

Experimental Design Tumorigenesis was induced by activation of either mutant KRAS or EGFR. Mice then received either rosiglitazone or carboplatin monotherapy, or a combination of both drugs. Change in tumor burden, pathology, and evidence of apoptosis and cell growth were assessed.

Results Tumor burden remained unchanged or increased in the mice after monotherapy with either rosiglitazone or carboplatin. In striking contrast, we observed significant tumor shrinkage in mice treated with these drugs in combination. Immunohistochemical analyses showed that this synergy was mediated via both increased apoptosis and decreased proliferation. Importantly, this synergy between carboplatin and rosiglitazone did not increase systemic toxicity.

Conclusions These data show that the PPARγ ligand/carboplatin combination is a new therapy worthy of clinical investigation in lung cancers, including those cancers that show primary resistance to platinum therapy or acquired resistance to targeted therapy.