Search

Tropolones are promising organic compounds that can have important biologic effects. We developed a series of new 2-quinolyl-1,3-tropolones derivatives that were prepared by the acid-catalyzed reaction of 4,7-dichloro-2-methylquinolines with 1,2-benzoquinones. 2-Quinolyl-1,3-tropolones have been synthesized and tested for their anti-proliferative activity against several human cancer cell lines. Two compounds (3d and mixture B of 3i–k) showed excellent activity against six cancer cell lines of different tissue of origin. The promising compounds 3d and mixture B of 3i–k also demonstrated induction of apoptotic cell death of ovarian cancer (OVCAR-3, OVCAR-8) and colon cancer (HCT 116) cell lines and affected ERK signaling. In summary, 2-quinolyl-1,3-tropolones are promising compounds for development of effective anticancer agents.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer with poor survival and limited therapeutic options. HCC has different etiologies, typically associated with viral or carcinogenic insults or fatty liver disease and underlying chronic inflammation presents as a major unifying mechanism for tumor promotion. On the other hand, mechanisms of how inflammatory response can regulate anti-cancer immunity in HCC remain incompletely understood.Interleukin (IL)-27 receptor signaling plays an anti-inflammatory role in a variety of infectious and chronic inflammatory diseases. Here, using genetic and pharmacological approaches we found that IL-27 receptor (IL-27R) signaling promotes HCC development in vivo. Genetic loss of IL-27R suppressed HCC development in both toxin/carcinogen-induced diethylnitrosamine (DEN) and non-alcoholic steatohepatitis (NASH)-driven models. Elevated expression of IL-27RA rendered poor prognosis to HCC patients. Mechanistically, the pro-tumorigenic effect was mediated by immunoregulatory role of IL-27R signaling within the tumor microenvironment, particularly the suppression of Natural killer (NK) cells. IL-27R ablation enhanced the accumulation and activation of cytotoxic NK cells during acute liver injury and in HCC tumors, while depletion of NK cells abrogated the effect of genetic IL-27R disruption.Taken together, our data suggest an unexpected role of IL-27R signaling as a novel immunological checkpoint regulating NK cell activity and promoting development of HCC of different etiologies.

Pancreatic cancer is rapidly rising to become the 2nd leading cause of cancer deaths by 2020 in the USA. The rise in pancreatic cancer incidence is paralleled by the epidemic of obesity, type 2 diabetes, and associated increase in blood cholesterol, although mechanistic explanations for this are currently unknown. We and others have demonstrated that cancers with activated EGFR and KRAS signaling have increased demands for cholesterol and are vulnerable to interference with cholesterol uptake or endogenous cholesterol biosynthesis. We recently identified a metabolic step in the distal cholesterol pathway, mediated by SC4MOL and NSDHL enzymes, as a critical regulator of cell growth in the keratinocyte model of KRAS-induced carcinogenesis via the LXR agonistic effect of accumulating C4-methylsterols. Based on these preliminary data, we set out to test if pancreatic cancer initiation and progression depend on accelerated cholesterol biosynthesis in a genetic mouse model containing a conditional cholesterol pathway enzyme deficiency (conditional knockout of Nsdhlf/f) in the context of pancreatic cancer development in KPC mice (LSL-KrasG12D;Tp53f/f;Pdx1-Cre). Results: Conditional inactivation of NSDHL alone in pancreatic tissue during normal development produced no apparent phenotype. As expected, the NSDHL-sufficient KPC mice as well as heterozygous Nsdhlf/+ littermates did not survive beyond 8 weeks of age due to rapid development of progressive pancreatic tumors showing complete displacement of pancreatic tissue with adenocarcinoma and high-grade PanIN lesions. Contrastingly, the survival of pancreatic conditional NSDHL-null mice was significantly extended beyond the median survival of 50 days in NSDHL-sufficient age-matched controls. Furthermore, the progression of pancreatic lesions from ADM to PanIN3 was remarkably delayed on NSDHL-null background, with only a proportion of animals developing adenocarcinoma. Evaluation of pancreatic tissues revealed a dramatic reduction of tumor-induced desmoplasia at all stages of pancreatic cancer development. Our ongoing studies will address the role of cholesterol metabolism in pancreatic cancer progression via regulation of tumor-specific production of stroma-recruiting growth factors. Conclusions: Our studies demonstrated for the first time essential genetic evidence for metabolic dependency of pancreatic cancer on cholesterol metabolism. We identified NSDHL as a critical target in the endogenous pathway of cholesterol biosynthesis, and determined that blockade of NSDHL has dramatic consequences on the reciprocal signaling between the KRAS-transformed pancreatic cancer cells and the stroma. Citation Format: Linara Gabitova, Alena Klochkova, Diana Restifo, Aleksandra Mazitova, Edna Cukierman, Tiffiney Hartman, Igor Astsaturov. Cholesterol biosynthesis is a critical metabolic dependency in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 438. doi:10.1158/1538-7445.AM2017-438