Low-Dose Chemotherapy in Combination with COX-2 Inhibitors and PPAR-Gamma Agonists in Recurrent High-Grade Gliomas – A Phase II Study

Hau, Peter; Kunz‐Schughart, Leoni A.; Bogdahn, Ulrich; Baumgart, U.; Hirschmann, Birgit; Weimann, E.; Mühleisen, Helmut; Ruemmele, Petra; Steinbrecher, Andreas; Reichle, Albrecht

doi:10.1159/000120028

Cited by 62 publications

(43 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PPARγ agonists have therefore been proposed as novel anti-neoplastic agents for the treatment of glioma, although currently these drugs have not been evaluated in serum-free glioma cell cultures or direct-to-xenograft animal models (Ellis and Kurian, 2014). A Phase II clinical trial evaluating treatment with pioglitazone, a relatively specific PPARγ agonist, in combination with the chemotherapeutic temozolomide and the COX2 inhibitor rofecoxib, did not demonstrate improved prognosis, and individual patient responses did not correspond to protein expression levels of COX2 or PPARγ (Hau et al, 2007). More studies are needed to evaluate the biological and functional roles of PPARs in glioma.…”

Section: Peroxisome Proliferator-activator Receptors Are Central Regumentioning

confidence: 99%

Metabolic Reprogramming in Glioma

Strickland

Stoll

2017

Front. Cell Dev. Biol.

266

269

View full text Add to dashboard Cite

Many cancers have long been thought to primarily metabolize glucose for energy production—a phenomenon known as the Warburg Effect, after the classic studies of Otto Warburg in the early twentieth century. Yet cancer cells also utilize other substrates, such as amino acids and fatty acids, to produce raw materials for cellular maintenance and energetic currency to accomplish cellular tasks. The contribution of these substrates is increasingly appreciated in the context of glioma, the most common form of malignant brain tumor. Multiple catabolic pathways are used for energy production within glioma cells, and are linked in many ways to anabolic pathways supporting cellular function. For example: glycolysis both supports energy production and provides carbon skeletons for the synthesis of nucleic acids; meanwhile fatty acids are used both as energetic substrates and as raw materials for lipid membranes. Furthermore, bio-energetic pathways are connected to pro-oncogenic signaling within glioma cells. For example: AMPK signaling links catabolism with cell cycle progression; mTOR signaling contributes to metabolic flexibility and cancer cell survival; the electron transport chain produces ATP and reactive oxygen species (ROS) which act as signaling molecules; Hypoxia Inducible Factors (HIFs) mediate interactions with cells and vasculature within the tumor environment. Mutations in the tumor suppressor p53, and the tricarboxylic acid cycle enzymes Isocitrate Dehydrogenase 1 and 2 have been implicated in oncogenic signaling as well as establishing metabolic phenotypes in genetically-defined subsets of malignant glioma. These pathways critically contribute to tumor biology. The aim of this review is two-fold. Firstly, we present the current state of knowledge regarding the metabolic strategies employed by malignant glioma cells, including aerobic glycolysis; the pentose phosphate pathway; one-carbon metabolism; the tricarboxylic acid cycle, which is central to amino acid metabolism; oxidative phosphorylation; and fatty acid metabolism, which significantly contributes to energy production in glioma cells. Secondly, we highlight processes (including the Randle Effect, AMPK signaling, mTOR activation, etc.) which are understood to link bio-energetic pathways with oncogenic signals, thereby allowing the glioma cell to achieve a pro-malignant state.

show abstract

Section: Peroxisome Proliferator-activator Receptors Are Central Regumentioning

confidence: 99%

Metabolic Reprogramming in Glioma

Strickland

Stoll

2017

Front. Cell Dev. Biol.

266

269

View full text Add to dashboard Cite

show abstract

“…In two phase II studies, troglitazone had no effect in either patients with breast cancer or colorectal cancer 176, 177 . Some clinical trials examining the effect of PPARγ ligands combined with other therapeutics revealed no effect for some studies 178, 179 , but positive results for patients with thyroid carcinoma and glioma 180–182 . It is also worth noting that a chromosomal translocation that fuses the paired box 8 gene ( PAX8 ) with the PPARG gene is found in some cases of thyroid cancer 183 .…”

Section: Ppars and Cancer Treatment And Preventionmentioning

confidence: 99%

The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention

2012

View full text Add to dashboard Cite

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, inflammation, proliferation and differentiation. Although all of these functions might contribute to the influence of PPARs in carcinogenesis, there is a distinct need for a balanced review of the literature and additional experimentation to determine the potential for targeting PPARs for cancer therapy and cancer chemoprevention. As PPAR agonists include drugs used for the treatment of metabolic diseases, a more complete understanding of the roles of PPARs in cancer will aid in determining any increased cancer risk for patients undergoing therapy with PPAR agonists.

show abstract

“…Combination therapy of PPARγ agonists and other agents has been shown to be more effective than using either agent alone. 108,109 Moreover, some studies suggest a cross-talk between PPARγ and EGFR signalling pathways. 77 should be given to the ligand employed.…”

Section: Safety Issues and Pparγ Agonists In Clinical Developmentmentioning

confidence: 99%