Clinical development of cancer therapeutics that target metabolism.

Glucose and glutamine metabolism in cancer cells are markedly elevated relative to non-transformed normal cells. This metabolic reprogramming enables the production of adenosine triphosphate and the anabolic precursors needed for survival, growth and motility. The recent observations that mutant oncogenic proteins and the loss of tumor suppressors activate key metabolic enzymes suggest that selective inhibition of these enzymes may yield effective cancer therapeutics with acceptable toxicities. In support of this concept, pre-clinical studies of small molecule antagonists of several metabolic enzymes in tumor-bearing mice have demonstrated reasonable therapeutic indices. We will review the rationale for targeting metabolic enzymes as a strategy to treat cancer and will detail the results of several recent clinical trials of metabolic inhibitors in advanced cancer patients.

6-Phosphofructo-2-kinase (PFKFB3) promotes cell cycle progression and suppresses apoptosis via Cdk1-mediated phosphorylation of p27.

The control of glucose metabolism and the cell cycle must be coordinated in order to guarantee sufficient ATP and anabolic substrates at distinct phases of the cell cycle. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are well established regulators of glucose metabolism via their synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent allosteric activator of 6-phosphofructo-1-kinase (Pfk-1). PFKFB3 is overexpressed in human cancers, regulated by HIF-1α, Akt and PTEN, and required for the survival and growth of multiple cancer types. Although most functional studies of the role of PFKFB3 in cancer progression have invoked its well-recognized function in the regulation of glycolysis, recent observations have established that PFKFB3 also traffics to the nucleus and that its product, F2,6BP, activates cyclin-dependent kinases (Cdks). In particular, F2,6BP stimulates the Cdk-mediated phosphorylation of the Cip/Kip protein p27 (threonine 187), which in turn results in p27's ubiquitination and proteasomal degradation. As p27 is a potent suppressor of the G1/S transition and activator of apoptosis, we hypothesized that the known requirement of PFKFB3 for cell cycle progression and prevention of apoptosis may be partly due to the ability of F2,6BP to activate Cdks. In this study, we demonstrate that siRNA silencing of endogenous PFKFB3 inhibits Cdk1 activity, which in turn stabilizes p27 protein levels causing cell cycle arrest at G1/S and increased apoptosis in HeLa cells. Importantly, we demonstrate that the increase in apoptosis and suppression of the G1/S transition caused by siRNA silencing of PFKFB3 expression is reversed by co-siRNA silencing of p27. Taken together with prior publications, these observations support a model whereby PFKFB3 and F2,6BP function not only as regulators of Pfk-1 but also of Cdk1 activity, and therefore serve to couple glucose metabolism with cell proliferation and survival in transformed cells.

Adherence to the Swiss guidelines for management of COPD: experience of a Swiss teaching hospital.

QUESTIONS UNDER STUDY: Swiss guidelines for the management of chronic obstructive pulmonary disease (COPD) were published in 2002. We aimed at assessing adherence to the proposed guidelines by the physicians in charge for all patients referred to our hospital for acute exacerbations of COPD over a one year period. METHODS: In a prospective observational study, data from a questionnaire and from records of all patients referred to our hospital with acute exacerbation of COPD were collected. Diagnostic steps as well as therapeutic and prophylactic interventions were reviewed. Where applicable, interventions were stratified according to proposed levels of evidence A-D. RESULTS: 45 patients in whom the diagnosis of COPD had been made before were included. Diagnosis was established by spirometry in 71%, in the remaining diagnosis was based on clinical grounds only. Non-smoking advice was given to 69%, and 16% were offered a nicotine-replacement trial (level A). Information about a disease management plan was given in 40% of the patients (level B), 22% had done a six minute walking distance test. 27% of the patients had participated in a pulmonary rehabilitation program (level A). 93% were on regular bronchodilator therapy (level B), and 56% had regular inhaled corticosteroids (level B). CONCLUSION: Confirmation of the diagnosis of COPD by spirometry is lacking in a significant number of patients. Most patients were treated with regular bronchodilators, however, relevant over-treatment with beta-adrenergic substances and overuse of inhaled corticosteroids in mild disease stages are common. Efforts for disease prevention and education as well as awareness of the potential benefits of pulmonary rehabilitation programs are still insufficient. Efforts to improve the adherence to the Swiss guidelines for the management of COPD should be intensified.