Targeting phosphoinositide 3-kinase signalling in lung cancer

Lung cancer is the leading cause of cancer-related mortality worldwide and more than 1 million people annually die in consequence of lung cancer. Although an improvement in lung cancer treatment could be achieved, especially in the last decade, the development of additional therapeutic strategies is urgently required in order to provide improved survival benefit for patients. Lung cancer formation is caused by genetic modifications commonly caused by tobacco smoking. Numerous studies have demonstrated the role of extracellular growth factors in lung cancer cell proliferation, metastasis, and chemoresistance. Mutations and amplifications in molecules related to receptor tyrosine signalling, such as EGFR, ErbB2, c-Met, c-Kit, VEGFR, PI3K, and PTEN are only some of the alterations known to contribute to the development of lung cancer. The phosphoinositide 3-kinase (PI3K) pathway, fundamental for cell development, growth, and survival, is known to be frequently altered in neoplasia, including carcinomas of the lung. Based on the high frequency of alterations, which include mutations and amplifications, leading to over-activation of certain upstream/downstream mediators, targeting components of the PI3K signalling pathway is considered to be a promising therapeutic approach in cancer treatment. In this article we will summarize the current knowledge about the involvement of PI3K signalling in lung cancer and discuss the development of targeted therapies involving PI3K pathway inhibitors.

Continent urinary diversion

During the last decade continent urinary diversion, especially orthotopic bladder substitution has become increasingly popular following radical cystectomy for bladder cancer. In general, if sphincter sparing surgery is possible, orthotopic bladder substitution is performed, if not then continent catheterisable reservoirs are a viable option. Strict patient selection criteria and improved surgical technique have had a positive influence on outcome, not only on survival but also on quality of life issues. It is becoming increasingly obvious, that a nerve sparing surgical technique not only improves sexual function but also continence. In addition, the length of the intestinal segment has an influence on continence and the degree of metabolic consequences, which are discussed in detail. Postoperative surveillance and instruction of patients is of utmost value for good functional results. Overall patient satisfaction and quality of life seem comparable in the various types of continent urinary diversions, and improved when compared to a urinary stoma. Continent urinary diversion offers a good quality of life with few long-term complications and should be considered the treatment of choice in the majority of patients, independent of sex.

Antisense molecules for targeted cancer therapy

The efficacy of traditional anti-cancer agents is hampered by toxicity to normal tissues, due to the lack of specificity for malignant cells. Recent advances in our understanding of molecular genetics and tumor biology have led to the identification of signaling pathways and their regulators implicated in tumorigenesis and malignant progression. Consequently, novel biological agents were designed which specifically target key regulators of cell survival and proliferation activated in malignant cells and thus are superior to unspecific cytotoxic agents. Antisense molecules comprising conventional single-stranded antisense oligonucleotides (ASO) and small interfering RNA (siRNA) inhibit gene expression on the transcript level. Thus, they specifically target the genetic basis of cancer and are particularly useful for inhibiting the expression of oncogenes the protein products of which are inaccessible to small molecules or inhibitory antibodies. Despite the somewhat disappointing results of recent antisense oncology trials, the identification of new cancer targets and ongoing progress in ASO and siRNA technology together with improvements in tumor targeted delivery have raised new hopes that this fascinating intervention concept will eventually translate into enhanced clinical efficacy.

Apoptosis regulation by autophagy gene 5

Autophagy is a cellular process, in which cellular proteins and cytoplasmic organelles are degraded. It reflects the response of a cell to stress or starvation with the primary goal of cell survival. On the other hand, if the autophagic activity is too high, cell death happens, suggesting that this process requires a tight control. Autophagic cell death has often been observed under conditions, in which apoptosis is blocked. Recent studies suggest that autophagy may promote apoptosis and that Bcl-2 cannot block only apoptosis, but also autophagy and autophagic cell death. Here, we discuss recent findings regarding the interrelations between autophagy and apoptosis. In particular, we would like to draw the attention of the readers to Atg5, which exhibits, like Bcl-2, a dual function by modulating both autophagy and apoptosis.

Targeting the conversion of ceramide to sphingosine 1-phosphate as a novel strategy for cancer therapy

Sphingolipids not only function as structural components of cell membranes but also act as signaling molecules to regulate fundamental cellular responses, such as cell death and differentiation, proliferation and certain types of inflammation. Particularly the cellular balance between ceramide and sphingosine 1-phosphate seems to be crucial for a cell's decision to either undergo apoptosis or proliferate, two events which are implicated in tumor development and growth. Whereas ceramide possesses proapoptotic capacity in many cell types, sphingosine 1-phosphate acts as a counterplayer able to induce cell proliferation and protect cells from undergoing apoptosis. Therefore, tipping the balance in favour of ceramide production, i.e. by inhibiting ceramidase or sphingosine kinase activities has potential to support its proapoptotic action and hence represents a promising rational approach to effective cancer therapy. This review highlights most recent data on the regulation of cellular sphingolipid formation and their potential implication in tumor development, and provides perspectives for their use as targets in molecular intervention therapy.