Current Cancer Drug Targets - Volume 14, Issue 3, 2014

There is currently no cure for metastatic castration-resistant prostate cancer (CRPC). Chemoresistance and metastatic disease remain the main causes of treatment failure and mortality in CaP patients. Although several advances have been made in the control of CRPC with some newly developed drugs, there is still an urgent need to investigate the mechanisms and pathways of prostate cancer (CaP) metastasis and chemoresistance, identify useful therapeutic targets, develop novel treatment approaches, improve current therapeutic modalities and increase patients' survival. Cancer stem cells (CSCs), a minority population of cancer cells characterised by self-renewal and tumor initiation, have gained intense attention as they not only play a crucial role in cancer recurrence but also contribute substantially to chemoresistance. As such, a number of mechanisms in chemoresistance have been identified to be associated with CSCs. Therefore, a thorough and integral understanding of these mechanisms can identify novel biomarkers and develop innovative therapeutic strategies for CaP treatment. Our recent data have demonstrated CSCs are associated with CaP chemosensitivity. In this review, we discuss the roles of putative CSC markers in CaP chemoresistance and elucidate several CSC-associated signaling pathways such as PI3K/Akt/mTOR, Wnt/β-catenin and Notch pathways in the regulation of CaP chemoresistance. Moreover, we will summarize emerging and innovative approaches for the treatment of CRPC and address the challenging CRPC that is driven by CSCs. Understanding the link between CSCs and metastatic CRPC will facilitate the development of novel therapeutic approaches to overcome chemoresistance and improve the clinical outcomes of CaP patients.

Lung cancer is one of the most common malignant tumors and is the leading cause of cancer mortality worldwide. However, drug resistance induced by chemotherapeutants to lung cancer cells is the primary issue during the chemotherapy of lung cancer. Many mechanisms such as the changes of drug metabolism related genes and signal pathways are involved in chemoresistance. MicroRNAs (miRNAs) are a class of endogenetic, non-coding, short-chain and small RNAs that regulate cell growth, apoptosis and signal transduction. There are growing numbers of evidence suggesting that miRNA polymorphisms associate with drug metabolism and resistance. In addition, differentially expressed miRNAs play critical roles in the prediction of the sensitivity to chemotherapeutic agents in lung cancer. The recent progress demonstrates that regulation of specific miRNA expression will break novel paths for overcoming lung cancer resistance and the personalized therapy. Together, in this review we have discussed the current understanding of the role of miRNA on drug resistance, and the potential implications of miRNA in lung cancer targeted therapy.

Epithelial ovarian cancer (EOC) is the most deadly tumor of the female reproductive system. Despite improvements in understanding the biology of EOC, therapeutic strategies still depend on surgery and combination of taxane and platinum agents. Here, we provide a summary of clinically tested biomarkers potentially useful to predict drug response. Resistance against platinum derivatives can result from lower drug concentrations, alterations in the target molecule and changes in the cellular signal transduction pathways. Taxane resistance can develop due to decreased intracellular drug concentration, alterations in microtubuli structure and changes in the cellular response including ERBB2 (epidermal growth factor receptor 2). A few key genes have been suggested as biomarkers for hormonal therapy. Currently, the only targeted therapy agent approved for ovarian cancer is the VEGF (vascular endothelial growth factor) inhibitor bevacizumab. Response to bevacizumab is correlated with VEGF-A levels and hypertension. The primary problems in identifying reliable biomarkers for EOC are the usage of different clinical endpoints, multivariate analysis for a panel of clinical parameters and the lack of published comprehensive clinical information of patients enrolled in these studies. The future lies in adding targeted agents to the taxane/platinum gold standard and in a more detailed stratification of patients into sub-cohorts enabling a more effective therapy. In conclusion, a large-scale coordinated effort is needed for the robust validation of the numerous biomarker candidates available in EOC therapy.

Osteosarcoma (OS) is the most common primary malignancy of bone and is usually associated with poor prognosis due to its high incidence of metastasis and chemoresistance. Molecular pathogenesis of OS is poorly understood. We previously showed that OS cells are refractory to BMP9-induced osteogenesis and respond favorably to proliferation and tumor growth. Here we investigate if Notch signaling mediates the BMP9-promoted cell proliferation and tumor growth of human osteosarcoma (OS). We find that the expression of Notch1, Notch2, Notch3, DLL1, JAG1 and JAG2 is readily detected in most of the tested OS cell lines. BMP9-promoted OS cell proliferation, migration, and cell cycle S/G2 progression are effectively inhibited by a dominant-negative mutant of Notch1 (dnNotch1) or the γ-secretase inhibitor Compound E (ComE). Furthermore, BMP9-promoted tumor growth and osteolytic lesions in vivo are significantly inhibited by dnNotch1. BMP9 up-regulates the expression of Notch1, Notch3, DLL1, and JAG1 in OS cells. Accordingly, BMP9 stimulation induces a nuclear accumulation of NICD, which is blocked by ComE. Our results demonstrate that BMP9-promoted OS proliferation and tumor growth is at least in part mediated by Notch signaling, suggesting that osteogenic BMPs may function as upstream regulators of Notch signaling in OS tumorigenesis. Thus, pharmacologic intervention of Notch signaling may be explored as a new therapeutic strategy for human OS tumors.

Heparanase is the unique and specific functional endoglycosidase capable of cleaving heparan sulfate (HS) chains. It exerts its enzymatic activity catalyzing the cleavage of the β (1,4)-glycosidic bond between glucuronic acid and glucosamine residue. HS cleavage results in remodelling of the extracellular matrix as well as in regulating the release of many HS-linked molecules such as growth factors, cytokines and enzymes involved in inflammation, wound healing and tumour invasion. A pro-metastatic and pro-angiogenic role for this enzyme has been widely demonstrated in many primary human tumours since high levels of heparanase correlate with lymph node and distant metastasis, elevated micro vessel density and reduced survival of cancer patients. Recently, data have been reported that heparanase regulates heparan sulfate proteoglycan syndecan-1 and promotes its shedding from the cell surface. Shed syndecan-1 in turn controls tumour growth, metastasis and neo-angiogenesis mainly by promoting growth-factor signaling in the tumour milieu. Considering that, once inactivated, there are no other molecules capable of performing the same function, it is evident how this enzyme may be an effective and attractive drug target. Several heparanase inhibitors have been developed and some of them have undergone clinical trials showing efficacy against tumours. In this mini-review we will discuss current knowledge of heparanase involvement in cancer as well as its targeted inhibition as a promising therapeutic option in tumour treatment.

Secreted proteins are an attractive minefield for cancer drug targets. An iTRAQ-based tandem mass spectrometry approach was employed to relatively quantify proteins in the secretomes of four isogenic breast cancer cell lines with increasing metastatic potential. CXCL3 was found to be upregulated in aggressive cancer cells. SiRNA and antibody neutralization studies supported a role of CXCL3 in metastatic processes. Meta-analysis of the mRNA level of CXCL3 in 1881 breast tumors supported a role of CXCL3 in clinical breast cancer. Our results support a functional role of CXCL3 in breast cancer metastasis and as a viable target for cancer therapy.

Parkinson’s disease (PD) and cancer are often thought of as two sides of the same coin. At first glance, cancer and PD appear to have little in common. PD is caused by the degeneration of dopaminergic neurons, whereas cancer results from the uninhibited growth of tumor cells. Increasing numbers of genetic studies suggest that the pathogenesis of PD and cancer may involve similar genes, pathways, and mechanisms. The differences in the pathological and cellular mechanisms, and the associated genetic mutations, may result in two such divergent diseases. In this article, we highlight some molecular mechanisms and key biomarkers which might cause those two diseases from misfolding and degradation of proteins, mitochondrial damage, oxidative stress response, cell cycle control and DNA repair, and the PI3K/AKT/ mTOR pathway, in order to provide help to the understanding and treatment of these two diseases.