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Neurokinin-1 Receptor: A New Promising Target in the Treatment of Cancer

Polyphenols Inhibit Indoleamine 3,5-Dioxygenase-1 Enzymatic Activity -- A Role of Immunomodulation in Chemoprevention

Abstract: Metastasis is one of the cancer hallmarks described by Hanahan and Weinberg. Emerging evidence shows that it requires interplays between cancer cells and micro-environmental biofactors. Indoleamine 3,5-dioxygenase-1 (IDO-1) produced by cancer, local lymph nodes, and satellite cells have been demonstrated as one of the biofactors. Aberrant IDO-1 activity has partially contributed to immunosuppressive environment by repressing T lymphocyte and natural killer cell activities, and activating regulatory T cells (Treg, CD4+CD25+). Clinical investigations further show a negative correlation between the enzyme activity and prognosis in patients with various cancer types. The findings suggest a possible role of IDO-1 inhibitor in restoring host anti-tumor immunity and attenuating cancer metastasis. Data from preclinical and phase I/II clinical studies with IDO-1 inhibitors support this hypothesis. Polyphenols as antioxidants are shown to exhibit anticancer activities. However, the underlying mechanism has not been entirely characterized. We recently found that certain flavone molecules profoundly inhibit the enzymatic activity of IDO-1 but not mRNA expression in human neuronal stem cells (hNSC) confirmed by cell-based assay and qRT-PCR. To further the investigation, we studied additional anti-cancer phytochemicals including chalcone, flavonol, isoflavone, and diterpene. Here we summarize the results and show that the inhibitory sensitivity depends on the molecular structure in the following order: apigenin > wogonin > chrysin > biacalein ~ genistein > quercetin. Curcumin and isoliquiritigenin (a chalcone) exhibited toxicity to hNSCs. Although oridonin (a diterpene) showed a null toxicity toward hNSCs, it repressed the enzymatic function only marginally in contrast to its potent cytotoxicity in various cancer cell lines. While the mode of action of the enzyme-polyphenol complex awaits to be investigated, the sensitivity of enzyme inhibition was compared to the anti-proliferative activities toward three cancer cell lines. The IC50s obtained from both sets of the experiments indicate that they are in the vicinity of micromolar concentration with the enzyme inhibition slightly more active. These results suggest that attenuation of immune suppression via inhibition of IDO-1 enzyme activity may be one of the important mechanisms of polyphenols in chemoprevention or combinatorial cancer therapy. ... Read more

Prolactin in Breast and Prostate Cancer: Molecular and Genetic Perspectives

Abstract: Prostate and breast cancers affect millions of men and women, respectively. Advanced forms of the disease, which can no longer be controlled by hormonal disruption or chemotherapy, have very limited treatment options. Consequently, there is a major benefit to identify new targets for therapy in both types of cancer. The prolactin (PRL) signaling cascade, by virtue of its importance to the pathology of both diseases, has emerged as a potential treatment target. To date, several methods for antagonizing the PRL receptor (PRLR) and its signaling pathways have been developed which include protein-based and small molecule antagonists. However, a better understanding of the genetic and molecular characteristics of the PRL cascade is needed for the successful therapeutic application of antagonists. At the level of genetics, it is necessary to determine the functional significance of non-synonymous single nucleotide polymorphisms of the PRLR and their association with disease prevalence and severity. At the molecular level, a comprehensive knowledge of interactions of the PRL signaling pathway with other oncogenic molecules is warranted so as to identify beneficial combinatorial strategies. This review discusses multiple features of the PRL signaling cascade and how they can be exploited in the search for effective therapies for patients with breast and prostate cancers. ... Read more

Seeking Synergy in p53 Transcriptional Activation for Cancer Therapy

Abstract: Targeting the p53-MDM2 pathway is regarded as a viable therapeutic strategy and is supported by several preclinical mouse models which show that the restoration of p53 activity leads to tumor regression in vivo. Given that a large proportion of cancers, including hematological malignancies, retain the expression of the wildtype p53 allele, reactivating wildtype p53 in these cancers could lead to selective apoptosis and is regarded as a potential therapeutic strategy. The exploration of inhibitors and peptides targeting the p53-MDM2 pathway led to the discoveries of specific small molecule inhibitors that disrupt the MDM2-mediated inhibition of p53 transcriptional activity and protein stability. Nutlin is one of the specific small molecule that is well tolerated in vivo in mice but has been used in combinations with conventional chemotherapy and radiotherapy, as well as molecularly targeted drugs to further increase its specificity and potency in vivo. We attempt to identify pathways or new targets which when inhibited may synergize with nutlin in its activation of p53 transcriptional activity. Our previous results show that CDK inhibition synergizes with nutlin in p53 activation and p53-dependent apoptosis, converting a cell cycle arrest response to apoptosis. Here, using a siRNA screen against 726 human kinases, we identified several pathways, including the MAP kinase pathway, the sphingosine kinase pathway, and the CDK pathway which may have crosstalk with the p53 pathway. Selective inhibition of these pathways may synergize with nutlin in the induction of p53 transcriptional activity. ... Read more

Gene Therapy and Virotherapy: Novel Therapeutic Approaches for Brain Tumors

Abstract: Glioblastoma multiforme (GBM) is a deadly primary brain tumor in adults, with a median survival of ~12-18 months post-diagnosis. Despite recent advances in conventional therapeutic approaches, only modest improvements in median survival have been achieved; GBM usually recurs within 12 months post-resection, with poor prognosis. Thus, novel therapeutic strategies to target and kill GBM cells are desperately needed. Our group and others are pursuing virotherapy and gene therapy strategies for the treatment of GBM. In this review, we will discuss various virotherapy and gene therapy approaches for GBM currently under pre-clinical and clinical evaluation including direct or conditional cytotoxic, and/or immunostimulatory approaches. We also discuss cutting-edge technologies for drug/gene delivery and targeting brain tumors, including the use of stem cells as delivery platforms, the use of targeted immunotoxins, and the therapeutic potential of using GBM microvesicles to deliver therapeutic siRNAs or virotherapies. Finally, various animal models available to test novel GBM therapies are discussed. ... Read more

Glioblastoma Genetics: In Rapid Flux

Abstract: Glioblastoma is the most common and most lethal primary brain tumor. While small progress has been made in treating this cancer in recent years, glioblastoma remains largely resistant to all existing therapies. It has been hoped that dissection of the genetics of this cancer would lead to more targeted and effective treatments, and new advances may finally be bringing this closer to fruition. Within the last few years, high-throughput efforts such as The Cancer Genome Atlas and a massive sequencing project have yielded novel insights and classifications of this dreaded cancer. The likely impact on care delivery in the clinic may only be a few years away. The rapid and exciting pace of advances in glioblastoma genetics has prompted this up-to-date review. ... Read more

Advances and Challenges in the Treatment of Glioblastoma: A Clinician's Perspective

Abstract: Glioblastoma (GBM) is the most deadly form of human cancer. Most patients diagnosed with this WHO grade IV malignant glioma survive about 12 months. Despite international efforts, treatment of GBM remains one of the most challenging tasks in clinical oncology. While new molecular pathways active in the biology and invasiveness of glioma are being constantly discovered, translation of basic science achievements into clinical practice is rather slow. Advances in surgical approaches, radiotherapy, and chemotherapy are contributing to incremental improvements in survival of the patients with GBM and improved quality of life. Yet much more significant strides need to be made before we can witness positive outcomes, similar to those seen in certain other cancers that can now be treated successfully. This review will discuss standard of care approach to GBM therapy in a newly diagnosed and recurrent setting. It will summarize the recent developments in management of this disease as well as future directions, keeping a practicing clinician in mind. ... Read more

RNA Interference and Personalized Cancer Therapy

Abstract: Despite billions of dollars allocated to cancer research, cancer remains the number 2 cause of death in the United States with less than 50% of advanced cancer patients living one year following standard treatment. Cancer is a complex disease both intrinsically and in relation to its host environment. From a molecular standpoint no two cancers are the same despite histotypic similarity. As evidenced by the recent advances in molecular biology, treatment for advanced cancer is headed towards specific targeting of vulnerable signaling nodes within the reconfigured pathways created by "omic" rewiring. With advancements in proteo-genomics and the capacity of bioinformatics, complex tumor biology can now be more effectively and rapidly analyzed to discover the vulnerable high information transfer nodes within individual tumors. RNA interference (RNAi) technology, with its capability to knock down the expression of targeted genes (the vulnerable nodes), is moving into the clinic to target these nodes, which are integral to tumor maintenance, with a low risk of side-effects and to block intrinsic immunosuppressors thereby priming the tumor for immune attack. An RNAi based sequential approach, a so called "one-two punch," is being advocated comprising tumor volume reduction (ideally to minimal residual disease status) effected by integrated multi-target knockdown followed by immune activation. Examples and recent developments are provided to illustrate this highly powerful approach heralding the future of personalized cancer therapy. ... Read more

Tracking the Seed and Tending the Soil: Evolving Concepts in Metastatic Breast Cancer

Abstract: Metastasis, the process whereby cancer cells spread from their primary site of origin and grow in adjacent or distant sites, is the primary cause of death in cancer patients. The last 30 years has witnessed significant progress in decreasing cancer mortality rates -- largely as a result of improved screening and prevention, practical applications of cancer genomics, and less toxic, more targeted therapies. Despite these improvements, metastasis relentlessly drives mortality. The pervasive mortality from metastasis highlights the shortcomings of traditionally accepted hypotheses on the metastatic process. Historically, metastasis has been described as a unidirectional process, whereby cancer cells leave a primary tumor and seed metastasis in regional lymph nodes or distant sites. This anatomically based hypothesis has dictated much of our medical, and in particular, surgical approach to treating cancers. Alternatively, recent research indicates that metastasis is a multidirectional process whereby cancer cells can seed distant sites as well as the primary tumor itself. The multidirectional pathway of cancer cells, termed "self-seeding," has been corroborated in several experimental and clinical models. This review will evaluate the "self-seeding" hypothesis with attention both to the "seed" (cancer cells) as well as the "soil" (premetastatic niche). Increasingly, the role of the microenvironment surrounding metastases appears essential to the survival of metastatic colonies. The self-seeding model depends not only on the inherent mobility of cancer cells, but also on the supporting non-cancerous cells which enable circulating tumors cells to migrate to and survive in distant sites. The recognition that some of these non-cancerous cells include key components of the immune system has re-ignited the field of immunotherapy in cancer. One particular area of immunotherapy research, tumor entrained neutrophils, will be reviewed in more depth. Ultimately, understanding the dynamic interplay between cancer cells and the metastatic niche offers fertile ground for progress both in the treatment and prevention of metastasis. ... Read more

Promises and Drawbacks of Targeting Cell Cycle Kinases in Cancer

Abstract: The loss of ability in controlling cell cycle leads to aberrant cell growth and is a hallmark of cancer cells. Cell cycle regulation and progression mainly rely on protein phosphorylation events, therefore cell cycle kinases have long been viewed as potential targets for anticancer strategies. Consistently, cell cycle kinases are often dysregulated in different types of human cancer. Despite years of research and attempts directed at inhibiting cell cycle kinases, none of these approaches has been successfully translated to the clinic to halt tumorigenesis. Here, we review several currently pursued strategies and highlight both current challenges and some recent findings, which might help to develop new, better conceived therapeutic approaches based on cell-cycle kinase inhibition. ... Read more

Non-coding RNAs and Cancer: New Paradigms in Oncology

Abstract: Over the last decade, a growing number of non-coding transcripts have been found to have roles in gene regulation and RNA processing. The most well known small non-coding RNAs (ncRNAs) are the microRNAs (miRNAs), but the network of long and short non-coding transcripts is complex and is likely to contain as yet unidentified classes of molecules that form transcriptional regulatory networks. miRNAs and some other ncRNAs have been found to be involved in human tumorigenesis, revealing a new layer in the molecular architecture of cancer. Gene expression studies have shown that hundreds of miRNAs are deregulated in cancer cells, and functional studies have clarified that miRNAs are involved in all the molecular and biologic processes that drive tumorigenesis. Here, we summarize the recent advances in understanding miRNAs' and other ncRNAs' involvement in cancer and illustrate how this knowledge may be useful in medical practice. New diagnostic classifiers based on miRNAs will soon be available for medical practitioners, and even more importantly, miRNAs may become novel anti-cancer therapies. ... Read more

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