Cancer letters
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We present a rationale for further clinical development and assessment of metronomic chemotherapy on the basis of unexpected results obtained in translational mouse models of cancer involving treatment of advanced metastatic disease. Historically, mouse cancer therapy models have been dominated by treating established primary tumors or early stage low volume microscopic disease. Treatment of primary tumors is also almost always the case when using genetically engineered mouse models (GEMMs) of cancer or patient-derived xenografts (PDXs). ⋯ These include antiangiogenesis, stimulation of the immune system, stromal cell targeting in tumors, and possibly direct tumor cell targeting, including targeting cancer stem cells (CSCs). In addition, metronomic chemotherapy regimens minimize or even eliminate the problem of chemotherapy-induced host responses that may actually secondarily promote tumor growth and malignancy after causing an initial and beneficial anti-tumor response. We suggest that future preclinical studies of metronomic chemotherapy should be concentrated in the following areas: i) further comparative assessment of anti-tumor efficacy in primary vs metastatic treatment settings; ii) rigorous comparative assessment of conventional MTD chemotherapy vs metronomic chemotherapy using the same agent; iii) assessment of potential predictive biomarkers for metronomic chemotherapy, and methods to determine optimal biologic dose and schedule; and iv) a further detailed assessment of the potential of different chemotherapy drugs administered using MTD or metronomic regimens on stimulating or suppressing components of the innate or adaptive immune systems.
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Prostate cancer (PCa) is the 2nd leading cause of cancer-related death among men in the United States and its progression is tightly associated with the androgen/androgen receptor (AR) signals. Men castrated before puberty (eunuchs) or men with inherited deficiency of type II 5α-reductase (with failure to convert testosterone to the more potent dihydrotestosterone) (DHT) do not develop PCa. ⋯ However, patients on ADT with anti-androgen treatment eventually develop resistance, which might be accompanied with the unwanted side effects of enhanced metastasis. New therapeutic approaches via directly targeting the AR with ASC-J9®, Cisplatin, EPI-001, Niclosamide, and VPC compounds as well as silencing AR with siRNAs or non-coding RNAs have been developed to further suppress PCa at the castration resistant stages.
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The RAS-RAF-MEK-ERK cascade is a key oncogenic signal transduction pathway activated in many types of tumours in humans. Sorafenib, the medical treatment of reference against advanced stages of hepatocellular carcinoma (HCC), inhibits the RAF-MEK-ERK cascade in HCC cells. Based on previous studies suggesting that this cascade is an important target of sorafenib in HCC cells, we explored its regulation using mathematical modelling and ordinary differential equations. ⋯ In silico predictions derived from our mathematical model suggested that the disappearance of phosphorylated MEK and ERK proteins catalysed by cellular phosphatases is an essential mechanism underlying the anti-ERK efficacy of sorafenib in HCC cells. This prediction was experimentally validated using specific inhibitors of the phosphatases PP2A (Protein Phosphatase 2A) and DUSP1/6 (Dual-specificity phosphatases 1/6). These findings highlight an unexpected mode of action of sorafenib on the kinome of HCC cells, and open new perspectives regarding the therapeutic targeting of the RAF-MEK-ERK cascade in this context.
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Emerging evidence suggests that small nucleolar RNAs (snoRNAs) and their host genes (SNHGs) have malfunctioning roles in the development of human cancers. We globally investigated the molecular mechanisms by which snoRNA host gene 6 (SNHG6) promotes hepatocellular carcinoma (HCC) progression using human tissues and cell lines. We found that SNHG6 is overexpressed in HCC tissues and in hepatoma cell lines and is closely associated with histologic grade, hepatitis B virus DNA, Barcelona Clinic Liver Cancer stage and portal vein tumor thrombus in patients with HCC. ⋯ SNHG6 may act as a competing endogenous RNA, effectively becoming a sink for miR-101-3p and thereby modulating the derepression of zinc finger E-box binding homeobox 1, imposing an additional level of post-transcriptional regulation. Functionally, SNHG6 promotes tumor growth and metastasis by inducing epithelial to mesenchymal transition. Further investigations showed that SNHG6 could affect HCC tumorigenesis by binding to up-frameshift protein 1 and regulating Smad7 expression.