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The biology of metastatic pancreatic ductal adenocarcinoma (PDAC) is distinct from that of the primary tumor due to changes in cell plasticity governed by a distinct transcriptome. Therapeutic strategies that target this distinct biology are needed. We detect an upregulation of the neuronal axon guidance molecule Netrin-1 in PDAC liver metastases that signals through its dependence receptor (DR), uncoordinated-5b (Unc5b), to facilitate metastasis in vitro and in vivo. The mechanism of Netrin-1 induction involves a feedforward loop whereby Netrin-1 on the surface of PDAC-secreted extracellular vesicles prepares the metastatic niche by inducing hepatic stellate cell activation and retinoic acid secretion that in turn upregulates Netrin-1 in disseminated tumor cells via RAR/RXR and Elf3 signaling. While this mechanism promotes PDAC liver metastasis, it also identifies a therapeutic vulnerability, as it can be targeted using anti-Netrin-1 therapy to inhibit metastasis using the Unc5b DR cell death mechanism. [Display omitted] • Netrin-1 is upregulated in metastatic pancreatic cancer • Hepatic stellate cell-secreted retinoic acid upregulates Netrin-1 in the liver • Netrin-1 on extracellular vesicles pre-conditions the metastatic niche • Anti-Netrin-1 therapy inhibits metastasis and improves survival in murine PDAC Therapeutic strategies that target the unique biology of metastatic pancreatic cancer are needed. Netrin-1, an embryonic axon guidance molecule, is upregulated in pancreatic liver metastases through a mechanism involving hepatic stellate cell-secreted retinoic acid. Targeting Netrin-1 inhibits metastasis and improves survival in murine pancreatic cancer models. [ABSTRACT FROM AUTHOR]

Summary Meiosis-activating sterols (MAS) are substrates of SC4MOL and NSDHL in the cholesterol pathway and are important for normal organismal development. Oncogenic transformation by epidermal growth factor receptor (EGFR) or RAS increases the demand for cholesterol, suggesting a possibility for metabolic interference. To test this idea in vivo, we ablated Nsdhl in adult keratinocytes expressing KRAS G12D . Strikingly, Nsdhl inactivation antagonized the growth of skin tumors while having little effect on normal skin. Loss of Nsdhl induced the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, reduced the expression of low-density lipoprotein receptor (LDLR), decreased intracellular cholesterol, and was dependent on the liver X receptor (LXR) α. Importantly, EGFR signaling opposed LXRα effects on cholesterol homeostasis, whereas an EGFR inhibitor synergized with LXRα agonists in killing cancer cells. Inhibition of SC4MOL or NSDHL, or activation of LXRα by sterol metabolites, can be an effective strategy against carcinomas with activated EGFR-KRAS signaling. [ABSTRACT FROM AUTHOR]

Background The interval between neoadjuvant chemoradiation treatment and surgery has been described as an important predictor of pathologic response to therapy in nonesophageal cancer sites. We retrospectively reviewed our experience with patients who underwent neoadjuvant chemoradiation and esophagectomy to better understand the impact of the timing of surgery on pathologic complete response rates in esophageal cancer. Methods Two hundred thirty-one sequentially treated patients from 2000 to 2011 were identified for this study; 88 of these patients completed neoadjuvant chemoradiation followed by esophagectomy at our institution. The interval between completion of chemoradiation and surgery was calculated for each patient. The patients were categorized into quartiles and also into 3-week interval groups. Treatment factors and surgical morbidity data, including the estimated blood loss and length of operative stay, were also assessed. Results Quartiles for the neoadjuvant chemoradiation to surgery interval were less than 45 days, 46 to 50 days, 51 to 63 days, and 64+ days. Corresponding pathologic complete response rates were 12.5%, 20.0%, 22.7%, and 40.9% ( p = 0.03). Results for 3-week intervals were similar ( p = 0.02). There was no association between increasing time interval between the ending of neoadjuvant chemoradiation to surgery and length of stay longer than 2 weeks. Conclusions A longer interval between completion of neoadjuvant chemoradiation and surgery was associated with higher pathologic complete response rates without an impact on surgical morbidity. [ABSTRACT FROM AUTHOR]

Abstract: A core set of oncoproteins is overexpressed or functionally activated in many types of cancer, and members of this group have attracted significant interest as subjects for development of targeted therapeutics. For some oncoproteins such as EGFR/ErbB1, both small molecule and antibody agents have been developed and applied in the clinic for over a decade. Analysis of clinical outcomes has revealed an initially unexpected complexity in the response of patients to these agents. Diverse factors, including developmental lineage of the tumor progenitor cell, co-mutation or epigenetic modulation of genes encoding proteins in an extended EGFR signaling network or regulating core survival responses in individual tumors, and environmental factors including inflammatory agents and viral infection, all have been identified as modulating response to treatment with EGFR-targeted drugs. Second and third generation therapeutic strategies increasingly incorporate knowledge of cancer type-specific signaling environments, in a more personalized treatment approach. This review takes squamous cell carcinoma of the head and neck (SCCHN) as a specific example of an EGFR-involved cancer with idiosyncratic biological features that influence design of treatment modalities, with particular emphasis on commonalities and differences with other cancer types. [Copyright &y& Elsevier]

Cellular growth is highly dependent on sustained production of lipids. Sterol composition of cellular membranes determines multiple biochemical and biophysical properties of membrane-based processes including vesicle traffic, receptor signaling, and assembly of protein complexes. Lipid biogenesis has become an attractive biochemical target in cancer given the high level of dependency on sterols and lipids in a cancer cell. This review summarized the current knowledge of mechanisms of interaction between the metabolism of sterols and receptor signaling. [Copyright &y& Elsevier]

Summary: In healthy cells, controlled activation of aurora kinases regulates mitosis. Overexpression and hyperactivation of aurora kinases A and B have major roles in tumorigenesis, and can induce aneuploidy and genomic instability. In squamous-cell carcinomas of the head and neck, overexpression of aurora kinase A is associated with decreased survival, and a reduction in aurora kinase A and aurora kinase B expression inhibits cell growth and increases apoptosis. In this Review, we provide an overview of the biological functions of aurora kinases in healthy cells and in cancer cells, and we review small studies and high-throughput datasets that particularly implicate aurora kinase A in the pathogenesis of squamous-cell carcinomas of the head and neck. Early phase trials are beginning to assess the activity of small-molecule inhibitors of aurora kinases. We summarise trials of aurora kinase inhibitors in squamous-cell carcinomas of the head and neck, and discuss directions for future drug combination trials and biomarkers to use with drugs that inhibit aurora kinases. [Copyright &y& Elsevier]