Small cell lung cancer (SCLC) cells have rapid proliferation, universal Rb inactivation and high rates of MYC family amplification, making aurora kinase inhibition a natural target. Preclinical studies have demonstrated activity for Aurora A and pan Aurora inhibitors with some relationship to MYC family expression. A clinical trial showed activity for an Aurora kinase A inhibitor but no biomarkers were evaluated. We screened a panel of 23 SCLC lines with and without MYC family gene amplification or high MYC family gene expression for growth inhibition by the highly potent, selective aurora kinase B inhibitor barasertib. Nine of the SCLC lines were very sensitive to growth inhibition by barasertib with IC50 values of < 50 nM and > 75% growth inhibition at 100 nM. Growth inhibition correlated with cMYC amplification (p = 0.018) and cMYC gene expression (p = 0.026). Sensitive cell lines were also enriched in a published MYC gene signature (p = 0.042). In vivo the barasertib inhibited the growth of xenografts established from a SCLC line which had high cMYC gene expression, no cMYC amplification and was positive for the core MYC gene signature. Our studies suggest that SCLC tumors with cMYC amplification/high gene expression will frequently respond to Aurora B inhibitors and that clinical studies coupled with predictive biomarkers are indicated.
Purpose The emergence of EGFR-inhibitors such as gefitinib, erlotinib and osimertinib has provided novel treatment opportunities in EGFR-driven non-small cell lung cancer (NSCLC). However, most patients with EGFR-driven cancers treated with these inhibitors eventually relapse. Recent efforts have identified the canonical Wnt pathway as a mechanism of protection from EGFR-inhibition and that inhibiting tankyrase, a key player in this pathway, is a potential therapeutic strategy for the treatment of EGFR-driven tumors. Experimental Design We performed a preclinical evaluation of tankyrase inhibitor AZ1366 in combination with multiple EGFR-inhibitors across NSCLC lines, characterizing its anti-tumor activity, impingement on canonical Wnt signaling and effects on gene expression. We performed pharmacokinetic (PK) and pharmacodynamic (PD) profiling of AZ1366 in mice and evaluated its therapeutic activity in an orthotopic NSCLC model. Results In combination with EGFR-inhibitors, AZ1366 synergistically suppressed proliferation of multiple NSCLC lines and amplified global transcriptional changes brought about by EGFR-inhibition. Its ability to work synergistically with EGFR inhibition coincided with its ability to modulate the canonical Wnt pathway. PK and PD profiling of AZ1366-treated orthotopic tumors demonstrated clinically-relevant serum drug levels and intratumoral target inhibition. Finally, co-administration of an EGFR inhibitor and AZ1366 provided better tumor control and improved survival for Wnt-responsive lung cancers in an orthotopic mouse model. Conclusions Tankyrase inhibition is a potent route of tumor control in EGFR-dependent NSCLC with confirmed dependence on canonical Wnt signaling. These data strongly support further evaluation of tankyrase inhibition as a co-treatment strategy with EGFR inhibition in an identifiable subset of EGFR-driven NSCLC.
Exposure to drinking water disinfection byproducts (DBPs) is potentially associated with adverse developmental effects. Iodoacetic acid (IAA), an unregulated DBP, has been shown to be cytotoxic, mutagenic, genotoxic, and tumorigenic. However, its endocrine-disrupting effects remain unknown. This study evaluated the IAA-induced disruption of the thyroid endocrine system using in vitro and in vivo assays. Rat pituitary tumor GH3 cells were treated with IAA in the presence and absence of triiodothyronine (T3). IAA exposure significantly reduced T3-activated GH3 cell proliferation, indicating the antagonistic activity of IAA in vitro. Sprague-Dawley rats were also subjected to IAA treatment through oral gavage for 28 consecutive days. IAA exposure significantly down-regulated the mRNA expression levels of the thyrotropin receptor (TSHR), the sodium/iodide symporter (NIS), and type I deiodinase and simultaneously reduced the protein expression levels of TSHR and NIS. IAA exposure decreased T3 levels but increased the weights of hypothalamus and the levels of thyrotropin releasing hormone and thyrotropin. In addition, IAA induced the formation of smaller and more depleted follicles or even vacuolization in the thyroid. These results suggested that IAA potentially disrupts the thyroid endocrine system both in vitro and in vivo.
Different postconditioning (Postcon) methods have been demonstrated to protect heart from ischemia/reperfusion injury. The relationship between Postcon by percutaneous coronary intervention (PCI) and apoptosis is not clear. Our objective was to test whether Postcon by PCI in patients with acute myocardial infarction (AMI) reduces myocardial apoptosis. Seventy-five patients were randomly assigned to one of three groups before stenting. The Routine group (n = 26) received no Postcon intervention prior to the onset of reperfusion; Postcon-30s (n = 25) and Postcon-60s groups (n = 24) underwent three cycles of 30- or 60-s balloon deflation and 30- or 60-s inflation. Additionally, 34 normal controls (NC) were enrolled in the study. Plasma concentrations of soluble Fas/APO-1 ([sFas]) and Fas ligand ([sFasL]) were determined at baseline and 7 days after PCI via ELISA. The [sFas] and [sFasL] in AMI patients were significantly elevated at baseline as compared with NC (P < 0.01), and showed an upward trend in the Routine group, a slightly upward trend in Postcon-30s, and a downward trend in Postcon-60s at 7 days. Comparison among the three groups showed significant differences (P < 0.05, 3.8 vs. 4.6 vs. 5.1 ng ml(-1)). The [sFasL] in Postcon-60s was significantly decreased at 7 days (P < 0.05, 3.9 vs. 3.1 ng ml(-1)) compared with baseline, but not Postcon-30s and Routine. More importantly, Postcon-60s group had the lowest [sFasL], followed by Postcon-30s, which had a lower value than Routine at 7 days (P < 0.05, 3.1 vs.3.7 vs. 4.2 ng ml(-1)). Our results suggest that Postcon-60s was visibly better than Postcon-30s, which in turn was better than Routine for inhibition of the effects of myocardial apoptosis and reduction of reperfusion injury in patients with acute myocardial infarction.
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