Search

The purpose of this study was to identify new combination strategies for improving treatment of head and neck squamous cell carcinomas (HNSCCs). HNSCCs often express high levels of Aurora kinase A (AURKA), most studied as a kinase important for mitotic progression in normal cells. Notably the overexpression of AURKA in many cancers allows it to act throughout the cell cycle, acquiring new cancer-promoting activities. While several AURKA inhibitors are in clinical trials, limited efficacy is observed with single treatment, causing us to evaluate potential AURKA combination therapeutic combinations. Particularly relevant to HNSCC, which often overexpress and depend on EGFR, overexpression of AURKA can promote resistance to EGFR inhibitors by mechanisms variously identified as including activation of the EGFR effectors AKT, ERK, and BIM. Using viability and clonogenic assays, we have found that the AURKA inhibitor VIC-1911 synergizes with the EGFR inhibitors afatinib and erlotinib in multiple HNSCC cell lines and retains activity in HNSCC cell models selected for resistance to these EGFR inhibitors. However, AURKA inhibition increases levels of AURKA protein and its protein-stabilizing partner TPX2, counteracting drug effect. We also combined inhibition of AURKA with inhibition of WEE1, a regulator of the G2/M checkpoint, finding this dual inhibition enhanced levels of apoptosis in EGFR inhibitor resistant HNSCC cell lines. Intriguingly, one recent study reported AURKA can also modulate the glycolytic signaling pathway, increasing the cancer-promoting Warburg effect. We have found that inhibition of AURKA can significantly reduce glycolytic flux in HNSCC cell lines and alter expression and phosphorylation of key glycolytic enzymes. Dual inhibition of AURKA in combination with inhibitors of glycolytic enzymes, or enzymes regulating oxidative phosphorylation, showed marked synergy. These and other results investigating AURKA signaling mechanisms in HNSCC demonstrate that the non-canonical functions of AURKA include viable therapeutic targets that can enhance the efficacy of AURKA inhibition in HNSCC. Citation Format: Flaviane N da Silva, Theodore Nguyen, Jong Woo Lee, Barbara Burtness, Erica Golemis. Synthetic lethal targeting of AURKA in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 542.

High levels of dietary fats are associated with pancreatitis, diabetes, and pancreatic cancer. Sterol regulatory element binding protein Cleavage-Activating Protein (SCAP) is an essential intermediate in lipid-regulated activation of Sterol Regulatory Element Binding Protein (SREBP) transcription factors, which induce expression of genes regulating lipid homeostasis. We previously demonstrated that the elevated SREBP1 arising from inhibition of the cholesterol biosynthetic pathway in mice genetically predisposed to pancreatic cancer additionally transcribed genes that induced epithelial-mesenchymal transition, promoting basal rather than glandular cancer. To further evaluate SCAP and SREBP function in the pancreas, we developed a new mouse model with selective pancreatic knockout of the Scapf/f gene under the control of the Pdx1-Cre promoter (ScapΔpanc mice). Although size of the pancreas in ScapΔpanc neonates was unaffected, and number of islets was normal, there was a reduced number of acinar cells, and some evidence of disorganized tissue structure. Preliminary histopatholgical assessment of pancreatic tissue of ScapΔpanc neonates indicated no acinar cell apoptosis, and unimpaired acinar proliferation, suggesting loss of Scap may cause a differentiation defect. Further supporting this idea, siRNA depletion of Scap in the rat AR42J acinar cell line resulted in loss of markers of mature acinar cell identity. ScapΔpanc pancreata underwent progressive and selective loss of acinar cells as mice aged, with three-month old mice having large areas of acinar cell loss, and mislocalization of ductal cells. Coupled with this loss was a large increase in pancreatic adipocytes and mesenchymal cells, resulting in a highly disorganized tissue morphology accompanied by signs of inflammation. These phenotypes were exacerbated in mice maintained on high fat or high carbohydrate diet. Together, these results imply that SCAP and SREBP signaling in the pancreas plays an important role in mediating dietary modulation of pancreatic development, acinar cell homeostasis, and restraint of pancreatic adiposity. Intrapancreatic fat, associated with obesity and chronic pancreatitis, is a known risk factor for pancreatic cancer, and SCAP polymorphisms have been to interact with diet in regulating obesity and blood pressure in humans; we propose SCAP-SREBP signaling in the pancreas may mediate dietary promotion of pancreatic cancer risk. Citation Format: Anna C. Lilly, Aizhan Surumbayeva, Theodore Nguyen, Igor Astsaturov, Erica A. Golemis. Diet-modulated SCAP-SREBP signaling is essential for acinar cell differentiation, pancreatic morphogenesis, and pancreatic adiposity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2178.

Volatile organic compounds (VOCs) and intermediate volatility VOCs (IVOCs) are gas-phase organic compounds which may participate in chemical reactions affecting air quality and climate. The development of an inexpensive, field-portable quantification method for higher molecular weight VOCs and IVOCs utilizing commercially available components could be used as a tool to survey aerosol precursors or identify and monitor air quality in various communities. We characterized the performance characteristics for the HayeSep-Q adsorbent with a representative selection of anthropogenic and biogenic VOC standards and optimized experimental conditions and procedures for field collections followed by laboratory analysis. All VOCs were analyzed using gas chromatography coupled with mass spectrometry. Precision (average 22%) and accuracy were reasonable and the limit of detection ranged from 10 to 80 pmol/mol (ppt) for the studied compounds. The method was employed at the Los Angeles site during the CalNex campaign in summer 2010 and ambient mixing ratios agreed well (slope 0.69–1.06, R 2 0.67–0.71) with measurements made using an in-situ GC–MS – a distinctly different sampling and quantification method. This new technique can be applied to quantify ambient biogenic and anthropogenic C8–C15 VOCs and IVOCs.