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J. Evans



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    P2.03b - Poster Session with Presenters Present (ID 465)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P2.03b-082 - AQP11 as a Novel Factor of Lung Cancer Cell Resistance to Cisplatin (ID 6276)

      14:30 - 14:30  |  Author(s): J. Evans

      • Abstract

      Background:
      Platinum-based combination treatment is a standard of care treatment for lung cancer patients. Aquaporin 11 (AQP11), a non-ubiquitous member of aquaporins family, is an ER-specific water channel mostly present in epithelial cells and is implicated in the maintenance of ER homeostasis. We demonstrated that the induction of AQP11 expression is a pro-survival factor in normal epithelial cells under the stress and that cispaltin interacts with AQP11, as a non-DNA target, causing AQP11 structural and post-translational modification. This study evaluated the expression of AQP11 in lung cancer cells to determine whether the AQP11 expression correlates with cisplatin resistance and whether AQP11 expression in lung tumor associates with overall survival in patients with lung adenocarcinoma.

      Methods:
      18 lung cancer cell lines were tested for AQP11 expression using Western blotting. Growth inhibitory effect of cisplatin was examined using MTT assay and IC~50 ~values were determined. AQP11 knockdown cell lines were generated using a lentiviral vector with shRNA targeting AQP11; efficiency of AQP11 blockage was assessed by Western blotting. We analyzed TCGA database to identify connection between AQP11 mRNA expression and overall survival (OS) in lung adenocarcinoma patients.

      Results:
      All tested cancer cell lines expressed AQP11 and correlation analysis revealed significant association of AQP11 expression with cisplatin resistance (Spearman’s r=0.82, p=0.008). Analysis of stress markers showed that cisplatin-treated cells with higher AQP11 expression had lower stress. Using shRNA, we knocked down AQP11 in cispaltin resistant A549 and HCC827 cells and cisplatin sensitive H460 cells. Resulting knockdown A549 and HCC827 cells became 2.6- to 2.9-fold more sensitive to cisplatin compared to parental and control vector transduced cells. In sensitive H460 cells, knocking down AQP11 did not change sensitivity to cisplatin. Results suggest that high expression AQP11 contributes to cisplatin resistance. TCGA database analysis of previously untreated lung adenocarcinoma, detected 13% tumors with elevated AQP11 mRNA expression (6.18±0.55 vs. 4.28±0.77, p<0.001). Increased AQP11 expression was significantly associated with decreased OS. These patients showed lower median survival rate of 34.47 versus 52.5 months in patients with low AQP11 expression (longrank test p<0.05).

      Conclusion:
      AQP11 is the cispaltin non-DNA target that may significantly contribute to the development of resistance. High AQP11 level is a pro-survival factor protecting tumor cells from cisplatin-induced stress. High AQP11 expression associates with lower OS in lung adenocarcinoma patients and with cispaltin resistance in lung cancer cell lines. With further validation, AQP11 level might be a predictor of cisplatin resistance and overall survival in lung cancer.

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    P2.04 - Poster Session with Presenters Present (ID 466)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      P2.04-027 - Targeting Adenosine A2B Receptor for Modulation of Tumor Microenvironment, Primary Tumor Growth, and Lung Metastasis (ID 6107)

      14:30 - 14:30  |  Author(s): J. Evans

      • Abstract

      Background:
      Our work addresses two poorly understood areas of tumor metastases; the first is how tumor-conditioned immune cells initiate and drive premetastatic niche evolution and secondary tumor establishment and secondly, how the tumor microenvironment (TME) conditions shape the tumor immune response and function.

      Methods:
      We have developed a model that is fully capable of addressing these biological questions through in vivo EPR monitoring of the primary TME that allows simultaneous measurements of tumor pO~2~, pH, and inorganic phosphate (Pi) levels, which are parameters implicated in tumor metastasis and demonstrates how the TME contributes to metastasis. In combination, we employ an in vivo immune/tumor cell imaging platform in which mice are fitted with cutaneous window chambers containing syngeneic lung tissue transplant to create a lung metastatic site in which differentially-labeled tumor and immune subsets will be imaged via multiphoton microscopy.

      Results:
      Our EPR methodology accurately monitors TME changes that occur with tumor growth as well as their modulation by pharmacological inhibition of the A~2B~ adenosine receptor, giving reason to the use of specific A~2B~ receptor inhibitors as anti-tumor and anti-metastatic therapeutics. A~2B~ inhibition prevented the accumulation of Pi in the tumor interstitial space for every tumor model tested, which includes lung adenocarcinoma, breast adenocarcinoma, colon carcinoma, and melanoma. The exact role this plays in tumor initiation and progression is not completely elucidated but correlates with the reduction of tumor lung metastases and tumor growth. Secondly, our window chamber model enables spatiotemporal analysis of pre-metastatic niche enrichment, individual tumor cell recruitment, and subsequent secondary tumor growth with specific focus on metastatic lung disease. To our knowledge, no model exists capable of unifying these aspects of tumor biology and immunity.

      Conclusion:
      The project will lead to understanding a key process of metastasis and thus allow targeted immunotherapies to block metastasis and thus eliminate, or greatly reduce, the lethal aspect of cancer. Future work will also examine the potential anti-tumor therapeutic strategy of using specific A~2B~ adenosine receptor antagonists for TME modulation. Of which, PBF-1129 is undergoing pre-clinical and IND-enabling studies and demonstrates high anti-tumor efficacy, suggesting the possibility for clinical trials with A~2B~ antagonists for cancer therapy in the nearest future. Lastly, our methodology is targeting a glaring hole in the understanding of tumor metastasis, meaning the forthcoming information from our work holds great promise to identify novel therapeutic strategies aimed at greatly diminishing the chief cause of cancer morbidity.