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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
  • Moderators:
  • Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 17755

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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): A. Antonucci
    • 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.