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Browsing by Author "Prosceno, Isabella, author"

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    Analysis of tyrosine kinase inhibitor responses in mixed murine EML4-ALK-driven lung tumors to define dominance of their tumor immune microenvironments
    (Colorado State University. Libraries, 2024) Prosceno, Isabella, author
    Lung cancer is the leading cause of cancer-related deaths in the U.S. In recent studies, successes in precision oncology with tyrosine kinase inhibitors (TKIs) have yielded marked and durable tumor responses in tumor subsets defined by oncogenic mutations in the receptor tyrosine kinases (RTKs) EGFR, ALK, ROS1, and RET. Despite this progress, most patients show a partial response and these therapies fail to completely eliminate "drug tolerant persisters" also known as "residual disease". Thus, new therapeutic strategies are needed as presently there are no approved therapies after EGFR mutant lung cancer progression on the 3rd generation TKI, Osimertinib. This desperate need for additional precision therapies is crucial for 2nd and 3rd line therapies in oncogene-driven lung cancer patients. Anti-PD1/PD-L1 agents are approved treatments in lung cancers that disrupt tumor-mediated immune suppression. However, these drugs are ineffective in patients whose tumors bear oncogenic RTK genes despite evidence that adaptive immune cells contribute to the anti-cancer activity of TKIs in these cancers. In other words, immune checkpoint inhibitors are not able to be utilized. The Nemenoff and Heasley labs of University of Colorado Anschutz have generated a panel of murine EML4-ALK cell lines (EA1, EA2) that can be orthotopically implanted in immune competent mice. In order to address the question of immune dominance within a mixed EML4-ALK tumor, a project will deploy mixtures of EA1 and EA2 cell lines to intentionally establish heterogeneous tumors and assess the resulting immune microenvironment and the Alectinib response. The lab has generated EA1 and EA2 cells that incorporate specific fluorescent tags, allowing the assessment of each population in mice. In studying heterogeneous lung tumors composed of clones that avidly recruit anti-tumorigenic T cells and clones that recruit immune suppressive cells (neutrophils), we imagine that three different possibilities may be observed. Complete results are not available due to the experiment being ongoing, but it is hypothesized that the microenvironment of EA1 will suppress that of EA2's. This result will show only a partial response to Alectinib.