A new approach to anti-angiogenic therapy in lung cancer
Abstracts
Initial Award Abstract |
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The role of blood vessels in facilitating lung cancer growth is well recognized, and the blockade of lung cancer angiogenesis is currently utilized in patients as a therapeutic strategy. The current proposal investigates the novel endothelial-expressed miR-126/Egfl7 locus and its contribution to lung cancer angiogenesis and progression. MiR-126 is an intriguing microRNA which is located within intron 7 of a host gene, Egfl7, encoding an EGF-repeat secreted protein. Notably, miR-126/Egfl7 is expressed from a common transcript which is highly upregulated in lung tumor blood vessels as opposed to normal lung vasculature. We have created knockout mice for miR-126 and Egfl7 which have demonstrated that deletion of miR-126 results in compromised blood vessel growth in the embryo. Thus, a major goal of the current proposal is to use miR-126 or Egfl7 knockout mice to test the contribution of this locus to lung cancer angiogenesis and progression using rigorous genetic approaches and a well-validated KRasG12D; p53flox/flox mouse model of lung cancer. Additional components of this proposal include exploration of the molecular basis for miR-126/Egfl7 expression in tumor vasculature, and the demonstration of locus overexpression in human lung cancer specimens. Overall, this application explores a highly novel endothelial microRNA, miR-126, and will obtain proof-of-principle data linking it to lung cancer angiogenesis and progression and identifying it as an anti-angiogenic drug target. Analogous studies will be performed for the poorly understood host gene, Egfl7. These studies should contribute to our knowledge of lung cancer etiology and prevention, as well as identify miR-126/Egfl7 as a novel marker for human lung cancer angiogenesis. |
