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R. Subramanyan

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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-016 - EphB4 Receptor Kinase, a Novel Therapeutic Target for Lung Cancer (ID 2390)

      09:30 - 16:30  |  Author(s): R. Subramanyan

      • Abstract

      EphB4, a receptor tyrosine kinase and its ligand EphrinB2 are both cell membrane bound proteins that regulate cell migration, boundary formation, venous or arterial specification, vessel formation and maturation. EphB4-EphrinB2 interaction leads to bidirectional forward and reverse signaling. EphB4 is induced in certain cancers where it regulates cell survival, growth and metastasis.

      We have studied the expression of EphB4 in lung cancer. 89 cases of matched normal and lung tumor samples were analyzed by IHC using EphB4 specific monoclonal antibody. Biological function of EphB4 was studied specifically in Kras mutant lung adeno Ca due to induction of EphB4. In addition, an in vivo efficacy study was conducted with soluble EphB4 receptor fused in frame at the C-terminus with Albumin (sEphB4HSA).

      EphB4 is significantly over-expressed compared to paired normal tissues in adenocarcinoma (n=41; 4.3-fold mean difference), large cell carcinoma (n=15; 2.9-fold mean difference), small cell carcinoma (n=13; 2.4-fold mean difference), and squamous cell carcinoma (n=10; 2.7-fold mean difference) subtypes. Overall, lung tumors were found to express EphB4 3.2-fold more strongly than paired normal tissues. EphB4 gene amplification (>3 fold) was also seen in 23% of squamous cell carcinoma tissues. Knock down of EphB4 led to near 70% loss of cell viability indicating that EphB4 is downstream of Kras and plays essential role in Kras mutant lung adenoCa. sEphB4 blocks bidirectional signaling and albumin fusion provides long circulation time in vivo. Kras mutant human tumor xenografts showed tumor regression and combination with taxol resulted in complete regression in lung adenoca.

      sEphB4HSA cGMP material toxico-kinetic studies in non-human primates were performed and found to be safe up to a dose of 30mg/kg IV weekly. A first in human, phase I clinical trial of sEphB4HSA is approaching completion.