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Chair(s): Li, Jian Jian; Jung, Mira
(000) Targeting the Tie2 receptor tyrosine kinase pathway for radiosensitization of prostate cancer.
Garg, Madhur*,1, Shah, S.J.1, Deb, N.J.1, Liu, L.1, Guha, C.1, 1 Montefiore Medical Center, Bronx, NY, United States
ABSTRACT- Purpose/Objective: Angiogenesis is a crucial step for the continuous growth of solid tumors and the development of metastasis. The molecular events initiating the “angiogenic switch” remains elusive in prostate carcinoma (PC). The endothelial receptor tyrosine kinases, such as, the VEGF receptor and Tie-2 receptor are implicated in the “angiogenic switch” of PC. The Tie-2 receptor binds angiopoietins (Ang) and is selectively expressed in PC over normal prostate tissues. Since, Ang-1 promotes endothelial cell survival, we hypothesized that pre-treatment with a soluble murine Tie-2 receptor (mTek-Fc) would lead to blockade of Ang-1-mediated endothelial cell cytoprotection and would result in a cumulative inhibitory effect of RT on the PC growth. Materials/Methods: We have cloned a mouse Tek-Fc (mTek-Fc) fusion gene (extracellular domains of the mouse Tie2/Tek receptor fused with the mouse IgG1 Fc domain) in an E1A-deleted, replication-deficient, recombinant adenovirus vector and isolated viral plaques expressing recombinant mTek-Fc after recombination. Male C57Bl/6J mice with palpable (100mg), subcutaneous murine PC (RM-1) tumors were systemically injected with either Adeno-Tek-Fc or Adeno-GFP viruses as control (〈5 x 1010 particles i.v.). Tumor RT was initiated 24 hours after adenovirus injection (4 fractions of 6 Gy to a total dose of 24Gy). Additional animal cohorts received Adeno-Tek-Fc and/or Adeno-GFP virus injections 12 days prior to RT, while the control group received RT alone. Tumor growth delay was calculated from the time of initiation of treatment to the time the tumors reached a size of 500 mm3. Results: Tumor volume assessment in treatment cohorts using sequential administration of Ad Tek-Fc, prior to radiation demonstrated significant growth delay (p〈0.006), when compared to tumor growth in RT alone group. There was a significant (p 〈0.05) increase in overall survival in the Adeno-Tek-Fc + RT group. Conclusions: Antiangiogenic therapy with Adeno-TekFc, when combined with RT, significantly delayed tumor growth and increased survival in a murine PC tumor model, as compared to either treatment alone. Targeting the Tie-2 endothelial receptor tyrosine kinase pathway could be an effective adjuvant to RT in the treatment of PC. Tumor Growth Delay Treatment Tumor Growth delay (days) T-test (Compared to RT alone) AdTekFc + RT 22.3 Â± 1.5 p.006 AdTekFc Alone 11.2 Â± 1.2 NS AdGFP Alone 11.8 Â± 1.2 NS AdGFP + RT 12.7 Â± 1.7 NS RT Alone 14.2 Â± 3.0 .
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