Background: Pancreatic cancer is now the fourth leading cause of cancer-related mortality in United States. Its intransigence to current chemotherapy regimens stimulated our interest to explore novel targets for therapeutic development. Constitutive activation of Signal Transducer and Activator of Transcription-3 (STAT3) in pancreatic cancer cells is associated with VEGF expression, and when suppressed, leads to inhibition of VEGF expression, angiogenesis, tumor growth, and subsequent metastasis in vivo. In addition to VEGF expression, STAT3 activation also promotes tumor cell proliferation and survival pathways in vivo. EGF and IL-6 mediated mitogenic signaling pathways can also induce Jak2/STAT3 phosphorylation in pancreatic cancer. Thus, JAK2/STAT3 proteins are potential novel therapeutic targets in pancreatic cancer.
Currently available Jak2/STAT3 pathway inhibitors including AG490 can block STAT3 phosphorylation at concentrations of 50-100 µM but are not active in vivo. The striking similarity of AG490 to the natural products of the caffeic acid family, and our comparison of caffeic acid benzyl ester to AG490, showing no additional benefit for AG490 in vitro led us to the design of novel potent inhibitors. We have discovered a new class of compounds that inhibits IL-6 induced Jak2 and STAT3 phosphorylation and suppression of related downstream signaling pathways. Next, we selected compound WP1066 for more detailed evaluation in pancreatic cancer.
Aim: Determine the effects of novel Jak2/STAT3 inhibitor WP1066 on pancreatic cancer cells both in vitro and in vivo.
Methods and Results: WP1066 significantly inhibited proliferation and induced apoptosis of pancreatic cancer cells including Colo357FG and MIA PaCa-2 with IC50 of 2.5 μM. WP1066 potently blocked constitutive and IL-6 induced STAT3 phosphorylation in Colo357FG cells in a dose-dependent manner with maximal effects noted at 5 μM. WP1066 (5 μM) also suppressed expression of STAT3 dependent antiapoptotic proteins including Bcl-xL and survivin. Next, we evaluated in vivo effects of WP1066 in athymic nu/nu murine subcutaneous xenograft model for pancreatic cancer. WP1066 was injected intraperitoneally thrice weekly for 4 weeks at 40 mg/kg per mouse. WP1066 was well tolerated and no adverse events were noted. WP1066 significantly inhibited Colo357FG tumor growth by 4 fold after 4 weeks of treatment (p<0.005 with n=6 per group).
Conclusion: Our studies show that targeting Jak2/STAT3 pathway with novel drugs including WP1066 significantly blocked pancreatic cancer cell proliferation in vitro and tumor growth in vivo. Thus drugs including WP1066 should be potentially considered as one of the future strategies for treatment of pancreatic cancer.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA