So what does Dr. Rolf Brekken have going on these days?...
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Warfarin blocks Gas6-mediated Axl activation required for pancreatic cancer epithelial plasticity and metastasis
Amanda Kirane1, Kathleen F Ludwig2, Noah Sorrelle1, Gry Haaland3, Tone Sandal4, Renate Ranaweera3, Jason E Toombs5, Miao Wang1, Sean P Dineen1, David Micklem6, Michael T. Dellinger7, James B. Lorens8, and Rolf A Brekken9,*
- Author Affiliations
1Surgery, University of Texas Southwestern Medical Center 2Pediatrics, University of Texas Southwestern Medical Center 3Biomedicine, University of Bergen 4Biology, BerGenBio AS 5Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern 6Research, BerGenBio AS 7Surgery, University of Texas Southwestern Medical School 8Department of Biomedicine, University of Bergen, Norway 9Surgery, Pharmacology, University of Texas Southwestern Medical Center
* Corresponding Author: Rolf A Brekken, Surgery, Pharmacology, University of Texas Southwestern Medical Center, Hamon Center for Therapeutic Oncology Research, 6000 Harry Hines Blvd, MC 8593, Dallas, Texas, 75390-8593, United States Rolf.Brekken@UTSouthwestern.edu
Received October 1, 2014. Revision received June 14, 2015. Accepted July 1, 2015. Published July 23, 2015
Abstract
Repurposing 'old' drugs can facilitate rapid clinical translation but necessitates novel mechanistic insight. Warfarin, a vitamin K "antagonist" used clinically for the prevention of thrombosis for over 50 years, has been shown to have anti-cancer effects. We hypothesized that the molecular mechanism underlying its anti-tumor activity is unrelated to its effect on coagulation, but is due to inhibition of the Axl receptor tyrosine kinase on tumor cells. Activation of Axl by its ligand Gas6, a vitamin K-dependent protein, is inhibited at doses of warfarin that do not affect coagulation. Here we show that inhibiting Gas6-dependent Axl activation with low dose warfarin or with other tumor-specific Axl targeting agents, blocks the progression and spread of pancreatic cancer. Warfarin also inhibited Axl-dependent tumor cell migration, invasiveness and proliferation while increasing apoptosis and sensitivity to chemotherapy. We conclude that Gas6-induced Axl signaling is a critical driver of pancreatic cancer progression and its inhibition with low dose warfarin or other Axl targeting agents may improve outcome in patients with Axl-expressing tumors.
So why no mention of PS Targeting in the title... related to AXL Gas6 ..etc ??
well there is a relation and just further proof, that Peregrine and company are playing everything close to the vest...
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The AXL Receptor Is a Sensor of Ligand Spatial Heterogeneity
Aaron S. Meyer Annelien J.M. Zweemer Douglas A. Lauffenburger
Publication History Published Online: July 16, 2015 Accepted: June 16, 2015 Received in revised form: May 4, 2015 Received: February 7, 2015
Highlights
•The dynamics of AXL receptor activation are distinct from those of other RTK families •Spatially heterogeneous presentation of the ligand Gas6 leads to enhanced AXL response •Localization and activation of AXL can arise from Gas6/phosphatidylserine interactions •A diffusion-reaction model can account for the influence of phosphatidylserine
Summary
The AXL receptor is a TAM (Tyro3, AXL, MerTK) receptor tyrosine kinase (RTK) important in physiological inflammatory processes such as blood clotting, viral infection, and innate immune-mediated cell clearance. Overexpression of the receptor in a number of solid tumors is increasingly appreciated as a key drug resistance and tumor dissemination mechanism. Although the ligand-receptor (Gas6-AXL) complex structure is known, literature reports on ligand-mediated signaling have provided conflicting conclusions regarding the influence of other factors such as phosphatidylserine binding, and a detailed, mechanistic picture of AXL activation has not emerged.
"Bavituximab is a first-in-class phosphatidylserine (PS)-targeting monoclonal antibody that is the cornerstone of a broad clinical pipeline." -- Big Pharmas nightmare... unless they are fortunate enough to have The Bavi Edge!
