[Multiple Roles for the Receptor Tyrosine Kinase Axl in Tumor Formation]
>>Cancer Research 65, 9294-9303, October 15, 2005
Multiple Roles for the Receptor Tyrosine Kinase Axl in Tumor Formation
Sacha J. Holland1, Mark J. Powell1, Christian Franci1, Emily W. Chan1, Annabelle M. Friera1, Robert E. Atchison1, John McLaughlin1, Susan E. Swift1, Erlina S. Pali1, George Yam1, Stephen Wong1, Joe Lasaga1, Mary R. Shen1, Simon Yu1, Weiduan Xu1, Yasumichi Hitoshi1, Jakob Bogenberger1, Jacques E. Nör2, Donald G. Payan1 and James B. Lorens1
1 Rigel, Inc., South San Francisco, California and 2 University of Michigan School of Dentistry, Ann Arbor, Michigan
Requests for reprints: Sacha J. Holland, Rigel, Inc., 1180 Veteran's Boulevard, South San Francisco, CA 94080. Phone: 650-624-1283; E-mail: sholland@rigel.com.
A focus of contemporary cancer therapeutic development is the targeting of both the transformed cell and the supporting cellular microenvironment. Cell migration is a fundamental cellular behavior required for the complex interplay between multiple cell types necessary for tumor development. We therefore developed a novel retroviral-based screening technology in primary human endothelial cells to discover genes that control cell migration. We identified the receptor tyrosine kinase Axl as a novel regulator of endothelial cell haptotactic migration towards the matrix factor vitronectin. Using small interfering RNA–mediated silencing and overexpression of wild-type or mutated receptor proteins, we show that Axl is a key regulator of multiple angiogenic behaviors including endothelial cell migration, proliferation, and tube formation in vitro. Moreover, using sustained, retrovirally delivered short hairpin RNA (shRNA) Axl knockdown, we show that Axl is necessary for in vivo angiogenesis in a mouse model. Furthermore, we show that Axl is also required for human breast carcinoma cells to form a tumor in vivo. These findings indicate that Axl regulates processes vital for both neovascularization and tumorigenesis. Disruption of Axl signaling using a small-molecule inhibitor will hence simultaneously affect both the tumor and stromal cell compartments and thus represents a unique approach for cancer therapeutic development. <<
And here's the patent application:
appft1.uspto.gov
It would appear that BMS is looking at inhibition of vitronectin, also with small molecules, if I'm reading their patent application correctly (lots of serious, eye-glazing chemistry in there). They seem to be more focused on radiotherapy in this context, but their application does mention its use outside of radiotherapy. NVS also poking around here?
Cheers, Tuck |
