LOUISVILLE, Ky.—Disrupting signaling pathways is a promisingarea of therapeutic research in the fight against cancer, but it is also onethat has created some challenges. The discovery of a method to disrupt twocritical pathways at once—by blocking the activity of a cellular enzyme calledcholine kinase—on which University of Louisville (U of L) researchers recentlyreported, may get around those challenges.
The MAPK and PI3K/AKT cellular signaling pathways are twothat are known to be required for cancer cell survival and growth. The U of Lresearchers demonstrated that
a reservoir of a product of choline kinase, calledphosphocholine, is necessary for the activation of the MAPK and PI3K/AKTsurvival pathways in cancer, the researchers noted in their findings, whichappeared in the Oct. 28, 2009, online edition of the journal Oncogene. After demonstrating that choline kinase is requiredfor cancer survival signaling, the U of L team then inhibited the expression ofcholine kinase in a mouse model, which disrupted these internal signals andprevented the cancer cells from surviving and growing.
"By inhibiting the MAPK and the PI3K/AKT pathways at thesame time, we were able to reduce the growth and survival of several commontypes of cancer in mice," reports Dr. Jason Chesney, associate director fortranslational research at U of L's James Graham Brown Cancer Center, and leadinvestigator on this study. He adds that choline kinase has been shown to be anactive enzyme in malignant tumors of the lung, colon, breast, prostate, cervixand ovaries.
This research represents an important step in cancerresearch "because to date we've had poor clinical results from drugs thatdisrupt individual signaling pathways—they often cause alternative pathways toget super-activated and lead to more growth," Chesney says. "Our research foundthat the selective inhibition of choline kinase simultaneously disrupts two keycancer signaling pathways. These results indicate that choline kinaseinhibitors may prevent super-activation of alternative pathways and as a resulthave broad anti-cancer activity."
As Chesney notes, tens and perhaps hundreds of differentpathways exist that can be used by cancer cells to survive and grow in a humanhost. Only a handful of those, however, seem to be genetically altered and leadto actual cancer in humans. And of that handful, he notes, there are probablyfewer than 10 that are key for cancer proliferation, the two central onesseeming to be MAPK and PI3K/AKT and with a third, Rho GTPase, perhaps playing acritical role as well. Rho GTPas was not, however, part of this round of workfor the U of L researchers.
One of the other notable things about this research, Chesneynotes, is that choline kinase is not a kinase for a protein but rather for asmall-molecule metabolite, and the binding pocket for choline is a much morespecific and unique target than the broader ATP binding domains, which havebeen the target of so much therapeutic researcher related to kinases.
Armed with their findings on the MAPK and PI3K/AKT pathwaysand their relationship to phosphocholine, the researchers already havecomputationally searched a vast database of chemicals to identify compoundsthat might block choline kinase, Chesney says. The database was developed byDr. John Trent, director of molecular modeling at the James Brown Graham CancerCenter. One of the promising compounds they identified has been licensed by theLouisville-based pharmaceutical company Advanced Cancer Therapeutics. The hopeis Phase I testing in patients will begin by the end of 2010, Chesney says.
Other researchers involved in this study included Dr.Abdullah Yalcin, Dr. Brian F. Clem and Sucheta Telang.