U-M Research Group Uses Secret Weapons in Cancer Drug Development

August 03, 2011

“A dozen leading pharmaceutical companies are now pursuing work we pioneered,” says Haile Tecle, Ph.D., “but nobody would touch this in the beginning.”

Tecle is referring to the successful MEK kinase inhibitor cancer research he and Judith Sebolt-Leopold and their team have conducted since the 1990s when they both worked at Pfizer Pharmaceutical Research in Ann Arbor, Michigan.

Now their former Pfizer facility is the University of Michigan North Campus Research Complex, purchased by U-M in 2009 after Pfizer left town – and a testbed for translational and interdisciplinary research.

Both Tecle and Sebolt-Leopold, members of the Center for Molecular Imaging, have joined U-M’s Translational Oncology Program, with Tecle as senior chemist in radiation oncology and Sebolt-Leopold as research associate professor of radiology.

Tecle and Sebolt-Leopold chaired the project team that was the first in the pharmaceutical industry to design, synthesize and advance a small molecule MEK kinase inhibitor into the clinic. Collectively, they have roughly 50 patents and more than 100 publications to their credit, and are acknowledged as two of the top thought experts in their field.

Sebolt-Leopold has led multiple cross-disciplinary research teams, resulting in the advancement of clinical candidates, including the MEK inhibitors CI-1040 and PD0325901. These agents entered the clinical arena based on their promising activity in preclinical models, where they effectively block RAS onogenic signaling. MEK is a critical component of the RAS-MAP kinase signaling pathway that is activated in a large percentage of human cancers.

The success of Sebolt-Leopold, Tecle and their team in championing the anticancer drug potential of MEK inhibitors is reflected in the number of pharmaceutical companies subsequently launching research programs around the CI-1040/PD0325901 template. Consequently, there are nearly a dozen MEK inhibitors currently undergoing clinical evaluation.

More than 500 different kinases have been identified in humans. Their diversity and role in cell signaling makes them attractive targets for drug design. The therapeutic inhibition of protein kinases has revolutionized the treatment of certain cancers. New inhibitors are also targeting a host of other conditions from atherosclerosis to neurodegenerative diseases.

Although the first FDA-approved kinase-targeted drug was an antibody that targets the extracellular domain of the epidermal growth factor receptor, EGFR (1998, Herceptin®/Genentech), several small molecule EGFR kinase inhibitors have followed. These include PF-00299804, a potent panHER inhibitor that was developed by Tecle and his team and is now in Phase III clinical trials. Of the six research projects Tecle was involved in during his 30+ year tenure at Pfizer, PF-00299804 is one of an impressive five that advanced to clinical trial.

“We’ve been lucky in the past,” Tecle says modestly.

“Luck is important, but so is having the right team that works well together and isn’t afraid to think outside of the box,” says Sebolt-Leopold, research associate professor, department of radiology. “We now have the unique opportunity to combine the power of University of Michigan’s well-recognized imaging capabilities to extend MEK inhibitor research to a whole new translational level.”

Rounding out their team are U-M radiochemist Marcian Van Dort, Ph.D. and computational chemist Christopher Whitehead, Ph.D., another former Pfizer employee and a U-M Business School alumnus. The recruitment of this team by the Center for Molecular Imaging is part of an effort to design and develop small molecules that will be used for the early diagnosis of cancer. The ability to non-invasively diagnose and molecularly define an individual’s tumor will enable the development of personalized therapies.

Max S. Wicha, distinguished professor of oncology, professor of Internal Medicine, and director of the U-M Cancer Center, says, “We’re combining the talents of academia and the talents of the pharmaceutical industry into one research location. An enemy as formidable as cancer is only going to be defeated by creativity and collaboration.”