A Parkinson's therapy makes its way through the "valley of death"

Andrew West is pursuing a compound to inhibit LRRK2, an enzyme that appears to be a central enabler
of the brain cell death seen in Parkinson's disease.

In its long journey from the petri dish to the first human patient, every new drug has to cross a wasteland called the "valley of death." Therapeutic programs enter, but most don’t come out the other side.

"The government is good at funding basic research to identify drug targets, and Big Pharma is good at taking drugs and putting them through clinical trials," says Andrew West, Ph.D., John A. and Ruth R. Jurenko Endowed Professor in Neurology at UAB. "But all of the in-between work, the pre-clinical and drug development components, is called the 'valley of death' for research, because nobody funds it, nobody pays attention to it. That's a big part of the lack of new drugs."

In fact, less than 10 percent of drugs that make it into preclinical testing will end up getting FDA approval, according to the agency's figures. But West is part of a new approach to the drug-discovery process designed to upend those odds: a partnership between UAB and Birmingham-based Southern Research Institute known as the Alabama Drug Discovery Alliance (ADDA).

The Mix Quiz: Are You Smarter Than a Medical Resident?

Just like you, doctors love their smartphones. And they like playing games. But a new game pioneered at the UAB School of Medicine has lots more ROI than Farmville.

It's called Kaizen, a word borrowed from the Japanese auto industry that means something like "continuous improvement." This Web-based quiz game challenges medical residents at the School of Medicine's campuses in Birmingham and Huntsville with two questions every day. They're brief scenarios meant to highlight key practice skills and new evidence-based findings from a range of specialties.

Learn all about Kaizen in this feature from UAB Magazine. And test your medical knowledge with our five-question quiz.

Hit man: A suspect emerges in the chaos of aggressive brain cancer

New research from UAB oncologist Markus Bredel identifies the splicing enzyme PTBP1 as a key factor
in the spread of glioblastoma multiforme.  

Glioblastoma multiforme is one of the deadliest human cancers. "The tumor can double in size within a few weeks," says Markus Bredel, M.D., Ph.D., a professor in the UAB Department of Radiation Oncology and senior scientist in the neuro-oncology program at the UAB Comprehensive Cancer Center. "Usually, by the time we see a patient, they often have apple-size lesions."

That explosive growth "comes with a substantial amount of genetic chaos," Bredel says. "If you look at the whole genome in a brain tumor, out of the 30,000 genes, you very often have changes in up to 50 percent; they're up or down, lost, amplified, mutated."

A Change for the Worse

Markus Bredel

But in that chaos, patterns emerge with surprising regularity, Bredel says. "When Gene A is up, Gene B is very often down." In two papers published in JAMA in 2009, Bredel's research team argued that "there needs to be a reason why glioblastomas co-select for certain genetic events. The tumor cells must benefit."

In those papers, Bredel's lab identified dozens of gene-gene links that were candidates for additional scrutiny. They focused on one particular pair: The oncogene EGFR, or epidermal growth factor receptor, which is crucial for normal cell growth and wound healing, and the tumor-suppressor ANXA7 or annexin A7. EGFR is of interest in many cancers, because it is often hijacked to fuel the aggressive growth of tumor cells.

"We found that ANXA7 is probably a regulator of EGFR," Bredel says. "So it's to the benefit of the tumor cell to knock down this regulator." But it wasn't clear at the time how this was happening. "ANXA7 resides on a different chromosome from EGFR, so it's a completely independent event, but somehow the tumor cells were disabling it," says Bredel.