Tumors that test positive for phosphorylated PKB are invulnerable to Tarceva, and that fact could lead to a test to divert some patients into more efficacious treatment regimes, according to research on brain gliomas by a team at the University of California in San Francisco.
"Basically every big hospital or cancer center could set up such a diagnostic test," Daphne Haas-Kogan, an associate professor in the UCSF Department of Radiation Oncology, told Pharmacogenomics Reporter.
In a search for markers predicting response to Tarceva, the UCSF investigators conducted a retrospective study looking for associations with the drug's target the epidermal growth factor receptor, EGFR and proteins downstream from the receptor. Like preceding studies, their examination of glioma tumor samples from 41 patients revealed a link between EGFR expression level and Tarceva response in those diagnosed with glioblastoma multiforme. But the finding that high phosphorylated PKB levels can signal no response is new. Results of the study appear in the June 15 issue of the Journal of the National Cancer Institute.
"Patients with positive EGFR and negative phosphorylated PKB have a slightly greater than 50 percent chance of responding to just [Tarceva] alone," Haas-Kogan said. "If [PKB] was phosphorylated and activated, in our hands, not a single patient with that molecular characteristic responded" to Tarceva, she said. "None of the 22 patients who [tested] positive [for] phosphorylated PKB responded to the drug."
The researchers also associated the level of phosphorylated PKB to a tumor's time to progression.
When cells test positive in immunohistochemical staining for phosphorylated PKB, it is almost always because the entire pathway is stuck in the "on" position, said Haas-Kogan. "It just so happens that there's evidence in the literature that such patients may be particularly susceptible or sensitive to other targeted treatments, such as inhibitors of the mammalian target of rapamycin, or 'mTOR,'" including rapamycin itself, CCI-779, and RAD001, she said.
PKB can be activated by EGFR, but in cells with a normally functioning pathway, phosphorylated PKB should be hard to find, said Haas-Kogan. "If something downstream of EGFR goes awry, then the pathway [can become] constitutively activated, and it doesn't matter if you block EGFR" with Tarceva or another drug, "the pathway downstream of it is still firing at will," she said.
For its part, PKB is an important intermediary for several tumor properties. "It is involved in many different functions, including increased cell proliferation, increased survival, increased angiogenesis, and it's important in many disease processes not just cancer," said Haas-Kogan. In addition to EGFR, most growth factor receptors use the PKB pathway "as one branch of their activity," she said.
Studies showing that tumors expressing high levels of phosphorylated PKB are not responsive to mTOR inhibitors have only been conducted in vitro, said Haas-Kogan. But she and her colleagues expect to follow up on their findings. "That's our plan next to try to gauge and assess molecular features of patients' tumors before treatment, after they've had surgery, and then tailor their treatments to their exact molecular profile, and that would be, for example, one fork in the road," she said. That phase II trial would treat patients exhibiting high tumor EGFR and low phosphorylated PKB with Tarceva, while those with high phosphorylated PKB would receive another drug, such as an inhibitor of mTOR, Haas-Kogan added.
Chris Womack ([email protected])