New Mechanism of Resistance Identified in Brain Tumors

Paul S. Mischel, MD

Principal Investigator

Laboratory of Molecular Pathology San Diego Branch

Ludwig Institute for Cancer Research

San Diego, CA

Researchers have identified a mechanism of action that explains why patients with glioblastoma have not had successful outcomes when treated with inhibitors of mammalian target of rapamycin (mTOR) despite the fact that mTOR is overexpressed in approximately 90% of cases of the disease. Additionally, they are proposing a combination of mTOR inhibitors and low-dose arsenic as a potential treatment option for glioblastoma.

Paul S. Mischel, MD, principal investigator of Molecular Pathology at the Ludwig Institute for Cancer Research’s San Diego Branch in California, was among the researchers whose explorations into the novel treatment options for patients with glioblastoma were published recently in the Proceedings of the National Academy of Sciences.1 Cell lines cultured from brain tumor samples collected after surgical resection from patients treated at the University of California, Los Angeles were used in the research.

In an interview, Mischel explained that rapamycin and its analogs failed to hit their target hard enough, resulting in suboptimal inhibition of the target. Moreover, even when the therapy hits the target, alternative pathways emerge to maintain mTOR signaling through downstream effectors.

“Understanding the mechanisms of acquired resistance is essential for developing more effective treatments for patients that combine mTOR inhibitors with other agents to suppress this resistance,” Mischel said.

Investigations into these processes led Mischel and colleagues to study the relationship between mTOR and the promyelocytic leukemia (PML) gene. PML is a pleiotropic tumor suppressor that is responsible for cell apoptosis. However, certain tumor types overexpress the PML protein, such as chemotherapyresistant, quiescent leukemia-initiating chronic myeloid leukemia (CML) cells. Additionally, PML is associated with the mTOR signaling pathway and identified as an mTOR repressor. Mischel said that PML is able to suppress mTOR when mTOR levels are too high, making the cells quiescent in the process.

“Although the tumor cells grow more slowly, it enables the tumor to escape the treatment by rendering the tumor less dependent on the signal that you’re actually trying to target,” Mischel said.

The researchers found that when a patient receives an mTOR inhibitor, PML protein levels rise markedly. Mischel said they do not know exactly why this is happening, but they developed a strategy to rid cells of PML proteins so that the mTOR inhibitors could successfully treat glioblastoma.

“Reversing this upregulation of PML causes the tumor cells to be vulnerable to mTOR inhibitormediated cell death, which is of course the desired outcome,” Mischel said.

Mischel said that low-dose arsenic could be used in combination with mTOR inhibitors to address PML activity. A series of chemical modifications determines the stability of PML, and previous studies have shown that low-dose arsenic alters those modifications, leading to rapid degradation of PML.

While there is a cultural perception that arsenic should be avoided, Mischel said that research has shown that low-dose arsenic is able to degrade PML. Researchers in China found that patients with promyelocytic leukemia, a relatively rare hematologic malignancy, had good outcomes when they received traditional Chinese medicine containing low-dose arsenic. A more thorough molecular analysis was performed to determine how low-dose arsenic was able to have an effect on PML.2

“The fact is that there is really sound science behind this, and this is at a level that’s below the poisonous threshold,” Mischel said. “It’s a drug that you would think is a nonspecific poison but actually has a very specific and potent effect on degrading PML.”

Mischel said the study has prompted the researchers to design a clinical trial in which this combination is tested in patients. Since mTOR inhibitors and low-dose arsenic have both been used safely in patients with glioblastoma in previous clinical trials, Mischel said patients should be able to tolerate the two drugs together. Additionally, with so many patients exhibiting hyperactivated mTOR signaling, there is less of a need to worry about molecular stratification in the trial.

“It is likely that there may be differences in response to these agents based upon molecular context, but at this point, the data suggest that the target is activated in the majority of these patients, and that they are likely to be able to safely take these drugs,” Mischel said.

An international team of researchers contributed to the study, including scientists from the Keio University School of Medicine in Tokyo, Japan; the University of Verona in Italy; the University of California in Los Angeles and Irvine; and the laboratories of Webster Cavenee, PhD, and Frank Furnari, PhD, at the Ludwig Institute in San Diego.

References

• Iwanami A, Gini B, Zanca C, et al. PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies [published online ahead of print February 25, 2013]. Proc Natl Acad Sci U S A. 2013;110(11):4339-4344. doi: 10.1073/pnas.1217602110.
• Zhang X-W, Yan X-J, Zhou Z-R, et al. Arsenic trioxide controls the fate of the PML-RARα oncoprotein by directly binding PML. Science. 2010;328(5975):240-243.