Can you give a brief introduction to the mammalian target of rapamycin (mTOR) pathway?
The mammalian target of rapamycin, mTOR is a central integrator of the cell that coordinates growth factor receptor signaling with energy and nutrient status to control a wide array of activities, including the regulation of cellular proliferation and survival.
Thus, mTOR has emerged as a compelling cancer drug target, particularly for glioblastoma, the most common and lethal form of adult brain cancer.
Can you outline your recent research into the mTOR pathway?
Activation of the phosphoinositide 3-kinase (PI3K)/mTOR pathway is common in glioblastoma multiforme (GBM) tumors. It occurs in nearly 90% of tumors, thus prompting investigation of mTOR inhibitors for the treatment of this disease.
However, clinical trials using the mTOR inhibitor rapamycin to treat GBM patients have been unsuccessful because tumors develop resistance to these inhibitors. In this paper, we uncovered an unexpected, but important molecular mechanism of mTOR inhibitor resistance.
We hypothesized that that the promyelocytic leukemia (PML) protein, which suppresses PI3K/mTOR activity and has been implicated in drug resistance in leukemia, may function as a mechanism of mTOR inhibitor resistance in GBM, essentially by suppressing the drug target.
We found that by increasing the level of PML, the tumor cells were able to escape from mTOR inhibitor-mediated cell death. When we combined mTOR inhibitor treatment with a low-dose arsenic trioxide, the combination prevented tumor cells from increasing their levels of PML in response to the mTOR inhibitors. This caused tumor cell death and blocked the growth of GBMs in mice.
These results suggest a new strategy for suppressing mTOR inhibitor resistance, and a new combination therapy approach for the treatment of glioblastoma.
What happens to the promyleocytic leukemia gene (PML) when glioblastoma patients are treated with drugs that target the mTOR pathway?
When glioblastoma patients were treated with drugs that target the mTOR pathway, the levels of PML rose dramatically. A similar observation was seen when the tumor cells were treated in cell culture or in mouse xenografts.
Blocking this increase in the level of PML, either genetically, or using low-dose arsenic trioxide, prevented the PML upregulation and the tumor cells died in response to the mTOR inhibitor therapy.
The results provide the first clinical evidence that mTOR inhibition promotes PML upregulation in mice and patients, and that it mediates drug resistance. The clinical relevance was confirmed when we looked at before- and after-treatment tissue samples from patients treated with mTOR inhibitors, confirming that PML goes up significantly in post treatment of mTOR inhibitors.
What was the effect of adding low-dose arsenic?
Previous research had shown that the use of low-dose arsenic could cause degradation of the PML protein in patients with leukemia. Our team hypothesized that if arsenic could degrade PML, it may reverse resistance to mTOR inhibitors.
The combination of mTOR and low-dose arsenic in mice indeed showed a synergistic effect, with massive tumor cell death along with very significant shrinkage of the tumor in mice with no ill side effects. Independently neither agent was effective, but when combined they worked.
What therapies are currently under investigation to inhibit mTOR signalling?
mTOR has been an appealing therapeutic target for treating multiple cancers, alone or in combination with inhibitors of other pathways. However, clinical trials using rapamycin have been unsuccessful as glioblastoma (GBM) tumors develop resistance to these inhibitors.
A next generation of mTOR inhibitors that has better ability to block the full spectrum of mTOR’s activities are now being investigated in the clinic. The results of this paper show that these drugs may also increase PML levels, thus suggesting the potential benefit of combining them with low-dose arsenic trioxide.
What impact do you think this research will have on the potential treatment of glioblastoma?
These results present the first clinical evidence that mTOR inhibition promotes PML upregulation in mice and patients, and that it mediates drug resistance. Importantly, this study suggests a clinical strategy for treating GBM patients with mTOR inhibitor/arsenic trioxide combination therapy.
Of note, although we did not study other cancer types, the role of PML in mediating mTOR inhibitor resistance in other cancers is worthy of future investigation.
What plans are there for further research into this topic?
We can see that it works well in mouse models, but we are moving forward to test that possibility in people. Designing the clinical trials appropriately to make sure that the drugs are hitting their targets and that this has the anticipated positive effect in patients will be critical next steps.
Where can readers find more information?
The paper has been published ahead of print in the Proceedings of the National Academy of Sciences.
PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies
Akio Iwanamia, Beatrice Ginib,c,1, Ciro Zancab,1, Tomoo Matsutanib, Alvaro Assuncaod, Ali Naele, Julie Dangf, Huijun Yangb, Shaojun Zhug, Jun Kohyamag, Issay Kitabayashih, Webster K. Caveneeb,i, Timothy F. Cloughesyj, Frank B. Furnarib,i,k, Masaya Nakamuraa, Yoshiaki Toyamaa, Hideyuki Okanol, and Paul S. Mischel. PNAS. 2013 Feb 25.
About Dr. Paul Mischel
Dr. Paul Mischel heads the San Diego Branch's Laboratory of Molecular Pathology and also holds a professorship in the UCSD Department of Pathology.
Dr. Mischel is a board certified neuropathologist with expertise in signal transduction biology. His laboratory has expertise in quantitative analysis of signal transduction pathways, stem-cell related pathways, and gene expression networks in clinical samples.
He is a member of the American Society for Clinical Investigation (ASCI), past President (2010-2011) of the ASCI and Ludwig Institute for Cancer Research Member based at UCSD.
Dr. Mischel graduated Alpha Omega Alpha with an M.D. from Cornell University Medical College and trained in Anatomic Pathology and Neuropathology at UCLA. He obtained his post-doctoral research training in the laboratory of Dr. Louis F. Reichardt at the Howard Hughes Medical Institute at UCSF and joined the UCLA faculty in 1998.
Dr. Mischel has received a number of awards, including the Farber Award in 2007, the top brain tumor research award given jointly by the Society for Neuro-oncology and the American Association of Neurosurgery. Dr. Mischel's work was profiled by the Journal of Cell Biology in June 2008.
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