Navigation Links
Novel combination therapy shuts down escape route, killing glioblastoma tumor cells
Date:2/26/2013

February 26, 2013, New York, N.Y. and San Diego, Calif. Glioblastoma, the most common and lethal form of brain tumor in adults, is challenging to treat because the tumors rapidly become resistant to therapy. As cancer researchers are learning more about the causes of tumor cell growth and drug resistance, they are discovering molecular pathways that might lead to new targeted therapies to potentially treat this deadly cancer.

Scientists at the Ludwig Institute for Cancer Research in San Diego worked collaboratively across the laboratories of Drs. Paul Mischel, Web Cavenee and Frank Furnari to investigate one such molecular pathway called the mammalian target of rapamycin or mTOR. This signaling pathway is hyperactivated in close to 90 percent of glioblastomas and plays a critical role in regulating tumor growth and survival. Therapies that inhibit mTOR signaling are under investigation as drug development targets, but results to date have been disappointing: mTOR inhibitors halt the growth but fail to kill the tumor cells.

A study published this week in the Proceedings of the National Academy of Sciences uncovers an unexpected but important molecular mechanism of mTOR inhibitor resistance and identifies a novel drug combination that reverses this resistance.

The story begins with a closer look at a gene-encoded protein called promyleocytic leukemia gene or PML. The study investigators explored the role of PML in causing resistance to mTOR inhibitor treatment. They found that when glioblastoma patients are treated with drugs that target the mTOR pathway, the levels of PML rise dramatically. Further, they showed that PML upregulation made the tumor cells resistant to mTOR inhibitors, and that if they suppressed the ability of the tumor cells to upregulate the PML protein, the tumor cells died in response to the mTOR inhibitor therapy.

"When we looked at cells in in vivo models and patients treated in the clinic, it became clear that the glioblastoma cells massively regulated PML enabling them to escape the effects of mTOR inhibitor therapy," reported senior author Paul Mischel, MD, Ludwig Institute member based at the University of California at San Diego.

"Our team hypothesized that if we could use a pharmacological approach to get rid of PML and combine it with an mTOR inhibitor, it could change the response from halting growth to cell death. The question was how?" added Mischel.

Previous research had shown that the use of low-dose arsenic could cause degradation of the PML protein in patients with leukemia. The 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.

"Current therapy upregulates PML, turning off the mTOR signaling pathway. The tumor cells hide, waiting for the target signal to return," said Mischel. "When low-dose arsenic is added, not only does it stop the cell from returning, it shuts down the escape route killing the tumor cell."

These results present 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 researchers 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.

"These data suggest a new approach for potential treatment of glioblastoma," said Mischel. "We are moving forward to test that possibility in people."

Post-doctoral students Akio Iwanami and Beatrice Gini from the Mischel lab as well as Ciro Zanca from the Furnari/Cavenee lab, also contributed significantly to this paper.


'/>"/>
Contact: Rachel Steinhardt
rsteinhardt@licr.org
212-450-1582
Ludwig Institute for Cancer Research
Source:Eurekalert

Related biology news :

1. Researchers discover novel therapy for Crohns disease
2. New clinical trial explores novel noninvasive colon cancer screening test
3. Notre Dame researchers using novel method to combat malaria drug resistance
4. Unique adaptations to a symbiotic lifestyle reveal novel targets for aphid insecticides
5. Key proteins newly discovered form and function may provide novel cancer treatment target
6. Novel discovery by NUS scientists paves the way for more effective treatment of cancers
7. London researchers discover novel mechanism involved in key immune response
8. Mexican rock heroes trial novel green trading system
9. VTT and GE Healthcare developing novel biomarkers to predict Alzheimers disease
10. Cleveland Clinic researchers receive $5 million grant to discover novel pathways to heart disease
11. Novel nano-structures to realize hydrogens energy potential
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/11/2017)... No two people are believed to ... York University Tandon School of Engineering and Michigan ... partial similarities between prints are common enough that ... and other electronic devices can be more vulnerable ... in the fact that fingerprint-based authentication systems feature ...
(Date:4/5/2017)... KEY FINDINGS The global market for stem ... 25.76% during the forecast period of 2017-2025. The rise ... growth of the stem cell market. Download ... The global stem cell market is segmented on the ... cell market of the product is segmented into adult ...
(Date:3/30/2017)... 2017 Trends, opportunities and forecast in this ... technology (fingerprint, AFIS, iris recognition, facial recognition, hand geometry, ... end use industry (government and law enforcement, commercial and ... and others), and by region ( North America ... Asia Pacific , and the Rest of the ...
Breaking Biology News(10 mins):
(Date:10/11/2017)... ... October 11, 2017 , ... ... in its endogenous context, enabling overexpression experiments and avoiding the use of exogenous ... RNA guides is transformative for performing systematic gain-of-function studies. , This complement ...
(Date:10/11/2017)... (PRWEB) , ... October 11, 2017 , ... ComplianceOnline’s Medical ... place on 7th and 8th June 2018 in San Francisco, CA. The Summit brings ... well as several distinguished CEOs, board directors and government officials from around the world ...
(Date:10/11/2017)... a leading provider of patient support solutions, has announced the ... which will launch this week. The VMS CNEs will address ... enhance the patient care experience by delivering peer-to-peer education programs ... to help women who have been diagnosed and are being ... ...
(Date:10/11/2017)... ... 11, 2017 , ... Disappearing forests and increased emissions are the main causes ... each year. Especially those living in larger cities are affected by air pollution related ... the most pollution-affected countries globally - decided to take action. , “I knew I ...
Breaking Biology Technology: