Novel combination therapy shuts down escape route, killing glioblastoma tumor cells

February 26, 2013

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 and plays a critical role in regulating 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 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 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 . 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.

Explore further: Common genetic alteration found in head and neck cancers may not be key to effective treatment

Related Stories

Common genetic alteration found in head and neck cancers may not be key to effective treatment

January 29, 2013
Although a large majority of head and neck cancers have a deregulation of the PI3K/AKT/mTOR pathway, data recently published in Cancer Research, a journal of the American Association for Cancer Research, indicated that deregulation ...

Renal cancer drug temsirolimus shows promise against mesothelioma

May 1, 2011
A drug commonly used to treat kidney cancer may increase the effectiveness of chemotherapy for mesothelioma, according to a study published in the May issue of the Journal of Thoracic Oncology.

Drug class linked to worse outcomes after transplant

October 14, 2012
(HealthDay)—Kidney transplant patients who receive mammalian target of rapamycin (mTOR) inhibitors after transplant have a greater probability of death or transplant failure than patients receiving calcineurin inhibitors, ...

Patients with aberrations in two genes respond better to drugs blocking a well-known cancer pathway

November 7, 2012
Cancer patients with mutations or variations in two genes -– PIK3CA and PTEN -– who have failed to respond to several, standard treatments, respond significantly better to anti-cancer drugs that inhibit these genes' pathways ...

Recommended for you

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Immune cells the missing ingredient in new bladder cancer treatment

July 24, 2017
New research offers a possible explanation for why a new type of cancer treatment hasn't been working as expected against bladder cancer.

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Molecular changes with age in normal breast tissue are linked to cancer-related changes

July 20, 2017
Several known factors are associated with a higher risk of breast cancer including increasing age, being overweight after menopause, alcohol intake, and family history. However, the underlying biologic mechanisms through ...

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...

Discovery could lead to better results for patients undergoing radiation

July 19, 2017
More than half of cancer patients undergo radiotherapy, in which high doses of radiation are aimed at diseased tissue to kill cancer cells. But due to a phenomenon known as radiation-induced bystander effect (RIBE), in which ...

2 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

jacob_bush34
not rated yet Feb 26, 2013
Cancer has always been one of my favorite topics to study in biology, and I am looking to go into the field as an oncologist of some sort. Every day I read about new ways of curing or slowing down cancer. I love reading about these advancements because as I learn more about cancer, it interests me how scientists are tackling the issues it presents. Hopefully someday I can be one of the specialists that leads a team of cure researchers. For now I will stick to reading articles like yours. Thank you so much for the quality information. I love the website and will check it on a daily basis. It is extremely interesting to me.
Shakescene21
not rated yet Feb 27, 2013
@jacob -- I wish you success in fighting cancer. This is a great time to enter oncology because of the amazing breakthroughs that are being described on Physorg almost every week.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.