Starving Cancer Stem Cells Could Be the Trick to Treating Glioblastoma, Study Finds

Enhanced MRI of a glioblastoma

Because of their critical location and the way that they infiltrate brain tissue, glioblastomas cannot be completely removed with surgery. Source: BSIP/Science Source

Summary

Using genetically engineered mouse models and high-throughput screening technologies, MSK researchers have found a surprising new approach for targeting glioblastoma. It involves focusing in on cancer stem cells.

The type of brain tumor known as glioblastoma (GBM) is one of the most difficult cancers to treat. Complete removal by surgery is impossible because of where and how these tumors infiltrate brain tissue. Additionally, the most commonly used treatments for glioblastoma — radiation therapy and the chemotherapy drug temozolomide (Temodar®) — are not very effective over the long term.

Researchers in Memorial Sloan Kettering’s Brain Tumor Center, led by developmental biologist Luis F. Parada, are focused on finding more effective ways of attacking this deadly cancer. In a study published in Nature, they report on the identification of a compound that kills glioblastoma cells using a mechanism that’s completely different from earlier treatments. The scientists say one of the keys to finding better drugs is developing models that accurately reflect the cells that make up these tumors.

“We use genetically engineered mouse models to study the biological features of glioblastoma in a way that you cannot do with other laboratory methods,” Dr. Parada says. “We’ve found that a critical component of cells within these tumors are cancer stem cells. This required us to take a different approach to developing new therapies.”

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Focusing on Cancer Stem Cells

Like normal stem cells, cancer stem cells can give rise to many other types of cells. This means they have the ability to rebuild a tumor, even after most of it has been removed, leading to cancer relapse and metastasis.

“The pharmaceutical industry has traditionally used established cancer cell lines to screen for new drugs, but these cell lines don’t always reflect how cancer behaves in the body,” explains Dr. Parada, whose lab is in the Sloan Kettering Institute’s Cancer Biology and Genetics Program. Cell lines are idiosyncratic populations derived from a single cancer cell that are grown in the lab.

“The therapies that are currently in use were designed to target cells that are rapidly dividing,” he adds. “But what we’ve concluded in our studies is that glioblastoma stem cells divide relatively slowly within tumors, leaving them unaffected by these treatments.” Even if most of the tumor is destroyed, the stem cells allow it to regrow.

Glioblastoma is driven primarily by a small number of gene mutations, including three genes that have been used to model the tumor in mice. The investigators in Dr. Parada’s lab demonstrated that when mice were engineered to carry these three mutations, 100% of them developed glioblastoma.

Next they pooled the cells from the mouse-derived tumors. Their hope was that this population of cells would be more accurate than traditional cell lines in reflecting the range of cell types making up a typical glioblastoma tumor. With these cells in hand, the team was ready to use them to begin looking for new drugs.

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Finding a Needle in a Haystack of Drugs

What they sought were compounds that could kill glioblastoma tumor cells, including cancer stem cells, without killing normally dividing cells. 

Using high-throughput screening, a method in which hundreds of thousands of compounds can be evaluated in a single test, the list of potential drugs was whittled from 200,000 to 5,000 to 2,000 to 60. More in-depth studies were conducted on the 60 most promising compounds.

The treatments traditionally used to treat glioblastoma are not very effective over the long term.

One drug — which the team eventually dubbed Gboxin, short for “glioblastoma toxin” — rose to the top. It was effective at curbing the growth of glioblastoma tumors in mice and did not seem to make them sick.

“Once we identified this compound, the next step was to test it on glioblastoma cells derived from patients with glioblastoma,” Dr. Parada says. “We found that the human glioblastoma cells all succumbed to Gboxin.”

After the researchers showed that Gboxin was effective at treating glioblastoma in mice and killing human glioblastoma cells, they set out to determine how and why it worked.

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An Unexpected Mechanism Opens Up New Possibilities for Treatment

Through a series of complex experiments, they made an unexpected discovery: that Gboxin killed cancer stem cells by affecting a specific component of their metabolism and starving them of energy. Several labs at MSK study the metabolism of cancer cells, including those of MSK President and CEO Craig Thompson and Sloan Kettering Institute cell biologist Lydia Finley. But until now, this hasn’t been a focus of Dr. Parada’s work.

Specifically, the researchers found that Gboxin prevents cells from making ATP — the cell’s energy currency — by way of a process called oxidative phosphorylation. This highly efficient process of metabolism takes place in structures called mitochondria, sometimes referred to as a cell’s energy factories.

“Stem cells are very specialized and need a lot of energy to do their thing,” Dr. Parada says. “When Gboxin accumulates within cancer stem cells, it essentially strangles the mitochondria and shuts energy production down.”

Other dividing cells in the body, including other cancer cells, rely less on oxidative phosphorylation than stem cells. They employ instead a type of metabolism called glycolysis, which is better at generating the building materials required to make new cells. This makes them much less sensitive to Gboxin.

“Ideally, what we want in a glioblastoma drug is something that targets the cancer stem cells specifically, while sparing normal cells.” Dr. Parada says. “That’s what Gboxin seems to do.”

When Gboxin accumulates within cancer stem cells, it essentially strangles the mitochondria and shuts energy production down.
Luis F. Parada
Luis F. Parada developmental biologist
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A Promising Start to Research

There is still a lot of work to be done before Gboxin can be tested in clinical trials in humans. Among the next steps, the investigators need to determine that Gboxin will be able to cross what is called the blood-brain barrier. If it can’t, a version that is able to do so will need to be developed. Much more research is needed on the potential side effects of the drug as well.

Dr. Parada explains that because many tumors develop from cancer stem cells, the findings about Gboxin and glioblastoma stem cells may be applicable to other types of cancer. “What we know about cancer stem cells in general suggests that they all use similar mechanisms for their growth and proliferation,” he concludes. “If this drug turns out be effective against glioblastoma, we’ll be very happy. If it turns out to work against other types of cancer, that would be great, too.”

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Investigators from the University of Texas Southwestern Medical Center also contributed to this paper. This research was funded by National Cancer Institute Grants R35: CA210100 and R01: CA131313. It was also funded by a Basic Research Fellowship from the American Brain Tumor Association (in memory of Theodore Sapper), William H. and Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Center for Experimental Therapeutics at MSK, the Cancer Prevention and Research Institute of Texas, and the Robert A. Welch Foundation.

Dr. Parada served as consultant for Bio-Thera Pharmaceuticals from 2013–2018. He is a coauthor on the patent application ‘Substituted Benzimidazolium, Pyrido-Imidazolium, or Pyrazino-Imidazolium Compounds as Chemotherapeutic Agents’ (international application no. PCT/US2016/065751, pub. no. WO/2017/100525 (2017)).

Comments

Wow this is famtastic, i have Glioblastoma and go to MSKCC for treatmemt biweekly. Would volunteer for this trial if/when it becomes available, although i am a trial now, and am doing ok. Bless your whole team.

Dear Marc, it is still too early to know when — or if — this compound will ever be tested in human trials. We’re glad to hear you’re doing OK with your current trial at MSK. Thank you for your comment and best wishes to you.

Would this type of treatment help someone with Glisarcoma? My mother in law was diagnosed with Gliosarcoma in January 2019.

Dear Elizabeth, we’re sorry to hear about your mother-in-law’s diagnosis. It is still too early to what types of cancer it may be effective against, if it ever makes it to clinical trials. If your mother-in-law interested in learning about trials that are currently available at MSK, she can make an appointment online or call 800-525-2225 to learn more. Thank you for your comment and best wishes to you and your family.

How can we find out more about the study? When will the human trial begin? How can we be in contact with the study to put our name on the list for human trial?

Dear Angie, it is still too early to know when — or if — this compound will ever be tested in human trials. If you or someone you know is interested in learning about trials that are currently available at MSK, you can make an appointment online or call 800-525-2225 to learn more. Thank you for your comment and best wishes to you.

My 32 year old son has GBM4. He was diagnosed 7 years 5 months ago and at the moment is doing well. The cancer has been stable for over 6 years.
I’m keen to learn about research.

Dear Sharon, we’re sorry to hear about your son’s diagnosis, but glad to hear he is doing well. Thank you for your comment and best wishes to both of you.

My son's favorite teacher died of GBM almost 30 years ago. He is 39 sadly, has GBM himself. Why has nothing changed in 30 years for treatment or cure for GBM? Why has a cure for HIV been found and not cancer? Why is SOC the only "cure" offered and that is only to treat...not cure. I just don't understand....someone please explain to this hurting mother and all that have a loved one with cancer. Thank you.

Dear Donna, we are very sorry to hear about your son’s diagnosis. You may be interested in joining Connections, our online support group for people with cancer and their family members. Best wishes to you and your son.

Please contact me my husband was diagnosed this week. We are interested in your trials. I found the article above hopeful and wonderful and I understand it’s not ready to be tested but I wish it was. We love to learn about your other trials and we will be looking at treatment at University of Colorado in Denver but we have not started that and I’m not sure if They are offering any trials. This is 7 March 2019 please get in touch sincerely Andrea

Dear Andrea, we’re very sorry to hear about your husband’s diagnosis. Although the drug discussed in this article is still in very early stages of development in the laboratory, we do have other clinical trials for glioblastoma. if your husband would like to come to MSK in New York for a consultation, you can make an appointment online or call 800-525-2225. If he is not able to travel here we recommend that you discuss with his current care team whether any clinical trials are available.

Would you please explain why the drug has to be able to pass through the blood-brain barrier? Is it so it can be administered without direct "injection" into the tumor, or does it have to do with something else?

Dear Marie, this drug is still in the very early stages of development and it is still too early to know whether it will ultimately be effective and, if so, how it will be administered. Thank you for your comment.

My nephew, 38 year old active Army veteran , who served in Iraq, has been dx with Glioblastoma stage 4. Any help/guidance/ recommendations would be appreciated!

Dear Donna, we’re very sorry to hear about your nephew’s diagnosis. If he is interested in coming to MSK for a consultation he can make an appointment online or call 800-525-2225. Thank you for your comment and best wishes to you and your family.

My Husband had GBM surgery at MSK January 31, 2017 and passed away September 27, 2017. How is it possible for people to live for many years with GBM while the survival rate is only up to 15 months?

Dear Stella, we are very sorry for your loss. The 15-month figure is an average, which means that some people will live longer. Thank you for your comment and best wishes to you.

Hello,
I am 61 years old andIt will be two years on April 29th 2019 since I had a seizure from my GBM tumor. It was surgically removed and I did Temadar and radiation. It came back in an inoperable area and I had high energy focused radiation as well as having Avastin IV treatment. In about a month I will have another MRI to see how effective this has been. Not many places do trials with GBM once it reoccurs, but I am holding out hope that the drug in this article, or any other treatment for that matter, will become available. Consider me a volunteer if needed.

Dear Jim, thank you for sharing your experiences. If you are interested in speaking with someone at MSK about what treatment options may be available, including participating in a trial, you can make an appointment online or call 800-525-2225. Best wishes to you.

My husband was diagnosed in March 2017 and went through so many different treatments that were available. Tumor has come back again so we are going to try Cyberknife therapy again. Wish this trial was available. Sad to say this diagnosis seems to be more common anymore. They need to give more money for more trials and find a cure.

Dear Pamela, we’re sorry to hear your husband’s tumor has come back. Thank you for sharing your thoughts. Best wishes to both of you.

I recieved my diagnosis of GBM 24th May 2019. I am currently receiving TMZ Chemo and Radiation post surgey 24 May 2019. I am based in Australia and wondering if worthwhile look at clinical trials or alternate therapies ? Would need to understand costs and how i would go about this ?

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