Nav: Home

Malaria drug successfully treats 26-year-old brain cancer patient

January 17, 2017

After her brain cancer became resistant to chemotherapy and then to targeted treatments, 26-year-old Lisa Rosendahl's doctors gave her only a few months to live. Now a paper published January 17 in the journal eLife describes a new drug combination that has stabilized Rosendahl's disease and increased both the quantity and quality of her life: Adding the anti-malaria drug chloroquine to her treatment stopped an essential process that Rosendahl's cancer cells had been using to resist therapy, re-sensitizing her cancer to the targeted treatment that had previously stopped working. Along with Rosendahl, two other brain cancer patients were treated with the combination and both showed similar, dramatic improvement.

"When I was 21 they found a large mass in my brain and I had it resected right away. They tested it for cancer and it came back positive," Lisa says.

"Lisa is a young adult with a very strong will to live. But it was a high-risk, aggressive glioblastoma and by the time we started this work, she had already tried everything. For that population, survival rates are dismal. Miraculously, she had a response to this combination. Four weeks later, she could stand and had improved use of her arms, legs and hands," says paper first author Jean Mulcahy-Levy, MD, investigator at the University of Colorado Cancer Center and pediatric oncologist at Children's Hospital Colorado.

The science behind the innovative, off-label use of this malaria drug, chloroquine, was in large part built in the lab of Andrew Thorburn, PhD, deputy director of the CU Cancer Center, where Mulcahy-Levy worked as a postdoctoral fellow, starting in 2009. Thorburn's lab studies a cellular process called autophagy. From the Greek "to eat oneself," autophagy is a process of cellular recycling in which cell organelles called autophagosomes encapsulate extra or dangerous material and transport it to the cell's lysosomes for disposal. In fact, the first description of autophagy earned the 2016 Nobel Prize in Medicine or Physiology for its discoverer, Yoshinori Ohsumi.

Like tearing apart a Lego kit, autophagy breaks down unneeded cellular components into building blocks of energy or proteins for use in surviving times of low energy or staying safe from poisons and pathogens (among other uses). Unfortunately, some cancers use autophagy to keep themselves safe from treatments.

"My initial lab studies were kind of disappointing. It didn't look like there was much effect of autophagy inhibition on pediatric brain tumors. But then we found that it wasn't no effect across the board - there were subsets of tumors in which inhibition was highly effective," Mulcahy-Levy says.

Mulcahy-Levy's work with Thorburn (among others), showed that cancers with mutations in the gene BRAF, and specifically those with a mutation called BRAFV600E, were especially dependent on autophagy. In addition to melanoma, in which this mutation was first described, epithelioid glioblastomas are especially likely to carry BRAFV600E mutation.

With this new understanding, Mulcahy-Levy became an essential link between Thorburn's basic science laboratory and the clinical practice of oncologist, Nicholas Foreman, MD, CU Cancer Center investigator and creator of the pediatric neuro-oncology at Children's Hospital Colorado, who had been overseeing Lisa's care.

After many surgeries, radiation treatments and chemotherapy, Lisa had started the drug vermurafenib, which was originally developed to treat BRAF+ melanoma and is now being tested in pediatric brain tumors. Lisa's experience on the drug was typical of patients with BRAF+ cancers who are treated with BRAF inhibitors such as vemurafenib - after a period of control, cancer develops additional genetic mechanisms to drive its growth and survival and is able to progress past the initial drug.

At that point, one promising strategy is to predict and/or test for new genetic dependencies and then treat any new dependency with another targeted therapy. For example, many BRAF+ cancers treated with BRAF inhibitors develop KRAS, NRAS, EGFR or PTEN changes that drive their resistance, and treatments exist targeting many of these "escape pathways". However, some cancers develop multiple resistance mechanisms and others evolve so quickly that it can be difficult to stay ahead of these changes with the correct, next targeted treatment.

"It's like that story of the boy who puts his finger in the dam," Mulcahy-Levy says. "Eventually you just can't plug all the holes."

Instead of this genetic whack-a-mole, the group chose to explore cellular mechanisms outside what can be a never-ending sequence of new mutations.

"Pre-clinical and clinical experience invariably shows that tumor cells rapidly evolve ways around inhibition of mutated kinase pathways like the BRAF pathway targeted here," the paper writes. "However, based on our results, we hypothesize that by targeting an entirely different cellular process, i.e. autophagy, upon which these same tumor cells rely, it may be feasible to overcome such resistance and thus re-establish effective tumor control."

In other words, knowing that Lisa Rosendahl's tumor was positive for BRAFV600E mutation, and that this marked the tumor as especially dependent on autophagy - and also knowing that traditional options and even clinical trials were nonexistent - the group worked with Rosendahl and her father, Greg, to add the autophagy-inhibiting drug chloroquine to her treatment.

"In September 2015, the previous targeted drugs weren't working anymore," says Greg Rosendahl. "Doctors gave Lisa less than 12 months to live. We took all our cousins up to Alaska for a final trip kind of thing. Then they came up with this new combination including chloroquine."

Vemurafenib had initially pushed Lisa's cancer past the tipping point of survival. Then the cancer had learned to use autophagy to pull itself back from the brink. Now with chloroquine nixing autophagy, vemurafenib started working again.

"My cancer got smaller, which is awesome for me," Lisa says.

"We have treated three patients with the combination and all three have had a clinical benefit. It's really exciting - sometimes you don't see that kind of response with an experimental treatment. In addition to Lisa, another patient was on the combination two-and-a-half years. She's in college, excelling, and growing into a wonderful young adult, which wouldn't have happened if we hadn't put her on this combination," Mulcahy-Levy says.

Lisa recently bought a new wheelchair so that she could spend more time at the mall. She also applied for a handicap sticker to make it easier for her to visit a nearby park with food trucks. "She wants to get out and do more. She continues to have what she feels is a good quality of life," Mulcahy-Levy says.

Research accompanying these results in patients implies that the addition of autophagy inhibition to targeted treatments may have benefits beyond glioblastoma and beyond only BRAF+ cancers. Because chloroquine has already earned FDA approval as a safe and effective (and inexpensive) treatment for malaria, the paper points out that it should be possible to "quickly test" the effectiveness of adding autophagy inhibition to a larger sample of BRAF+ glioblastoma and other brain tumor patients, and also to possibly expand this treatment to other likely mutations and disease sites.

As Mulcahy-Levy's early studies show, many cancers do not depend on autophagy. But at the same time, many do. Because a safe and simple drug already exists to inhibit autophagy, the time between discovering an autophagy-dependent cancer and the ability to add autophagy-inhibiting chloroquine to a treatment regimen against this cancer may be short.

"I really like being able to really tailor therapy to the patient," Mulcahy-Levy says. "I like saying, 'I think this is going to be really important to you,' and not necessarily using the same treatment with another patient whose cancer is driven by different genetic alterations. This is the definition of patient-centered care - designing therapy based on that individual patient's information. It's not just glioblastoma, but a certain mutation and not just the mutation but a certain pattern of previous treatments and resistance."

"It makes me feel really lucky to be a pioneer in this treatment," says Lisa Rosendahl. "I hope it helps and I hope it helps people down the road. I want it to help."
-end-


University of Colorado Anschutz Medical Campus

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Climate Crisis
There's no greater threat to humanity than climate change. What can we do to stop the worst consequences? This hour, TED speakers explore how we can save our planet and whether we can do it in time. Guests include climate activist Greta Thunberg, chemical engineer Jennifer Wilcox, research scientist Sean Davis, food innovator Bruce Friedrich, and psychologist Per Espen Stoknes.
Now Playing: Science for the People

#527 Honey I CRISPR'd the Kids
This week we're coming to you from Awesome Con in Washington, D.C. There, host Bethany Brookshire led a panel of three amazing guests to talk about the promise and perils of CRISPR, and what happens now that CRISPR babies have (maybe?) been born. Featuring science writer Tina Saey, molecular biologist Anne Simon, and bioethicist Alan Regenberg. A Nobel Prize winner argues banning CRISPR babies won’t work Geneticists push for a 5-year global ban on gene-edited babies A CRISPR spin-off causes unintended typos in DNA News of the first gene-edited babies ignited a firestorm The researcher who created CRISPR twins defends...