rates for people with aggressive glioblastoma are dismal. 26-year-old Lisa Rosendahl's doctors gave her only a
few months to live after her brain cancer became resistant to chemotherapy and then to
Now a paper published 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
‘Adding the anti-malaria drug chloroquine stopped an essential process that the cancer cells had been using to resist therapy, re-sensitizing the 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
"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. 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, 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, 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.
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
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'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
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
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
"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
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,"
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."