Autophagy inhibition in pediatrics: One physician-scientist’s brave decision

Tue, 03/13/2018 - 13:05

Autophagy Pathway, Novus Biologicals, macroautophagy induction, autophagosome maturation, microautophagy, autolysosome, elongation

By Christina Towers, PhD.

The current time from when a discovery is first made on the bench to when that discovery might translate into an approved therapy in cancer patients is an astounding 10-15 years. Scientists and clinicians alike face a daunting uphill battle to find novel targeted therapies that can improve a patient’s outcome yet still maintain minimal adverse side effects. Recently, however, Dr. Jean Mulcahy Levy, a pediatric neuro-oncologist and physician-scientist, found a way to bypass some of these hurdles.  In 2012 she was working as a research-fellow at the University of Colorado in the laboratory of Dr. Andrew Thorburn, an expert in the field of autophagy – an essential biological process that cells use to recycle damaged organelles and proteins to fuel metabolism.  While working with cultured pediatric brain cancer cells, she made the discovery that cells harboring the oncogenic BRAF-V600E mutation are more sensitive to autophagy inhibition, both genetically and pharmacologically. Importantly, the pharmacological agent she used was the lysosomal inhibitor, chloroquine, a drug that has long been approved for clinical use in adults to treat malaria and rheumatoid arthritis. She also showed chloroquine could synergize with the BRAF specific inhibitor, vemurafenib, to kill BRAF mutant cancer cells1

Dr. Mulcahy Levy, biomarker identification of autophagy as therapy, Children's Hospital Colorado

Around this time, Dr. Mulcahy Levy serendipitously had a joint appointment at the nearby Colorado Children’s hospital where she treated kids with brain tumors.  One particular patient had recently failed her fourth treatment regimen and was out of approved therapy options.  Even though this patient’s brainstem ganglioma harbored the BRAF-V600E mutation, her tumor continued to grow during vemurafenib treatment based on MR imaging as well as progression of clinical signs. With her newly obtained in vitro data suggesting that BRAF mutant tumors might be more sensitive to autophagy inhibition, and the rare studies in the literature indicating the effectiveness of chloroquine in adult brain tumors, Dr. Mulcahy Levy and her colleagues made the brave decision to offer this pediatric patient chloroquine in combination with vemurafenib – a drug combination that had never been administered in children.   The patient showed rapid clinical improvement with this drug combination and within 6 weeks saw a 90% decrease in clinical signs.

After 6 months on the combination therapy, magnetic resonance imaging (MRI) showed a complete resolution at one of the recurrence sites and stable disease with no increased growth at the other site.  For over 2 years, this combination therapy dramatically improved the patient’s quality of life with minimal side effects.  Dr. Mulcahy Levy’s findings have led to huge advancements in the field of autophagy and pediatric neuro-oncology.  Counter to the bleak statistics of new drugs in oncology, Dr. Mulcahy Levy was able to make a discovery at the bench and quickly use that knowledge to extend the life of a patient.  Despite this progress there is still much work to be done, and Dr. Mulcahy Levy believes “the next step is to identify other biomarkers or genetic alterations that we can say make these patients autophagy dependent and extend this therapy beyond just the V600E population”. 

Learn More About Autophagy In The Brain

Christina TowersChristina Towers, PhD
University of Colorado (AMC)
Dr. Towers studies the roles of autophagy, apoptosis and cell death in cancer.


Levy JM, Thompson JC, Griesinger AM, Amani V, Donson AM, Birks DK, et al. Autophagy inhibition improves chemosensitivity in BRAF(V600E) brain tumors. Cancer Discov. 2014;4(7):773-80.



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