A treatment regimen that included the inexpensive anti-malaria drug chloroquine dramatically improved survival and quality of life for three patients with glioblastoma, according to researchers from University of Colorado Cancer Center.
Two of the patients maintained response to treatment for more than 2 years.
Jean Mulcahy Levy
“We were excited that the three patients who tried the combination all had some clinical benefit,” Jean Mulcahy Levy, MD, investigator at University of Colorado Cancer Center and pediatric oncologist at Children’s Hospital Colorado, told HemOnc Today. “This supports examining this combination in a broader clinical trial and assessing its efficacy in a larger patient population.”
Chloroquine inhibits a cellular process known as autophagy, a process of cellular recycling in which organelles called autophagosomes encapsulate dangerous or extra materials and transport them to the cell’s lysosomes for disposal.
Cancers with mutations in the BRAF gene rely on autophagy to stay safe from treatments. Laboratory studies showed malignancies that harbor BRAF V600E mutations are especially likely to depend on autophagy for survival.
Researchers initially observed BRAF V600E in melanoma, and now they are known to be carried by a variety of pediatric brain tumors, as well as most epithelioid glioblastomas.
The traditional method of targeting BRAF mutations is via small molecule inhibitors such as vemurafenib (Zelboraf, Genentech), originally developed to treat BRAF–positive melanoma and now under evaluation for treatment of children with brain tumors.
These drugs control cancer growth for a time, but cancer cells typically find alternate ways to survive and thrive.
“Preclinical and clinical experience invariably shows that tumor cells rapidly evolve ways around inhibition of mutated kinase pathways like the BRAF pathway targeted here,” Mulcahy Levy and colleagues wrote. “However, based on our results, we hypothesize that by targeting an entirely different cellular process — ie, autophagy, upon which these same tumor cells rely — it may be feasible to overcome such resistance and thus re-establish effective tumor control.”
Mulcahy Levy and colleagues combined vemurafenib with the autophagy-inhibiting drug chloroquine. They discovered a combination such as this may be the key to overcoming the ability of cancer cells to evolve and evade treatment, as well as to resensitize cancer to targeted treatments that may have stopped working.
“This combination offers a new way of not only improving small molecule inhibitor therapy, but also one of helping to combat the resistance that patients often develop to this therapy,” Mulcahy Levy told HemOnc Today. “Using chloroquine in combination with drugs that target the BRAF mutation improves the efficacy of the small molecule inhibitor.”
Mulcahy Levy and colleagues administered the combination to three patients, each of whom had been told by their doctors they’d only live a few months. All three patients exhibited tumor regression, as well as improvement in clinical symptoms and MRI results.
Two patients achieved prolonged responses and remained alive approximately 2.5 years after receiving the treatment. The other patient responded to the combination for 9 months but died of an unrelated medical condition.
The research team plans to conduct a clinical trial to test the combination in a larger group of pediatric, adolescent and young adult patients with BRAF V600E–positive brain tumors.
Researchers also want to determine if patients will develop resistance to autophagy inhibitors and, if so, how this can be combatted.
Because chloroquine is inexpensive and already FDA approved, Mulcahy Levy and colleagues hope the research can be conducted swiftly and efficiently.
Also, because autophagy is known to be an essential process in other cancer types, this approach is being investigated in melanoma, pancreatic cancer, multiple myeloma and other malignancies.
“This is the definition of patient-centered care — designing therapy based on that individual patient’s information,” Mulcahy Levy said in a press release. “It's not just glioblastoma, but a certain mutation ... [and] a certain pattern of previous treatments and resistance.” – by Kyle Doherty
For more information:
Jean Mulcahy Levy, MD, can be reached at Children’s Hospital Colorado, Anschutz Medical Campus, 13123 E. 16th Ave., Aurora, CO 80045; email: email@example.com.
Disclosure: The researchers report no relevant financial disclosures.