UCLA: Researchers from
UCLA and Long Beach Memorial Medical Center have found that two targeted
therapies could be more effective if used in combination to treat
squamous cell carcinomas of the lung. The two drugs, MLN128 and CB-839,
individually target the metabolism of key nutrients glucose and
glutamine, respectively, prohibiting the cancer from switching metabolic
gears between glucose (a simple sugar) and glutamine (an amino acid) to
tap vital sources of energy. This switch enables the cancer cells to
adapt their metabolism and evade treatments.
BACKGROUND
Non-small cell lung cancer makes up about 85 percent of all lung
cancers, and within this population about 20 percent of patients get
squamous cell carcinomas. These carcinomas are aggressive and highly
resistant to most current therapies — including chemotherapy and
targeted therapies. Although squamous cell carcinomas can rapidly adapt
their metabolism to evade therapies, not much is understood about the
mechanisms governing metabolic adaptation in these tumors. Because
people with this disease have worse survival odds than those with other
subtypes of non-small cell lung cancer, researchers have been working to
better understand the mechanisms that drive these metabolic adaptations
in order to improve treatment.
METHOD
Through positron emission tomography, or PET, scanning as well as
mass spectrometry, researchers profiled metabolism in cancer cells to
determine the molecules involved in cell functions. They then were able
to identify a dual reliance on glucose and glutamine for metabolic
needs, finding that squamous cell carcinomas typically rely on high
levels of glucose to meet metabolic needs arising from rapid tumor
growth. When glucose supplies are cut off, however, the cancer cells can
make a metabolic switch that allows them to derive energy from
glutamine. This switch uses cellular pathways that support the disease’s
spread. Based on this discovery, the team consulted The Cancer Genome
Atlas databases to find molecular signals and markers of cell activity
that could be pharmaceutical targets for new therapies. Specifically,
the drug candidates CB-839 and MLN128, when used together, could reduce
tumor growth in squamous cell carcinoma.
IMPACT
In uncovering changes in metabolic pathways that squamous cell
carcinomas use to maintain their need for energy, researchers were able
to identify potential ways to thwart the cancer cells in their switch
from one energy source to another. Their findings point to metabolic
signals that could be used to differentiate cancer patients by the
nutrient-demands of their tumors. In addition, the researchers found at
least two existing anti-cancer compounds that, when used in concert,
could prove to halt the proliferation and growth of squamous cell
carcinomas by blocking cellular metabolism changes in cancer.
AUTHORS
Lead author is David Shackelford, associate professor in the division
of pulmonary and critical care medicine at UCLA and a member of the
UCLA Jonsson Comprehensive Cancer Center. The first author is Milica
Momcilovic, also with the division of pulmonary and critical care
medicine. Other authors are Francesco Parlati and Susan Demo of
Calithera Biosciences; Michael Gricoski, Robert Shuman and Julio Ibarra
of MemorialCare Health System of Long Beach; Deborah Fridman of Hoag
Memorial Hospital Presbyterian of Newport Beach; and Sean Bailey of
University of North Carolina Chapel Hill. Also of UCLA are Jason Lee,
Michael Fishbein, Daniel Braas, James Go, Thomas Graeber, Rui Li, Tonya
Walser, Michael Phelps, Karam Badran, Maie St. John, Noah Federman,
Nicholas Bernthal, Jane Yanagawa, Steven Dubinett, Saman Sadeghi and
Heather Christofk.
JOURNAL
The research is published in Cancer Cell.
FUNDING
The research was supported by the David Geffen School of Medicine at
UCLA, U.S. Department of Defense, American Cancer Society, American Lung
Association, Bonnie J. Addario Lung Cancer Foundation, Stop Cancer
Foundation, National Cancer Institute and National Institutes of Health.
