YSM Issue 90.1

NEWS
molecular biology
BREATHE EASY
New drug reduces lung cancer cell growth
►BY EILEEN NORRIS
Wouldn’t it be nice if killing lung cancer cells was as easy as
flipping a switch? As it turns out, effectively targeting these
cells is more like a dimmer rather than a switch, but it can
be done, according to new research spearheaded by Joseph
Contessa, associate professor of Therapeutic Radiology and
Pharmacology at the Yale School of Medicine. Contessa led
the discovery of a drug that reduces non-small cell lung cancer
(NSCLC) tumor cell growth, proliferation, and survival,
without causing toxic effects to healthy cells.
NSCLC comprises about 80 to 85 percent of lung cancers and
generally spreads more gradually than small cell lung cancer.
Much cancer biology research surrounds the role of receptor
tyrosine kinases (RTKs), cell surface receptor proteins, in the
behavior of tumor cells. RTKs stimulate signals within cells
that direct the cell to grow, divide, and proliferate, and can
trigger survival signals in toxic environments. In cancer cells,
RTK genes are overexpressed, causing more RTKs to appear
on the cell surface, leading to more resilient and fastergrowing
cancer cells.
Contessa’s lab aimed to better understand how RTKs
affect tumor growth and survival, and therefore explore how
scientists can target these receptors to control tumors. Prior
hypotheses extrapolate that if one can block the function of
RTKs, turning them “off,” tumors can be treated with more
success. Current drugs and compounds such as Gefitinib
and Erlotinib target specific RTKs but do not work as well as
hypotheses predict. Early in his research, Contessa postulated
that these drugs failed due to redundant signaling, or the
presence of dominant and backup receptors that all signal
NSCLC tumor cell growth and proliferation. Therefore,
drugs and compounds that only target one receptor are
ineffective in treating the NSCLC tumor cells.
Thus, Contessa looked for ways to target multiple
receptors without creating a toxic environment for normal
cells. He found that all of the receptors are glycoproteins—
they have sugar chains attached to them. Contessa then
hypothesized that by interrupting glycosylation—the
addition of sugar chains—the function of the glycoprotein
RTKs could be blocked.
“What people thought before was that adding these sugar
chains was a switch like a light switch, turning on and turning
off. What we’ve shown is there’s actually a spot that you can
hit it that’s more like a dimmer switch, where you can just
turn it down. What we found is a small molecule, a drug-like
compound, that can act this way—it can turn the dimmer
switch down,” Contessa said.
This drug, N-linked glycosylation inhibitor-1 (NGI-
1), targets non-small cell lung cancer cells by inhibiting an
enzyme that attaches sugar chains to RTK precursors and
creates the mature glycoprotein RTKs. Contessa’s research
showed that this drug reduces the expression of epidermal
growth factor receptor (EGFR), a specific RTK, on the surface
of the lung cell. In the drug-treated cells, the EGFRs were
found inside of the cell, indicating that NGI-1 prevents the
transport of RTKs to the cell surface.
Contessa’s research further confirmed that NGI-1 is
specific; although it inhibits RTK signaling, it does not
inhibit the transport of all glycoproteins to the cell surface, so
glycoproteins essential to healthy cell function are unaffected.
“It means that tumor cells that are highly dependent on
RTKs become very sensitive to this drug,” Contessa said.
His research shows that NGI-1 arrests cellular growth and
division in RTK-dependent NSCLC tumor cells.
The project was not without difficulties. “The whole project
was a challenge… it was a collaborative effort, and we worked
with a couple different groups,” Contessa said. The process
sounds easy—a step-by-step path towards a new method of
battling lung cancer. In reality, this one drug resulted from
five years of dedicated research and testing, screening over
350,000 drugs.
“You’re kind of on this detective hunt. You’re screening and
you find this inhibitor, and then you don’t know exactly how
it works. So you have to call on some expertise to help you,
and then hopefully you get a little lucky and you figure out
the mechanism and you can advance it to your experimental
models,” Contessa reflected.
Contessa’s detective mindset, along with the advice of
many collaborators and a bit of luck, led the researchers
to a potential drug candidate for battling NSCLC tumors.
Contessa looks to translate their successes in laboratory cell
models into successes in live animal tumor models, and we
will hopefully see NGI-1 in future clinical studies.
PHOTOGRAPHY BY JARED PERALTA
►A member of Joseph Contessa’s lab at work at the Yale
School of Medicine.
8 Yale Scientific Magazine December 2016 www.yalescientific.org