Blocking Metastasis in Breast Cancer

From a cancer cell’s point of view, metastasis is
a risky, complicated migration. First the cell must escape
the primary tumor and launch itself into the bloodstream.
Then it must find a way to exit this flow and establish itself
on the shores of a distant organ. Finally it must develop
the means to multiply and colonize a hostile foreign
environment. Every stage is fraught with physiological
hazards and requires a knack for adapting to new conditions. Scientists have long been curious about how cancer cells
survive their metastatic journey. The cells don’t change
their essential genetic nature, which is why breast cancer
cells, for example, are recognizable wherever they land after
metastasis. Rather, the cells rely on reversible modifications
in gene expression through epigenetic changes, using
enzymes that help them stay alive while moving from one
environment to the next. But which enzymes? And how
do those enzymes function in metastasis? Identifying these
regulators of gene expression is the necessary first step to
stop the migration of cancer cells. A team at Yale Cancer Center led by Qin Yan, PhD,
Associate Professor of Pathology, has discovered a
regulating enzyme called RBP2 that breast cancer cells
need in order to metastasize to the lung. “We found
that not only is this enzyme implicated in metastasis,”
explained Dr. Yan, “but also that if you suppress it,
metastasis is suppressed. That suggests that RBP2 is a good
candidate for a targeted cancer therapy against metastasis.”
This is an exciting breakthrough, since breast cancer
strikes more women than any other cancer and is
particularly adept at aggressive metastasis, usually to the
lungs, bones, or brain. Once this cancer metastasizes, the
options for treatment dwindle, along with survival rates. Tracking down RBP2 (also known as JARID1A or
KDM5A) and deciphering its function took Dr. Yan and
his colleagues three years. First they used gene expression
datasets of breast cancer patients to identify RBP2 as a
recognized regulator of metastasis. Then they did global
genome-wide profiling to determine which genes were
regulated by RBP2 and to confirm its importance. Next
they completed cell-based assays, which confirmed that
RBP2 expression is critical in breast cancer tumorigenesis
and metastasis. Lastly they tested these findings in two
mouse models, one of which required them to use a
genetically engineered mouse model that Dr. Yan created.
Experiments in the mouse models validated their findings
derived from the clinical datasets. Dr. Yan and his colleagues also began screening
small molecules to look for inhibitors of RBP2. They
identified some first-in-class compounds that modulate
or suppress the enzyme’s activity. “We are further
Cancer Genetics and Genomics RESEARCH PROGRAM
developing those compounds so that we can use them in
the clinic,” said Dr. Yan. Some of that work is being done through the National
Cancer Institute’s Experimental Therapeutics Program,
called NExT, which aims to advance breakthrough
discoveries in the laboratory into new therapies for
cancer patients. Dr. Yan’s team is taking a three-pronged
approach. The first prong is using traditional medicinal
chemistry, to search for derivatives of the inhibitory
compounds that are more potent and specific. The
second is an expansion of the initial molecular screening
from 10,000 molecules to 100,000, again with the goal of
finding stronger, more specific compounds. The third
approach involves computational-based drug design for
inhibitors of RBP2. “We have already identified some better compounds,”
said Dr. Yan, “but in a year or so we hope to have much
more potent ones.” He and his colleagues will test the new
compounds first in biochemistry assays, then in cells, then
in mice. If all goes well, the next stage would be a clinical
trial. Dr. Yan expects to see that in about three years. Our hope is to take what we know from the clinic and
run it through the experimental system, and after we know
the mechanism and the inhibitors, we bring it back into
the clinic, so we are learning in both directions.”