Brigham. US: Timing may be decisive when it comes to overcoming cancer’s ability
to evade treatment. By hitting breast cancer cells with a targeted
therapeutic
immediately after chemotherapy, researchers from Brigham and Women’s
Hospital (BWH) were able to target cancer cells during a transitional
stage when they
were most vulnerable, killing cells and shrinking tumors in the lab and
in pre-clinical models. The team reports its findings in Nature Communications on February 11.
“We were studying the fundamentals of how resistance develops and
looking to understand what drives relapse. What we found is a new
paradigm for thinking
about chemotherapy,” said senior author Shiladitya Sengupta, PhD,
associate bioengineer at BWH.
Previous studies have examined cancer stem cells (CSCs) – small
populations of cells within a tumor that are resistant to chemotherapy.
Sengupta and his
colleagues took breast cancer cells that did not have the markings
of CSCs and exposed them to docetaxel, a common chemotherapy drug. The
team found that
after exposure to chemotherapy, the cells began developing physical
markings usually seen in CSCs, including receptors on the cell surface
to which
specific proteins can bind. These “markers of stemness” suggested
that the cells were transitioning into a different state, during which
time they might be
vulnerable to other cancer drugs.
To test this, the researchers treated the cells with a variety of
targeted therapeutics immediately after chemotherapy. The researchers
observed that two
drugs each killed a large fraction of the cells that had begun
transitioning: dasatinib, a drug that targets the Src Family Kinase
(SFK) and RK20449, a new
drug in pre-clinical testing that specifically targets one of the
SFK proteins called Hck. The researchers confirmed these findings
in a mammary carcinoma mouse model – treatment with dasatinib just a
few days after administering two high doses of chemotherapy prevented
tumor growth and
increased survival rates. Treating cells simultaneously with
docetaxal and dasatinib or administering dasatinib after a longer period
of time did not
produce the same effects. The researchers theorize that the cancer
cells go through a temporary transition state, which means that
administering the drugs
in a very specific timeframe and sequence is important.
“By treating with chemotherapy, we’re driving cells through a
transition state and creating vulnerabilities,” said first author Aaron
Goldman, PhD, a
postdoctoral fellow in biomedical engineering at BWH. “This opens up
the door: we can then try out different combinations and regimens to
find the most
effective way to kill the cells and inhibit tumor growth.”
To make these observations, the researchers developed and leveraged
three-dimensional “explants” – tissue derived from a patient’s tumor
biopsy and grown
in serum from that specific patient for research purposes. This
model mimics the tumor’s microenvironment and preserves the tumor’s
cellular diversity.
In a continuation of this work, Goldman is also using mathematical
modeling to pursue the most effective dose of chemotherapy to induce the
vulnerable
transition state of the cancer cell demonstrated in this research.
“Our goal is to build a regimen that will be efficacious for
clinical trials,” said Goldman. “Once we understand specific timing,
sequence of drug delivery
and dosage better, it will be easier to translate these findings
clinically.”
This work was supported by a DoD BCRP Collaborative Innovator Grant
(W81XWH-09-1-0700), NIH RO1 (1R01CA135242), DoD Breakthrough Award
(BC132168), an
American
Lung Association Innovation Award (LCD-259932-N), Indo-US Joint
Center Grant from IUSSTF, American Cancer Society Postdoctoral
Fellowship and NSERC,
Canada.