Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

One-two punch catches cancer cells in vulnerable state

11.02.2015

Transition state may offer important window of time for treatment.

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.


This confocal microscopy image depicts drug-tolerant cancer cells. By hitting breast cancer cells with a targeted therapeutic immediately after chemotherapy, researchers were able to target cancer cells during a transitional stage when they were most vulnerable.

Credit: Image courtesy of Aaron Goldman

"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.

Haley Bridger | EurekAlert!

More articles from Life Sciences:

nachricht Newly designed molecule binds nitrogen
23.02.2018 | Julius-Maximilians-Universität Würzburg

nachricht Atomic Design by Water
23.02.2018 | Max-Planck-Institut für Eisenforschung GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Attoseconds break into atomic interior

A newly developed laser technology has enabled physicists in the Laboratory for Attosecond Physics (jointly run by LMU Munich and the Max Planck Institute of Quantum Optics) to generate attosecond bursts of high-energy photons of unprecedented intensity. This has made it possible to observe the interaction of multiple photons in a single such pulse with electrons in the inner orbital shell of an atom.

In order to observe the ultrafast electron motion in the inner shells of atoms with short light pulses, the pulses must not only be ultrashort, but very...

Im Focus: Good vibrations feel the force

A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.

By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...

Im Focus: Developing reliable quantum computers

International research team makes important step on the path to solving certification problems

Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Basque researchers turn light upside down

23.02.2018 | Physics and Astronomy

Finnish research group discovers a new immune system regulator

23.02.2018 | Health and Medicine

Attoseconds break into atomic interior

23.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>