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!
Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München
Second research flight into zero gravity
21.10.2016 | Universität Zürich
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.
In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...
'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.
Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
21.10.2016 | Health and Medicine
21.10.2016 | Information Technology
21.10.2016 | Materials Sciences