David Bowtell, Ph.D., head of the Cancer Genomics and Genetic Program at the Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues generated these data in one of the first studies to investigate using patient tumor samples as the mechanisms responsible for the emergence of chemotherapy resistance in high-grade serous ovarian cancer.
"High-grade serous cancers account for about two-thirds of deaths from epithelial invasive ovarian cancer," Bowtell said. "We were interested in identifying the molecular changes that occurred in a tumor between the time when a woman first presented for surgery and chemotherapy, and the time when the tumor recurred and eventually became resistant to chemotherapy."
To examine this, the researchers analyzed metastatic lesions from individual patients and 22 paired pretreatment and post-treatment tumor samples for spatial and temporal genomic variation.
"Spatial variation is a measure of genomic heterogeneity in different deposits of tumor present at primary surgery – variation that the tumor could draw on to evolve over time, especially in the face of chemotherapy," Bowtell explained. "Temporal variation gives us an indication of how much the tumor changes over time, and after one or more lines of chemotherapy."
The researchers compared the level of genomic change among women who were initially chemosensitive and those who were resistant to primary chemotherapy. Tumors that were initially sensitive to chemotherapy but later became resistant evolved further than those tumors that were resistant from the outset. "We were surprised by the extent of variation that was present among the tumor deposits collected at surgery, and by how far the tumors could evolve during therapy," Bowtell said. "The existence of multiple cancer genomes in an individual patient could provide many opportunities for the cancer to circumvent chemotherapy and may help explain why it has been so difficult to make progress with this disease," he said.
The most frequently occurring genomic change found was a deletion and/or downregulation of LRP1B, which encodes a member of a family of proteins that transport lipids into cells. To validate their findings further, the researchers examined the effect of engineering gain or loss of LRP1B in ovarian cancer cell lines. Loss of LRP1B contributed to the emergence of resistance to liposomal doxorubicin, a type of chemotherapy, in women exposed to the drug during their treatment.
"Many women with high-grade serous ovarian cancer experience an excellent response to initial chemotherapy, but unfortunately the disease often returns and becomes resistant to treatment. Currently, we have few tools to predict response to chemotherapy in the relapse setting. LRP1B adds to a handful of other mechanisms so far identified," Bowtell said. "If we can comprehensively map the mechanisms that confer resistance, we may be able to predict whether some women are likely to respond to a certain drug or not, and find ways of reversing resistance."
The study forms part of the International Cancer Genome Consortium (ICGC). Bowtell said that international collaboration is needed to systematically map the emergence of chemotherapy resistance in ovarian cancer and other solid cancers, given that it is difficult to obtain paired pre- and post-treatment samples. He believes that the collection of biopsy tissue in the relapse setting will increasingly be seen as essential for predicting response in the clinic and understanding why treatment failure occurs.
The study was funded by the Association for International Cancer Research.
Follow the AACR on Twitter: @aacr #aacr
Follow the AACR on Facebook: http://www.facebook.com/aacr.orgAbout the AACR
For more information about the AACR, visit www.AACR.org.
Jeremy Moore | EurekAlert!
Finnish research group discovers a new immune system regulator
23.02.2018 | University of Turku
Minimising risks of transplants
22.02.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg
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...
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...
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...
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...
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...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
23.02.2018 | Physics and Astronomy
23.02.2018 | Health and Medicine
23.02.2018 | Physics and Astronomy