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!
Study tracks inner workings of the brain with new biosensor
16.08.2018 | Rheinische Friedrich-Wilhelms-Universität Bonn
Foods of the future
15.08.2018 | Georg-August-Universität Göttingen
Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...
Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.
When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...
Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.
Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....
Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.
Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...
Scientists have discovered that the electrical resistance of a copper-oxide compound depends on the magnetic field in a very unusual way -- a finding that could help direct the search for materials that can perfectly conduct electricity at room temperatur
What happens when really powerful magnets--capable of producing magnetic fields nearly two million times stronger than Earth's--are applied to materials that...
08.08.2018 | Event News
27.07.2018 | Event News
25.07.2018 | Event News
16.08.2018 | Life Sciences
16.08.2018 | Earth Sciences
16.08.2018 | Life Sciences