cancer-cells

Columbia University scientists, in collaboration with researchers from Nimbus Therapeutics, have demystified a metabolic enzyme that could be the next major molecular target in cancer treatment.

The team has successfully determined the 3D structure of human ATP-citrate lyase (ACLY) – which plays a key role in cancer cell proliferation and other cellular processes – for the first time.

The findings, published in Nature, represent a first step in better understanding the enzyme in order to create effective molecular targeted therapies for patients.

While previous experiments have succeeded with fragments of the enzyme, the current work reveals the full structure of human ACLY at high resolution.

“ACLY is a metabolic enzyme that controls many processes in the cell, including fatty acid synthesis in cancer cells. By inhibiting this enzyme, hopefully we can control cancer growth,” said Liang Tong, William R. Kenan Jr. professor and department chair of Biological Sciences at Columbia and senior author of the study. “In addition, the enzyme has other roles, including cholesterol biosynthesis, so inhibitors against this enzyme could also be useful toward controlling cholesterol levels.”

Targeted therapy is an active area of cancer research that involves identifying specific molecules in cancer cells that help them grow, divide and spread. By targeting these changes or blocking their effects with therapeutic drugs, this type of treatment interferes with the progression of cancer cells.

Earlier this year, another group of researchers presented results of a phase 3 clinical trial for bempedoic acid, an oral therapy for the treatment of patients with high cholesterol. The drug, a first-generation ACLY inhibitor, was shown to reduce low-density lipoprotein (LDL) cholesterol by 30 percent when taken alone and an additional 20 percent in combination with statins.

ACLY has been found to be over-expressed in several types of cancers and experiments have found that ‘turning off’ ACLY leads cancer cells to stop growing and dividing. Knowledge of the complex molecular architecture of ACLY will point to the best areas to focus on for inhibition, paving the way for targeted drug development.

Tong and Jia Wei, an associate research scientist in his lab, performed an imaging technique known as cryogenic electron microscopy (cryo-EM) to resolve the complex structure of ACLY. Cryo-EM allows for high-resolution imaging of frozen biological specimens with an electron microscope. A series of 2-dimensional images are then computationally reconstructed into accurate, detailed 3D models of intricate biological structures like proteins, viruses, and cells.

“A critical part of the drug discovery process is to understand how the compounds work at the molecular level,” said Tong, whose lab specialises in the mechanism and function of biological molecules. “This means determining the structure of the compound bound to the target, which in this case is ACLY.”

The cryo-EM results revealed an unexpected mechanism for effective inhibition of ACLY. The team found that a significant change in the enzyme’s structure is needed for the inhibitor to bind. This structural change then indirectly blocks a substrate from binding to ACLY, preventing enzyme activity from occurring as it should. This novel mechanism of ACLY inhibition could provide a better approach for developing drugs to treat cancer and metabolic disorders.

microfluidics

Scientists have developed a microfluidic device that is able to isolate individual cancer cells from patient blood samples.

Researchers at the University of Illinois at Chicago and Queensland University of Technology of Australia developed the device that can be used to separate the various cell types found in blood by size.

“This new microfluidics chip lets us separate cancer cells from whole blood or minimally-diluted blood,” said Dr Ian Papautsky, the Richard and Loan Hill Professor of Bioengineering in the UIC College of Engineering and corresponding author on the paper.

“While devices for detecting cancer cells circulating in the blood are becoming available, most are relatively expensive and are out of reach of many research labs or hospitals. Our device is cheap, and doesn’t require much specimen preparation or dilution, making it fast and easy to use.”

The researchers mentioned how their device could enable rapid, cheap liquid biopsies to help the detection of cancer, and may even aid the development of targeted treatment.

 The ability of the device to isolate cancer cells is a crucial step, and would eliminate the discomfort and cost of tissue biopsies. Liquid biopsy could also track to efficacy of chemotherapy over time, and even to detect cancer in organs.

The isolation of these cancer cells is extremely difficult, since they are present in tiny quantities. For many cancers, circulating cancer cells are present as levels as low as one per one billion blood cells.

“A 7.5-milliliter tube of blood, which is a typical volume for a blood draw, might have ten cancer cells and 35-40 billion blood cells,” said Prof Papautsky. “So we are really looking for a needle in a haystack.”

“Using size differences to separate cell types within a fluid is much easier than affinity separation which uses ‘sticky’ tags that capture the right cell type as it goes by. Affinity separation also requires a lot of advanced purification work which size separation techniques don’t need.”

The developed device works through the phenomena of inertial migration and shear-induced diffusion to separate cancer cells from blood as it passes through ‘microchannels’ formed in plastic.

“We are still investigating the physics behind these phenomena and their interplay in the device, but it separates cells based on tiny differences in size which dictate the cell’s attraction to various locations within a column of liquid as it moves.”

After ‘spiking’ healthy blood with non-small cell lung cancer cells, the device was able to recover 93 percent of the cancer cells. When run on actual samples from patients with non-small cell lung cancer, the microfluidic device was able to separate cancer cells from six of the eight samples.

The study was published in the journal Microsystems and Nanoengineering.