Tag: cancer

Structural surprise in motor protein may point to new strategies for controlling disease

Structural surprise in motor protein may point to new strategies for controlling disease

Motor proteins are tiny “machines” inside cells that use chemical energy to move along molecular tracks and carry out essential processes like chromosome segregation during cell division. When a cell splits to make two new cells (called daughter cells), it carefully shares its instructions (chromosomes) so each new cell knows how to grow and work properly.

A group of motor proteins known as kinesin-8 proteins helps regulate how chromosomes are distributed between daughter cells — a process that, when disrupted, can lead to genomic instability. This instability is a key factor in the development of many diseases, including cancer.

“You can think of kinesins as tiny robots walking along train tracks to help organize and move chromosomes during cell division,” says John Allingham, professor and associate head of research in the Department of Biomedical and Molecular Sciences at Queen’s University.

While most research on kinesins has focused on the “feet” or motor domains — regions that walk along microtubule tracks — Allingham’s group turned their attention to the less-studied “body” or stalk region, which connects the feet and enables them to work together.

Recently, Allingham and his colleagues determined the structure of the stalk region of the fungal kinesin-8 protein Kip3, using Canada’s only synchrotron research facility, the Canadian Light Source (CLS) at the University of Saskatchewan. Their findings, published in Structure, reveal an unexpected architecture that could reshape our understanding of how kinesin-8 proteins assemble and function.

“What we expected to find was a long, coiled structure typical of other kinesin families,” says Allingham. “Instead, we discovered that this region folds into a compact helical bundle — more like a folded camping chair than a long, flexible pole.”

Read more on the CLS website

Image: John Allington (far right) and his research team

Credit: CLS

New strategy for targeting cancer-causing protein previously considered “undruggable”

New strategy for targeting cancer-causing protein previously considered “undruggable”

A cancer-causing protein long thought to be resistant to medication could soon be the target of new drugs, thanks to the work of Quebec researchers who used synchrotron light to find and exploit its weak spot.

Dr. Steven LaPlante, a professor at Quebec’s Institut National de la Recherche Scientifique (INRS), and his team studied a type of protein called Ras, “which is highly related to a good percentage of the cancers that are out there,” especially those of the head, neck and urinary tract. Ras proteins act as a molecular “switch,” flipping between active and inactive modes; they play a critical role in cell signaling and growth regulation and are often mutated in cancers. Major pharmaceutical companies have studied Ras for years, trying to develop new medications, says LaPlante, but have only recently begun to make some breakthroughs.

LaPlante, who worked in the a pharmaceutical industry before joining INRS, said he wanted to take a new approach to the problem, “to start everything from scratch, like making a nice cake – you start from scratch and when you do that, you really have control over how to optimize every segment (of the process) and make a really good cake.”

Using the Canadian Light Source (CLS) at the University of Saskatchewan, LaPlante and his team gathered atomic-level, 3D information about the protein; they discovered a “pocket” in it that appears to be an ideal target for molecular drug treatment. But, he added, it is “a cryptic pocket – it’s there sometimes and not there other times,” depending on the state of the protein.

The researchers found that, when the Ras protein is in its mutated, cancer-causing state, “molecules snuggle inside the pocket.” “Using crystallography, we were able to look at the mutant proteins to better understand what their structures are,” says LaPlante. Their work was recently published in the journal ACS Omega.

Read more on CLS website

Improved stability of gold nanoparticles for cancer therapy

Improved stability of gold nanoparticles for cancer therapy

A study carried out by researchers from POLYMAT-University of the Basque Country, INIFTA-Universidad Nacional de la Plata and the ALBA Synchrotron has made promising advances in the stabilization of gold nanoparticles (AuNPs) for use in cancer therapy. The work, published in the scientific journal Small, describes the synthesis of anisotropic hybrid particles of gold nanoparticles and nanogel, which overcome the challenges that have held back the clinical application of AuNPs, while maintaining their optical properties for the first time.

Gold nanoparticles are considered a powerful tool in photothermal cancer treatment due to their ability to convert light into heat, which is concentrated on tumor cells to destroy them. However, research has shown that unprotected anisotropic gold nanoparticles are prone to to undergo evaporation and condensation processes that result in the loss of their photothermal properties during the duration of the irradiation treatment. A new study, published in the scientific journal Small, presents a novel approach for stabilizing these particles while preserving their critical optical characteristics and, therefore, with the potential to improve the efficacy of cancer therapies.

Anisotropic gold nanoparticles are non-spherical photothermal particles that can be designed for thermal conversion by near-infrared irradiation, which is particularly advantageous in medical applications because of their high penetration depth in biological tissues and low toxicity to normal cells. However, their structural instability precludes prolonged therapeutic use. For this reason, previous studies have attempted to coat gold nanoparticles in gels such as polyethylene glycol (PEG). Yet, while these coatings improved stability, they also altered the unique shape and optical properties of the gold nanoparticles, significantly reducing their photothermal efficacy.

In this new study, researchers from POLYMAT-University of the Basque Country, INIFTA-La Plata National University, and the ALBA Synchrotron, devised a one-pot synthesis method that stabilizes anisotropic gold nanoparticles by coating them in an ultra thin, in situ polymeric nanogel. Using polyacrylamide (pAA) and poly-(N-isopropylacrylamide) (pNIPAM), the team achieved nanogel shells between 2–8 nanometers thick around each individual gold nanoparticle. This ultra thin coating preserved the nanoparticles’ dimensions and shape, ensuring that their unique optical and photothermal properties were unaffected. Notably, rod-shaped and star-shaped nanoparticles retained their structural integrity and optical characteristics, with rod-shaped hybrids showing particularly promising stability and efficiency for photothermal applications. The researchers also found that pNIPAM coatings offered the best protection for the nanoparticles, while pAA coatings exhibited optimal photothermal conversion efficiency.

Read more on ALBA website

Cancer Research Horizons and Diamond Light Source establish drug discovery partnership

Cancer Research Horizons and Diamond Light Source establish drug discovery partnership

Cancer Research Horizons, the innovation arm of Cancer Research UK, is partnering with Diamond Light Source, the UK’s national synchrotron, to build a world-leading fragment-based drug discovery programme

Diamond Light Source accelerates electrons to near light speed, producing bright light that is directed into research instruments known as beamlines. Cancer Research Horizons and its drug discovery site at Newcastle University have already been using Diamond’s beamlines and XChem facility for fragment-based screening, a powerful approach to identify chemical entities that can be developed rapidly into potent candidates.

The new partnership will build on this existing relationship to improve the throughput, running and analysis of these experiments. By leveraging their combined expertise and resources, the partnership aims to accelerate the drug discovery process and help bring new cancer treatments to patients faster.

Under the agreement, Cancer Research Horizons will fund two on-site postdoctoral research assistants dedicated to optimising the delivery of its in-house and industry-partnered projects. In return, Diamond will provide early access to any proprietary developments to its platform.

The partnership will establish a governance framework to enable Cancer Research Horizons to provide feedback on the industrialisation of Diamond’s Fragment Screening platform. This initiative aims to enhance its appeal to Cancer Research Horizons’ pharmaceutical and biotech partners, driving broader industry engagement.

Read more on Diamond website

Tracking the ‘medication taxis’

Tracking the ‘medication taxis’

A team of researchers has been using the X-ray source PETRA III to visualise the spread of an anticancer drug in tumor cells

How can cancer drugs be delivered safely to their destination? An international team of researchers has been using the X-ray source PETRA III to test a technique for visualising how a drug is distributed inside tumor cells. In the future, this approach could help to develop more targeted and hence more effective cancer therapies. The working group has presented its findings in the journal Advanced Functional Materials.

Some anticancer drugs present a special challenge. They do not dissolve easily in the blood or they break down too quickly and because of this they are unable to reach the site where they are needed: the tumor. Researchers have come up with an ingenious strategy to overcome this: they enclose the drug in a molecular capsule. On being administered, this medication taxi makes its way through the body. Once it reaches the tumor, the capsule dissolves and releases the drug.

The only trouble is that it is difficult to observe how well this strategy is working. How do the drug capsules find their way into the tumor cells? And do they actually release the drug inside them? To answer these questions, researchers have until now had to label the drugs using special dyes. When a laser beam is shone at these, they light up like signal lamps and reveal the distribution of the drug inside a cell.

This method has its drawbacks, however. The markers are usually similar in size to the drug molecules themselves, and this can distort the readings. “It’s as if you were trying to track a fish through the ocean by fitting it with a transmitter that is as big as the creature itself,” explains Marvin Skiba, a PhD student in Wolfgang Parak’s group at the University of Hamburg’s Centre for Hybrid Nanostructures. “In that case, it’s doubtful whether the fish would move around in the same way as it would without the transmitter.” It would be helpful, therefore, to have a way of seeing the drug inside the medication taxi without having to label it with a dye.

One promising approach is X-ray fluorescence, a technique that can detect minute traces of a chemical element. The principle is straightforward. “When an X-ray beam strikes a sample, it excites the elements in it,” explains DESY physicist Gerald Falkenberg. “The excited atoms want to shed this energy quickly by emitting X-ray quanta. We use detectors to capture these quanta.”

The crucial point is that every element emits a different “X-ray colour”, thereby leaving its own distinctive fingerprint. The X-ray beam scans the sample line by line, creating a map of the elements. This requires a very powerful, narrow X-ray beam, such as the one generated by DESY’s X-ray source PETRA III at beamline P06.

To determine the suitability of this method for studying drugs transported in medication taxis, Skiba and Falkenberg’s team focused on a compound containing the element selenium, a potential therapeutic for treating tumors. “We enclosed the compound in a variety of different microparticles,” explains Marvin Skiba. “We then injected these into a cell culture and used X-rays to track how the selenium was distributed in the cells.”

Read more om DESY website

Image: Depending on the route of administration, the intracellular distribution of the selenium-based drug changes. When non-biodegradable polymers are used as the building blocks of the capsules, the selenium remains in the container and is not released (upper picture). The situation is different when amino acid and sugar-based vehicles are used which are digested by the cell and result in intracellular redistribution of the drug (lower picture). Cells are shown in grey while selenium is pseudocoloured from blue to yellow, depending on the concentration.

Credit: DESY, Marvin Skiba

New insights to advance targeted brain cancer therapy

New insights to advance targeted brain cancer therapy

Despite an increase in new chemotherapies, the overall prognosis for patients with glioblastoma multiforme (GBM) remains extremely poor, with just 5% of patients surviving for more than five years. This aggressive form of brain cancer is highly resistant to treatment, prompting researchers to explore new treatment avenues. Riluzole, a drug that has already been approved by the FDA to treat amyotrophic lateral sclerosis (ALS), is currently being explored as a treatment for several cancers including GBM. However, there is a need for novel drug delivery methods to enhance riluzole’s effectiveness and overcome barriers to targeted therapy, including minimizing harmful side effects in healthy cells, and maintaining the drug’s anti-cancer efficacy until it reaches tumor cells.

In this study, which was led by Tanja Dučić, scientist in the MIRAS beamline team at the ALBA Synchrotron, and published in ACS Omega, researchers engineered carbon-based nanoparticles, or carbon dots, made of 2-acrylamido-2-methylpropanesulfonic acid (AMPS). This organic delivery system (AMPS-CDs NPs) showed biocompatibility with glioblastoma cells, and researchers were keen to test its potential to act as a nanocarrier for the drug riluzole.

Several Spanish institutions and researchers collaborated in this project, including Manuel Algarra from INAMAT2 (Institute for Advanced Materials and Mathematics), at the Public University of Navarra; Elena Gonzalez-Munoz, Maria Soledad Pino-González and Juan Soto from the University of Malaga; Pablo Guerra from the Institute of Molecular Biology of Barcelona (IBMB-CSIC); and Tanja Dučić from ALBA.

The study demonstrates the successful complementarity between synchrotron light and electron microscopy. By combining the MIRAS beamline and the Cryo-TEM at IBMB-CSIC, part of the Joint Electron Microscopy Center at ALBA (JEMCA), the collaboration achieved its first publication using both instruments. Pablo Guerra, coordinator of the Cryo-TEM, performed the microscope data acquisition. “Using the Cryo-TEM we confirmed the nanoparticles’ shape and size, with a diameter of 4.5-5 nm, which was impossible to observe with other methods”, says Tanja Dučić.

The nanoparticles were extensively characterized to determine their exact surface composition using techniques that included XPS (X-ray photoelectron spectroscopy) and NMR (nuclear magnetic resonance) spectroscopy, as well as cryo-transmission electron microscopy. The synthesized nanoparticles are covered in sulfonated, carboxylic, and substituted amide groups. These functional groups make the AMPS-CDs potentially suitable nanocarriers for riluzole.

Read more on ALBA website

Image: Researchers Tanja Dučić from ALBA and Pablo Guerra from IBMB-CSIC at the control room of the EM01-Cryo-TEM of the Joint Electron Microscopy Center at ALBA

Credit: JEMCA

New imaging technique for deeper insights in breast cancer metastasis

New imaging technique for deeper insights in breast cancer metastasis

A collaborative effort between researchers from DESY, the University Medical Center Hamburg-Eppendorf (UKE), Chalmers University in Sweden and the Paul Scherrer Institute in Switzerland has yielded a cutting-edge multimodal imaging approach to investigate breast cancer tissue. With the help of this technique, researchers can simultaneously extract information about the nanostructure of the tumor and quantify the chemical elements present in a millimeter-scale sample in all three dimensions. A unique combination of research possibilities at PETRA III and new analysis methods enables this high level of detail. 

Breast cancer caused 685 000 deaths globally in 2020 according to the WHO. It is not life-threatening in its earliest form. But if the cancer cells are able to spread further in the tissue to nearby lymph nodes or important organs, this metastasis can be fatal. In a recent pilot study published in Nature Scientific Reports, the team applied this revolutionary imaging approach to a breast cancer sample. The results show how key molecules collectively influence the metastatic mechanism. This breakthrough paves the way for an in-depth investigation of breast cancer metastasis, promising novel therapeutic approaches and personalised treatment strategies, which could ultimately improve patients’ lives if recognized early enough.

Traditional experimental models often fall short, relying on 2D cell cultures or animal models that do not faithfully replicate the complex physiological patterns of human tumor environments. The multimodal imaging approach presented in this study represents a significant step forward by providing simultaneous nanoscale morphological and physiological information from real samples, thus giving researchers information about the shape and composition of real cancer tissue.

André Conceição, the first author and beamline scientist at the PETRA III SAXSMAT beamline P62, emphasises, “Although demonstrated for breast cancer, this approach’s versatility extends to other organs and diseases.”

The study opens avenues for further exploration of breast cancer metastasis and pre-metastatic niches (PMNs). Advanced X-ray multimodal tomography can generate complementary 3D maps for different breast cancer molecular subtypes. It holds the potential to contribute to the development of more targeted and effective strategies for diagnosis and treatment.

Read more on DESY website

Image: 3D vector field of the collagen direction and degree of orientation obtained by SAXS-Tensor-Tomography

Detection of early pancreatic cancer lesions using infrared and machine learning

Detection of early pancreatic cancer lesions using infrared and machine learning

A group of researchers from the CIRI beamline in their latest publication entitled Pancreatic intraepithelial neoplasia detection and duct pathology grading using FT-IR imaging and machine learning published in Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy presented the results of their PanIN classification method, which provides opportunities for early recognition of changes in the cells lining the pancreatic ducts using infrared and machine learning.

Pancreatic intraepithelial neoplasia (PanIN) manifests itself by changes in the cells lining the pancreatic ducts. It is an early pre-cancerous lesion divided into low-grade and high-grade PanIN. In particular, high-grade PanIN is a lesion that often leads to Pancreatic ductal adenocarcinoma (PDAC). In the case of pancreatic cancer, due to the lack of characteristic symptoms of the disease in its early stage, patient survival is low. The basic examination performed to diagnose the disease is to take a fine-needle biopsy from the patient. The most common method of treatment is to remove part of the tissue affected by cancer, which increases the patient’s chances of survival, especially if it is done at an early stage of the disease. Therefore, it is so important to understand the biochemistry of lesions such as PanIN and their progression to cancer. 

Read more on SOLARIS website

Image : Scheme of sample collection (figure upper part), and FT-IR imaged TMA processing using: Random Forest classification (figure middle part), PLS Regression (figure bottom part).

Repairing genetic damage with sunlight

Repairing genetic damage with sunlight

DNA damage to the genetic material DNA drives cancer, ageing, and cell death. Therefore, DNA repair is crucial for all organisms, and a deeper understanding of this basic function helps us better comprehend how life around us survives and thrives. An international team of researchers has now revealed how the enzyme photolyase efficiently channels the energy of sunlight into DNA repair chemistry.

All life under the sun must cope with harmful UV rays. UV damage can take many forms, but DNA, the molecule that carries the genetic information of all living organisms, is especially vulnerable. For instance, UV can drive chemical cross-linking reactions of DNA, potentially introducing errors into the genetic code. This cross-linking can lead to cell death or – in the worst cases – mutagenesis and cancer. Such damage is not uncommon; under bright sunlight, a human skin cell can undergo 50-100 cross linking reactions per second.

“To survive, life has evolved powerful DNA repair mechanisms. One especially elegant solution is provided by the enzyme photolyase,” explains DESY scientist Thomas J. Lane, who is also a researcher in the Cluster of Excellence “CUI: Advanced Imaging of Matter” at Universität Hamburg. The enzyme uses sunlight to repair damage caused by sunlight. Photolyase is able to recognize the location where UV irradiation has cross-linked DNA and grabs onto those bits of damaged DNA. Then, it can capture a blue photon from the sun, and use it to perform repair chemistry, turning the DNA back into its original, healthy form.

To better understand how photolyase works, the scientists were particularly interested first in the form of the enzyme immediately after absorbing a photon, but before repairing the DNA. Second, they wanted to find out the exact sequence of bond-breaking chemical reactions necessary to turn damaged DNA into healthy DNA. As a third step, the team sought to better understand how photolyase can specifically recognize which DNA is damaged.

Conducting time-resolved crystallography at the SwissFEL X-ray free-electron laser of PSI the scientists were able to capture the excited state of the photolyase chromophore, letting them understand how the enzyme efficiently channels the energy of sunlight into DNA repair chemistry. “This research was only made possible by the recent development of X-ray free-electron laser sources. Their intense femtosecond-duration pulses let us record flash X-ray photographs that freeze all atomic motion so that we can follow the reaction step by step at the speed of molecules,” says first author Nina-Eleni Christou from DESY.

Read more on PSI website

Image: PSI researcher Camila Bacellar is pleased about the success in precisely analysing the DNA repair enzyme photolyase at the Alvra beamline of the Swiss X-ray free-electron laser SwissFEL.

Credit: Paul Scherrer Institute/Markus Fischer

Bleomycin: cancer drug with a hidden flaw

Bleomycin: cancer drug with a hidden flaw

Scientists at the B23 beamline of the Diamond Light Source have used synchrotron light to make an important discovery about a common cancer therapy. Bleomycin is used to shrink a variety of tumours, but little is known about how this drug interacts with proteins in the bloodstream. The beamline scientists used synchrotron-grade circular dichroism to study how bleomycin interacts with two common blood proteins, one of which is normally elevated in people with cancer. Reporting in the International Journal of Molecular Sciences, they found that the drug bound more firmly to the protein elevated in cancer patients, suggesting there may be less of the free form available to elicit its therapeutic effect. On closer analysis, the team discovered that one of two variants of bleomycin binds more strongly to this protein than the other. They caution that the ratio of these two variants may need to be adjusted to improve the therapeutic benefit of this drug.

While screening compounds produced by bacteria in the 1960s, scientists made a serendipitous discovery. They stumbled upon a molecule called bleomycin with anticancer properties. Since then, this life-saving drug has been used to treat a variety of tumours from squamous cell carcinomas to lymphomas. The drug works by chopping up DNA in cancer cells, and this DNA-drug interaction has been characterised in the past. However, when bleomycin enters the bloodstream, it may interact with plasma proteins and less is known about how this impacts the drug’s effectiveness. Bleomycin shows promising outcomes when tested on cancer cells grown in the lab, but the serum extracts used in lab cultures have a different mix of proteins to the sera of cancer patients, so it’s worth exploring whether plasma proteins in patients could sequester the drug and reduce its effectiveness.

Beamline scientists at B23 were determined to explore this overlooked issue. Led by Rohanah Hussain, they harnessed ultraviolet light from synchrotron radiation to explore how the drug binds plasma proteins using a technique called circular dichroism.

Circular dichroism is the differential absorption of left- and right-circularly polarised ultraviolet light passing through a liquid solution containing biomolecules, in this case proteins with drugs The CD measurement is displayed as a curve (spectrum) of which shape reflects the architecture on  how the protein in solution is folded in helical, ribbon, turn and unordered segments.  Drug binding to protein can affect such a folding that is used to identify and quantify drug binding interaction, in this case bleomycin with the two major blood proteins. Another unique experiment carried out at B23 beamline is the use of the powerful synchrotron beamlight to irradiate multiple of times the protein-drug mixtures for photostability assessment, which varies depending upon the strength of the drug binding interactions.

Hussain explained:

The high photon flux available at the B23 beamline (Diamond Light Source) generated by synchrotron radiation is sufficient for disrupting the folding of biological macromolecules in a time scale of minutes to hours, providing a useful tool for accelerated photo-stability studies.

First, the team assessed whether Blenoxane®, a commercial preparation of bleomycin, could bind to two common plasma proteins: one was human serum albumin (HSA), an abundant serum protein that facilitates the delivery of drugs around the body through the bloodstream. The other was α1-acid glycoprotein (AGP), a protein produced by the liver in response to inflammation that is found in cancer patients at ten times the normal level.

To explore binding interactions with these two proteins, the team examined the circular dichroism curve for each protein across a spectrum of ultraviolet light, and then they observed whether addition of Blenoxane® altered the protein curve. Sizeable differences were observed with AGP, suggesting the drug binds and induced marked changes to the protein’s shape, but the curve didn’t shift for HSA. This doesn’t indicate that the drug doesn’t bind HSA, only that it doesn’t alter its shape upon interaction. The team adapted their circular dichroism experiments to confirm that Blenoxane® did bind to HSA by heating the sample to unfold (denature) the proteins’ architecture and then observing spectral changes with and without the drug present.

Read more on Diamond Light Source  website

Image: Rohanah Hussain is a Senior Beamline Scientist, working on the B23 beamline at Diamond

Newly identified protein could help fight cancer

Newly identified protein could help fight cancer

Researchers from the University of British Columbia (UBC) have identified a new protein that helps an oral bacterium thrive in other locations around the body. The discovery could eventually lead to the development of new drugs that specifically target the protein.

“This bacterium is common in the mouths of humans and generally doesn’t cause disease in that location. However, it can travel through the bloodstream to other areas of the body, which leads to some pretty big health concerns,” says Dr. Kirsten Wolthers, Associate Professor of Biochemistry and Microbiology at UBC’s Okanagan Campus.

Most notably, this bacteria is prevalent in the tumors of colorectal cancer patients. The presence of the bacteria can contribute to tumor growth, spread of cancer to other sites in the body, and resistance to chemotherapy.

With the help of the CMCF beamline at the Canadian Light Source (CLS), located at the University of Saskatchewan, Wolthers and her colleagues determined that the new protein they identified enables the bacteria to take essential nutrients, such as iron, from our blood cells.

Read more on the CLS website

Image: Alexis Gauvin, inspecting a protein sample for particulate matter, using the glove box. Gauvin is a biochemistry student and a member of Dr. Kirsten Wolthers’s research group in the Department of Chemistry, University of British Columbia (Okanagan Campus).

Tiny proteins found across the animal kingdom play a key role in cancer spread

Tiny proteins found across the animal kingdom play a key role in cancer spread

Researchers from McGill University have made an exciting discovery about specific proteins involved in the spread of certain cancers.

Dr. Kalle Gehring, professor of biochemistry and founding director of the McGill Centre for Structural Biology, and his team have focused on unravelling the mystery around phosphatases of regenerating liver (PRLs). These proteins are found in all kinds of animals and insects — from humans to fruit flies – and play a unique role in the growth of cancerous tumours and the spread of cancer throughout the body.

“It’s important for us to study PRLs because they are so important in cancer,” said Gehring, “In some cancers, like metastatic colorectal cancer, the proteins are overexpressed up to 300-fold.”

This overexpression of PRLs makes cancer cells more metastatic and drives the spread to other organs.

In his most recent paper, published in the Journal of Biological Chemistry, Gehring and his colleagues confirmed that PRLs exist in all kinds of single- and multi-cell animals. Data collected at the Canadian Light Source (CLS) at the University of Saskatchewan confirmed the role of PRLs in binding magnesium transporters, helping to further the understanding of how these proteins influence human disease.

Read more on the Canadian Light Source website

Researchers study molecular bindings to develop better cancer treatments

Researchers study molecular bindings to develop better cancer treatments

A research team based in Winnipeg is using the Canadian Light Source (CLS) at the University of Saskatchewan to find new, cutting-edge ways to battle cancer.

Dr. Jörg Stetefeld, a professor of biochemistry and Tier-1 Canada Research Chair in Structural Biology and Biophysics at the University of Manitoba, is leading groundbreaking research into how netrin-1 — a commonly found molecule related to cell migration and differentiation —  creates filaments and binds to receptors in cells.

As netrin-1 is considered the key player for the migration of cancer cells, Stetefeld said this research could inform new cancer treatments.

“If you understand how netrin binds these receptors, you are sitting in the driver’s seat to develop approaches to block this interaction,” he said. “Why do we want to block it? Because if you block this interaction, you kill the cancer cell.”

Earlier research published in 2016 led to the development of new antibody treatments in Europe for combating breast cancer, said Stetefeld. He hopes this new research, which was published in the journal Nature, can lead to better drugs and treatments as well.

Read more on the CLS website

Using light to switch drugs on and off

Using light to switch drugs on and off

Scientists at the Paul Scherrer Institute PSI have used the Swiss X-ray free-electron laser SwissFEL and the Swiss Light Source SLS to make a film that could give a decisive boost to developing a new type of drug. They made the advance in the field of so-called photopharmacology, a discipline that develops active substances which can be specifically activated or deactivated with the help of light. The study is being published today in the journal Nature Communications.

Photopharmacology is a new field of medicine that is predicted to have a great future. It could help to treat diseases such as cancer even more effectively than before. Photopharmacological drugs are fitted with a molecular photoswitch. The substance is activated by a pulse of light, but only once it has reached the region of the body where it is meant to act. And after it has done its job, it can be switched off again by another pulse of light.

This could limit potential side effects and reduce the development of drug resistance – to antibiotics, for example.

Licht-switchable drugs

To make conventional drugs sensitive to light, a switch is built into them. In their study, the scientists led by the principal authors Maximilian Wranik and Jörg Standfuss used the active molecule combretastatin A-4, which is currently being tested in clinical trials as an anti-cancer drug. It binds to a protein called tubulin, which forms the microtubules that make up the basic structure of the cells in the body, and also drive cell division. Combretastatin A-4, or “CA4” for short, destabilises these microtubules, thereby curbing the uncontrolled division of cancer cells, i.e. it slows down the growth of tumours.

In the modified CA4 molecule, a bridge consisting of two nitrogen atoms is added, which makes it particularly photoactive. In the inactive state, the so-called azo bridge stretches the molecular components to which it is attached to form an elongated chain. The pulse of light bends the bond, bringing the ends of the chain closer together – like a muscle contracting to bend a joint. Crucially, in its elongated form, the molecule does not fit inside the binding pockets of the tubulin – depressions on the surface of the protein where the molecule can dock in order to exert its effect. However, when the molecule is bent, it fits perfectly – like a key in a lock. Molecules like this, which fit into corresponding binding pockets, are also called ligands.

Read more on the PSI website

Image: Jörg Standfuss (left) and Maximilian Wranik in front of the experimental station Alvra of the Swiss X-ray free-electron laser SwissFEL, where the photopharmacological studies were carried out. In the long term, the aim is to develop drugs that can be switched on and off by light.

Credit: Paul Scherrer Institute/Markus Fischer

Antibody rigidity regulates immune activity

Antibody rigidity regulates immune activity

Scientists at the University of Southampton have gained unprecedented new insight into the key properties of an antibody needed to stimulate immune activity to fight off cancer, using the ESRF’s structural biology beamlines, among others.

The interdisciplinary study, published in Science Immunology, revealed how changing the flexibility of the antibody could stimulate a stronger immune response. The findings have enabled the team to design antibodies to activate important receptors on immune cells to “fire them up” and deliver more powerful anti-cancer effects. The researchers believe their findings could pave the way to improve antibody drugs that target cancer, as well as automimmune diseases.

In the study, the team investigated antibody drugs targeting the receptor CD40 for cancer treatment. Clinical development has been hampered by a lack of understanding of how to stimulate the receptors to the right level. The problem being that if antibodies are too active they can become toxic. Previous research by the same team had shown that a specific type of antibody called IgG2 is uniquely suited as a template for pharmaceutical intervention, since it is more active than other antibody types. However, the reason why it is more active had not been determined. What was known, however, is that the structure between the antibody arms, the so called hinges, changes over time.

This latest research harnesses this property of the hinge and explains how it works: the researchers call this process “disulfide-switching”. In their study, the team analysed the effect of modifying the hinge and used a combination of biological activity assays, structural biology, and computational chemistry to study how disulfide switching alters antibody structure and activity.

Read more on the ESRF website

Image: Flexibility of the monoclonal antibody F(ab) arms is conferred by the hinge region disulphide structure

Credit: C. Orr

Paving the way for more effective pancreatic cancer research

Paving the way for more effective pancreatic cancer research

A team of scientists led by the University of Surrey used Diamond’s B16 Beamline, a flexible and versatile beamline for testing new developments in optics and detector technology and for trialling new experimental techniques, to better understand the structure of cancer cells. 

By using the synchrotron, the team were able to complete sophisticated examinations of the characteristics of cell structures at a nano level and even at an atomic scale and to investigate how cells and materials interact with each other.  

To improve cancer screening and treatment, researchers need accurate models of cancer tissues on which to experiment. Previous research made significant progress in building accurate, novel 3D models which mimic features of a pancreatic tumour, such as structure, porosity and protein composition.

Read more on the Diamond website

Image: Inside the experimental hutch at Diamond’s B16 beamline.

Credit: Diamond Light Source