cancer – Lightsources.org

Newly identified protein could help fight cancer

2023/07/122023/08/15

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

2023/04/252023/04/27

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

2023/04/192023/04/20

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

2023/03/202023/04/03

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

2022/07/132022/07/15

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

2021/11/252021/12/02

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.

Cell cytoskeleton as target for new active agents

2021/05/062021/07/01

Through a unique combination of computer simulations and laboratory experiments, researchers at the Paul Scherrer Institute PSI have discovered new binding sites for active agents – against cancer, for example – on a vital protein of the cell cytoskeleton. Eleven of the sites hadn’t been known before. The study is published in the journal Angewandte Chemie International Edition.

The protein tubulin is an essential building block of the so-called cell cytoskeleton. In cells, tubulin molecules arrange themselves into tube-like structures, the microtubule filaments. These give cells their shape, aid in transporting proteins and larger cellular components, and play a crucial role in cell division.

Thus tubulin performs diverse functions in the cell and in doing so interacts with numerous other substances. “Tubulin can bind an astonishing number of different proteins and small molecules, several hundred for sure,” says Tobias Mühlethaler, a doctoral candidate in the PSI Laboratory of Biomolecular Research and first author of the study. The functions of the protein are guided by means of such bonds. Also, many drugs dock on tubulin and take effect, for example, by preventing cell division in tumours.

Read more on the PSI website

Image: The research team in front of the Swiss Light Source (from left): Andrea Prota, Tobias Mühlethaler and Michel Steinmetz

Credit: Paul Scherrer Institute/Mahir Dzambegovic

How cellular proteins control cancer spread

2020/08/112020/08/11

New finding may help focus the search for anti-cancer drugs

A new insight into cell signals that control cancer growth and migration could help in the search for effective anti-cancer drugs. A team of researchers has revealed key biochemical processes that advance our understanding of colorectal cancer, the third most common cancer among Canadians.

Using the CMCF beamline at the Canadian Light Source (CLS) at the University of Saskatchewan, scientists from McGill University and Osaka University in Japan were able to unlock the behavior of an enzyme involved in the spread of cancer cells. The team found that there is a delicate interaction between the enzyme, PRL3, and another protein that moves magnesium in and out of cells. This interaction is crucial to colorectal cancer growth.

Read more on the Canadian Light Source website

Image: Members of the Gehring research laboratory discussing the results of a protein purification.

Promising new drug carrier could improve bone repair and cancer treatments

2020/07/142020/07/21

Researchers from Western University and the Shanghai Institute of Ceramics, Chinese Academy of Sciences used the Canadian Light Source (CLS) at the University of Saskatchewan to explore a promising drug carrier that could be used to deliver cancer treatments and therapeutics for severe injuries.

Their work advances drug carrier technology to make the carrier more compatible with our bodies. This allows the drug carrier to deliver the desired treatment precisely to a tumor, or to allow a slower release of the medicine. In a new paper published in The Royal Society of Chemistry, the team investigated using calcium phosphate as a potential drug carrier. Their approach uses phosphate from the biomolecule that stores and transports energy in our cells, which allows the carrier to be more compatible with the human body. Using this drug delivery system solves the limitations of other carriers, including biocompatibility and toxicity. Their carrier is highly compatible with our biological system, allowing for a better response while also being non-toxic.

“Calcium phosphate is an important biomaterial in bones and teeth. If you can use this material as a drug carrier then you don’t need to worry about what happens after it is done with delivery,” said Tsun-Kong (TK) Sham, Professor of Chemistry at Western University.

Read more on the Canadian Light Source website

Image: TK Sham, a Professor of Chemistry at Western University, using beamlines at the CLS.

Faster diagnosis of esophageal cancer

2020/05/252020/05/27

Scientists from SOLARIS National Synchrotron Radiation Centre (Kraków, Poland), University of Exeter (UK), Beckman Institute (University of Illinois at Urbana-Champaign – USA), and Institute of Nuclear Physics Polish Academy of Sciences (Kraków, Poland) performed research that will facilitate the rapid and automated diagnosis of esophageal cancer.

Dr. Tomasz Wróbel`s group focuses on cancer detection through a combination of Infrared Imaging (IR) and the use of Machine Learning (ML) algorithms. Thanks to this approach, it is possible to develop an effective model, which will allow histopathologists to confirm the diseased area automatically and in a much shorter time.

Infrared Imaging (IR), which will soon also be available on the newly built beamline at SOLARIS, has found widespread use in biomedical research over the last couple of decades and is currently being introduced into clinical diagnostics.

Read more on the Solaris website
Image: The above graphic shows two esophageal biopsies: the top of the graphic contains a biopsy taken from a patient suffering from esophageal cancer, the bottom of the graphic contains a biopsy taken from a healthy patient. In the left part of the graphic, microscopic images of the mentioned biopsies are visible after the H&E staining (Hematoxylin and Eosin) (in this image of the stained biopsy, the histopathologist visually assigns tissue types), in the middle of the graphic, biopsy images obtained using infrared imaging are visible, the right part of the graphic presents a histological picture of a biopsy obtained after assigning tissues and structures to three classes (cancer, other, benign) by Machine Learning (ML).
Red – cancer
Blue – other
Green – benign

Developing microbeam radiation therapy for inoperable cancer

2020/05/132020/06/02

An innovative radiation treatment that could one day be a valuable addition to conventional radiation therapy for inoperable brain and spinal tumors is a step closer, thanks to new research led by University of Saskatchewan (USask) researchers at the Canadian Light Source (CLS).

Microbeam radiation therapy (MRT) uses very high dose, synchrotron-generated X-ray beams—narrower than a human hair—to blast tumours with radiation while sparing healthy tissue. The idea is that MRT would deliver an additional dose of radiation to a tumor after maximum conventional radiation therapy has been tried, thereby providing patients with another treatment that could extend their lives.

But the longstanding questions have been: What is the optimal X-ray energy range of the MRT radiation dose that will both penetrate the thickness of the human body and still spare the healthy cells? How can the extremely high radiation doses be delivered and measured with the accuracy necessary for human treatment?

Read more on the Canadian Light Source website
Image : Farley Chicilo at the Canadian Light Source.

Imaging how anticancer compounds move inside the cells

2020/02/262020/03/05

Chemotherapeutics are key players in the clinical setting to fight most types of cancer, and novel chemicals hold the promise to facilitate new and unique intracellular interactions that modulate the cell machinery and destroy the tumour cells. Equally necessary are new tools that enable the unequivocal location and quantification of such molecules in the intracellular nano-space, so that their therapeutic action is fully understood.

Researchers from IMDEA Nanociencia, the ALBA Synchrotron, the European Synchrotron Radiation Facility (ESRF) and the National Centre for Biotechnology (CNB) have developed a new family of organo-iridium drug candidates about a hundred times more potent than the clinically used drug cisplatin.
In order to understand the therapeutic potential of the compound, it is mandatory to accurately localize its fate within the cell ultrastructure with minimal perturbation. To this aim researchers have correlated on the same cell, for the first time, two 3D X-ray imaging techniques with a resolution of tenths of nanometers: cryo soft X-ray tomography, at MISTRAL beamline at ALBA Synchrotron, and cryo X-ray fluorescence tomography, at ID16A beamline at ESRF. These techniques help elucidate the 3D architecture of the whole cell and to reveal the intracellular location of different atomic elements, respectively.

>Read more on the ALBA website

ALS reveals vulnerability in cancer-causing protein

2020/02/172020/02/20

A promising anticancer drug, AMG 510, was developed by Amgen with the help of novel structural insights gained from protein structures solved at the Advanced Light Source (ALS).

Mutations in a signaling protein, KRAS, are known to drive many human cancers. One specific KRAS mutation, KRAS(G12C), accounts for approximately 13% of non-small cell lung cancers, 3% to 5% of colorectal cancers, and 1% to 2% of numerous other solid tumors. Approximately 30,000 patients are diagnosed each year in the United States with KRAS(G12C)-driven cancers.

Despite their cancer-triggering significance, KRAS proteins have for decades resisted attempts to target their activity, leading many to regard these proteins as “undruggable.” Recently, however, a team led by researchers from Amgen identified a small molecule capable of inhibiting the activity of KRAS(G12C) and driving anti-tumor immunity. Protein crystallography studies at the ALS provided crucial information about the structural interactions between the potential drug molecule and KRAS(G12C).

Image: A structural map of KRAS(G12C), showing the AMG 510 molecule in the binding pocket. The yellow region depicts where AMG 510 covalently attaches to the KRAS protein.
Credit: Amgen

Learning how breast cancer cells evade the immune system

2020/02/042020/02/20

Cancer cells have ways to evade the human immune system, but research at UK’s Synchrotron, Diamond could leave them with nowhere to hide.

Announced on World Cancer Day, the latest research (published in Frontiers in Immunology) by Dr Vadim Sumbayev, together with an international team of researchers, working in collaboration with Dr Rohanah Hussain and Prof Giuliano Siligardi at Diamond Light Source. They have been investigating the complex defence mechanisms of the human immune system and how cancer cells in breast tumours avoid it. In particular, they sought to understand one of the biochemical pathways leading to production of a protein called galectin-9, which cancer cells use to avoid immune surveillance. Dr Vadim Sumbayev explains, The human immune system has cells that can attack invading pathogens, protecting us from bacteria and viruses. These cells are also capable of killing cancer cells, but they don’t. Cancer cells have evolved defence mechanisms that protect them from our immune system, allowing them to survive and replicate, growing into tumours that may then spread across the body. Unfortunately, the molecular mechanisms that allow cancer cells to escape host immune surveillance remain poorly understood. So, with a growing body of evidence suggesting that some solid tumours also use proteins called Tim-3 and galectin-9 and to evade host immune attack, we chose to study the activity of this pathway in breast and other solid and liquid tumours.

Image: Breast cancer cell-based pathobiochemical pathways showing LPHN-induced activation of PKCα, which triggers the translocation of Tim-3 and galectin-9 onto the cell surface which is required for immune escape.

New biocompatible nanoparticles for breast cancer therapy

2019/11/202019/11/21

A research team has studied the efficacy of new CHO/PA polymeric nanoparticles for the sustained delivery of a drug used in breast cancer therapy. Some of the experiments have been carried out in the NCD-SWEET beamline at ALBA.

According to data from the Spanish Association against Cancer (AECC) observatory, breast cancer is the second most common type of cancer in Spain with 33,307 new cases in 2019. The number of deceased has reached 6,689 this year. Many research groups are exploring new ways to fight against this disease.
Dasatinib, an FDA-approved compound for the treatment of chronic myeloid leukemia, has become a potential candidate for the treatment of other cancers. It has been recently demonstrated that it could have a relevant role in breast cancer therapy. However, the solubility of this compound is extremely low, leading to poor absorption by the organism. Thus, the administration of a higher dosage is needed in order to obtain a better effect.
An alternative solution to enhance its therapeutic effect is the development of polymeric nanoparticles for a sustained and controlled delivery of the drug.
>Read more on the ALBA website

Image: 2D SAXS and WAXS patterns of the CHO/PA nanoparticles recorded at NCD-SWEET beamline, which confirm the lack of well-structured mesophase.

2019/10/032019/11/08

A research, led by the ALBA Synchrotron and funded by the European project NANOCANCER, has analysed the impact of nanoparticles in radiotherapy of glioma tumour cells.

Combining radiotherapy with nanoparticles can increase the efficacy of cancer treatments. The experiment has been carried out at the MIRAS beamline of ALBA, devoted to infrared microspectroscopy.

The use of nanotechnology in medicine is nothing short of revolutionary. Nanosensors for diagnosis, nanoparticles for drug delivery or nanodevices that can regenerate damaged tissue are changing the way we face and treat several diseases.

Combining radiotherapy with nanoparticles is a promising strategy to increase the efficacy of cancer treatments. High-atomic number nanoparticles are used as tumour radiosensitizers: tumour cells previously loaded with nanoparticles enhance the radiation effects when exposed to radiotherapy. “It’s a kind of knock-on effect; the interaction of the radiation with the nanoparticles generates short-range secondary radiation that induces a local dose enhancement in the tumour cells. However, the mechanisms underlying the synergistic effects involved in these techniques are not clearly understood’, says Immaculada Martínez-Rovira, Marie Curie scientist of ALBA and expert in the development of innovative radiotherapy approaches.

>Read more on the ALBA website

Image: Researcher Imma Martínez-Rovira, Marie Curie scientist of ALBA and expert in the development of innovative radiotherapy approaches.