Revealing the path of a metallodrug in a breast cancer cell

Some types of cancer cannot be treated with classical chemotherapy. Scientists from Inserm, CNRS, Sorbonne University, PSL university, University Grenoble Alpes and ESRF, the European Synchrotron, are working on a metallorganic molecule as an antitumor drug. Their research has given thorough insights into its mechanism in attacking cancer cells. This study is published in Angewandte Chemie.

Triple-negative breast cancer, which represents 10-20% of breast cancers, is not fuelled by hormones. In fact, it tests negative for estrogen and progesterone receptors and excess HER2 protein. This means that it does not respond to hormonal therapy and antibody medicines. Given that it is more aggressive and often has a higher grade than other types of breast cancer, the scientific community is relentlessly trying to find a treatment.

>Read more on the ESRF website

Image: X-ray fluorescence maps of potassium, an essential physiological element of the cell (K, in pink), and, osmium a constitutive element of the metallocifen (Os, in green), in hormone-independent breast cancer cells exposed to the osmocenyl-tamoxifen derivatives.
Credit: Sylvain Bohic.

X-ray fluorescence imaging could open up new diagnostic possibilities in medicine

Using gold to track down diseases

A high-precision X-ray technique, tested at PETRA III, could catch cancer at an earlier stage and facilitate the development and control of pharmaceutical drugs. The test at DESY’s synchrotron radiation source, which used so-called X-ray fluorescence for that purpose, has proved very promising, as is now being reported in the journal Scientific Reports by a research team headed by Florian Grüner from the University of Hamburg. The technique is said to offer the prospect of carrying out such X-ray studies not only with higher precision than existing methods but also with less of a dose impact. However, before the method can be used in a clinical setting, it still has to undergo numerous stages of development.

The idea behind the procedure is simple: tiny nanoparticles of gold having a diameter of twelve nanometres (millionths of a millimetre) are functionalised with antibodies using biochemical methods. “A solution containing such nanoparticles is injected into the patient,” explains Grüner, a professor of physics at the Centre for Free-Electron Laser Science (CFEL), a cooperative venture between DESY, the University of Hamburg and the Max Planck Society. “The particles migrate through the body, where the antibodies can latch onto a tumour that may be present.” When the corresponding parts of the patient’s body are scanned using a pencil X-ray beam, the gold particles emit characteristic X-ray fluorescence signals, which are recorded by a special detector. The hope is that this will permit the detection of tiny tumours that cannot be found using current methods.

>Read more on the PETRA III at DESY website

Image: Gold nanoparticles spiked with antibodies can specifically attach to tumors or other targets in the organism and can be detected there by X-ray fluorescence.
Credit: Meletios Verras [Source]

New approach to breast cancer detection

Phase contrast tomography shows great promise in early stages of study and is expected to be tested on first patients by 2020.

An expert group of imaging scientists in Sydney and Melbourne are using the Imaging and Medical Beamline (IMBL) at the Australian Synchrotron as part of ongoing research on an innovative 3D imaging technique to improve the detection and diagnosis of breast cancer.

The technique, known as in-line phase-contrast computed tomography (PCT), has shown advantages over 2D mammography with conventional X-rays by producing superior quality images of dense breast tissue with similar or below radiation dose.
Research led by Prof Patrick Brennan of the University of Sydney and Dr Tim Gureyev at the University of Melbourne with funding from the NHMRC and the support of clinicians in Melbourne including breast surgeon Dr Jane Fox, is now focused on demonstrating the clinical usefulness of the technique.
Together with Associate Professor Sarah Lewis and Dr SeyedamirTavakoli Taba from the University of Sydney heading clinical implementation, the technique is expected to be tested on the first patients at the Australian Synchrotron by 2020.

>Read more on the Australian Synchrotron website

Image: CT reconstruction of 3D image of mastectomy sample revealing invasive carcinoma

Just like lego – studying flexible protein for drug delivery

Researchers from the Sapienza University of Rome and its spin-off company MoLiRom (Italy) are spending the weekend at the ESRF to study a protein that could potentially transport anticancer drugs.

Ferritin is a large spherical protein (20 times bigger than haemoglobin) that stores iron within its cavity in every organism. Just like a lego playset, Ferritin assembles and disassembles. It is also naturally targeted to cancer cells. These are the reasons why Ferritin is a great candidate as a drug-transport protein to fight cancer. An international team of scientists from “Sapienza” University of Rome and the SME MoLiRom (Italy) came to the ESRF to explore a special kind of ferritin that shows promising properties. “This is an archaebacterial ferritin that have transformed into a humanised ferritin to try to tackle cancer cells”, explains Matilde Trabuco, a scientist at the Italian SME MoLiRom.

The mechanism looks simple enough: “Ferritin has a natural attraction to cancer cells. If we encapsulate anti-cancer drugs inside it, it will act as a Trojan horse to go inside cells, then it will open up and deliver the drug”.

Ferritins have been widely used as scaffolds for drug-delivery and diagnostics due to their characteristic cage-like structure. Most ferritins are stable and disassemble only by a harsh pH jump that greatly limits the type of possible cargo. The humanised ferritin was engineered to combine assembly at milder conditions with specific targeting of human cancer cells.


>Read more on the European Synchrotron Website


Probing tumour interiors

X-ray fluorescence mapping to measure tumour penetration by a novel anticancer agent.

A new anticancer agent developed by the University of Warwick has been studied using microfocus synchrotron X-ray fluorescence (SXRF) at I18 at Diamond Light Source. As described in The Journal of Inorganic Biochemistry, researchers saw that the drug penetrated ovarian cancer cell spheroids and the distribution of zinc and calcium was perturbed.  

Platinum-based chemotherapy agents are used to treat many cancer patients, but some can develop resistance to them. To address this issue, scientists from the University of Warwick sought to employ alternative precious metals. They developed an osmium-based agent, known as FY26, which exhibits high potency against a range of cancer cell lines. To unlock the potential of this novel agent and to test its efficacy and safety in clinical trials, the team need to fully understand its mechanism of action.

To explore how FY26 behaves in tumours, the team grew ovarian cancer spheroids and used SXRF at I18 to probe the depth of penetration of the drug. They noted that FY26 could enter the cores of the spheroids, which is critical for its activity and very encouraging for the future of the drug. SXRF also enabled them to probe other metals within the cells, which showed that the distribution of zinc and calcium was altered, providing new insights into the mechanism of FY26-induced cell death.

>Read more on the Diamond Light Source website

Figure: (extract) A) Structure of FY26and related complexes, [(ŋ6-p-cym)Os(Azpy-NMe2)X]+. B) Bright field images and SXRF elemental maps of Os, Ca and Zn in A2780 human ovarian carcinoma spheroid sections (500 nm thick) treated with 0.7 µM FY26(½ IC50) for 0 or 48 h. Raster scan: 2×2 µm2 step size, 1 s dwell time. Scale bar 100 µm. Calibration bar in ng mm-2. Yellow squares in bright field images indicate areas of the spheroid studied using SXRF. Red areas in SXRF elemental maps indicate the limits of the spheroids. C) Average Os content (in ng mm-2) as a function of distance from A2780 3D spheroid surface, after treatment for 16 h (green), 24 h (blue) or 48 h (red) with 0.7 µM FY26. 

Insights into the development of more effective anti-tumour drug

Natural killer cells are powerful weapons our body’s immune systems count on to fight infection and combat diseases like cancer, multiple sclerosis, and lupus. Finding ways to spark these potent cells into action could lead to more effective cancer treatments and vaccines.

While several chemical compounds have shown promise stimulating a type of natural killer cells, invariant natural killer T cells (iNKT) cells in animal models, their ability to activate human iNKT cells has been limited.

Now, an international team of top immunologists, structural biologists, and chemists published in Cell Chemical Biology the creation of a new compound that appears to have the properties researchers have been looking for. The research was co-led by Monash Biomedicine Discovery Institute’s (BDI) Dr Jérôme Le Nours, University of Connecticut’s Professor Amy Howell and Albert Einstein College of Medicine’s Dr Steve Porcelli. Dr Le Nours used the Micro Crystallography beamline (MX2) at the Australian Synchrotron as part of the study.

The compound – a modified version of an earlier synthesized ligand – is highly effective in activating human iNKT cells. It is also selective – encouraging iNKT cells to release a specific set of proteins known as Th1 cytokines, which stimulate anti-tumour immunity.

>Read more on the Australian Synchrotron website

Image: 3D structure of proteins behind interaction of new drug that stimulates immune response to cancer cells. (Entire image here)

Success in clinical trials driving a shift in the treatment of blood cancers

The Australian Synchrotron is proud to be growing Australia’s capacity for innovative drug development, facilitating the advance of world-class disease and drug research through to local drug trials. Recent success in clinical trials of Venetoclax, the chronic lymphocytic leukaemia (CLL) drug developed by researchers from the Walter and Eliza Hall Institute and two international pharmaceutical companies is driving a major shift in the treatment of a range of blood cancers, according to a media information from the Peter MacCallum Cancer Centre.

>Read more on the Australian Synchrotron website


Gold protein clusters could be used as environmental and health detectors

Peng Zhang and his collaborators study remarkable, tiny self-assembling clusters of gold and protein that glow a bold red. And they’re useful: protein-gold nanoclusters could be used to detect harmful metals in water or to identify cancer cells in the body.
“These structures are very exciting but are very, very hard to study. We tried many different tools, but none worked,” says Zhang, a Dalhousie University professor.

Peng Zhang and his collaborators study remarkable, tiny self-assembling clusters of gold and protein that glow a bold red. And they’re useful: protein-gold nanoclusters could be used to detect harmful metals in water or to identify cancer cells in the body.

“These structures are very exciting but are very, very hard to study. We tried many different tools, but none worked,” says Zhang, a Dalhousie University professor.

>Read more on the Canadian Light Source website

Image: The protein-gold structure. The protein, which both builds and holds in place the gold cluster, is shown in grey.

Supporting World Cancer Day 2018

Diamond is proud to be supporting World Cancer Day and highlighting our role, working with our user community, in pioneering synchrotron research in every area of cancer – from developing a better understanding of how cancer cells work to delivering new cancer therapies.
Despite major advances in diagnosis and treatment, cancer still claims the lives of 8.8 million people every year around the world. About 4 million of these die prematurely (under the age of 70). World Cancer Day aims to raise the awareness of cancer and its treatment around the world. With the tagline ‘We can. I can.’, World Cancer Day is exploring how everyone can play their part in reducing the global burden of cancer.

Diamond has published over 900 publications in the last 12 months, with around 10% of these focusing on cancer. The wide-ranging research currently covers at least 12 cancer types, with many more general studies on the structure of cancer cells and pathways, potential drug targets and possible drug candidates. Building on last year’s review of some of the key studies in cancer that have taken place at Diamond, here is an update on studies that have been published in the last 12 months.

>Read more on the Diamond Light Source website


Modified antibody clarifies tumor-killing mechanisms

The structure of an antibody was modified to selectively activate a specific pathway of the immune system, demonstrating its value in killing tumor cells.

Immunotherapy—the use of the immune system to fight disease—has made tremendous progress in the fight against cancer. Antibodies such as immunoglobulin G (IgG) can identify and attack foreign or abnormal substances, including tumor cells. But to control and amplify this response, scientists need to know more about how elements of the immune system recognize tumor cells and trigger their destruction. There are two main pathways for this: antibody-dependent mechanisms and complement-dependent mechanisms.

The antibody pathway involves coating the surfaces of tumor cells with antibodies that recruit “natural killer” (NK) cells and macrophages (a type of white blood cell) to destroy the tumor cells. The complement pathway (so named because it complements the antibody pathway) also engages NK cells and macrophages and includes a third mechanism—a cascade of events culminating in tumor-cell destruction via a membrane attack complex (MAC).

>Read more on the ALS webpage

Image: extract of a schematic illustration (see on the ALS webpage)

How do asbestos fibres lead to cancer? #weekendusers

Asbestos has been forbidden for some years in many countries around the world. Yet the peak of mortality related to asbestos-related diseases will take place in the next decade, as it takes a long time to develop the disease. Researchers from the Italian national research council (CNR-Nanotec) (Rome, Italy) hope that by studying the interactions between asbestos with host organisms can lead to develop more efficient medical treatments or prevention policies. They are on ID16A looking at the nanoscale at the elements making up the coating developing around asbestos once in the lungs.

Read more on the ESRF website

Image: Asbestos roofing sheets. Credits: Nick.

3D structure of a molecular scaffold with role in cancer

The research team is looking at ways of targeting parts of the scaffold molecule critical for its function

Melbourne researchers have used the Australian Synchrotron to produce the first three-dimensional structure of a molecular scaffold, known to play a critical role in the development and spread of aggressive breast, colon and pancreatic cancer.
Armed with the structure, the research team is looking at ways of targeting parts of the scaffold molecule critical for its function. They hope the research will lead to novel strategies to target cancer.

The research was the result of a long-standing collaboration between Walter and Eliza Hall Institute (WEHI) researchers Dr Onisha Patel and Dr Isabelle Lucet and Monash University Biomedical Research Institute researcher Professor Roger Daly.

Dr Santosh Panjikar, a macromolecular crystallographer at the Australian Synchrotron and Dr Michael Griffin from Bio21 Institute at the University of Melbourne made important contributions to the study, which was published in the journal Nature Communications.